Gio trnh Min dch hc

Mc lc

Chng I: I CNG V MIN DCH HC Chng II: CC C QUAN CA H THNG MIN DCH Chng III: KHNG TH Chng IV: KHNG NGUYN Chng V: CC T BO CH YU CA H THNG MIN DCH Chng VI: B TH Chng VII: CYTOKIN Chng VIII: MIN DCH CHNG VI SINH VT Chng IX: QU MN Chng X: THIU HT MIN DCH Chng XI: TNH T MIN V BNH T MIN Chng XII: CC K THUT MIN DCH THNG DNG

I CNG V MIN DCH HC Tn gi ting Anh immunity (tnh min dch) c ngun gc t ting Latinh immunitas c ngha l min tr s co buc php lut dnh cho cc ngh s quc hi trong thi gian ng chc. Trong lch s, min dch c dng ch s khng mc bnh, m c th l cc bnh nhim trng. Trong c th, tt c cc t bo v phn t ho hc chu trch nhim v tnh min dch hp thnh h thng min dch, v ton b nhng p ng ca chng to ra i vi nhng cht l xm nhp vo c th c gi l p ng min dch. Chc nng sinh l ca h thng min dch l bo v mt c th chng li cc vi sinh vt gy bnh xm nhp vo c th . Tuy nhin, nhng cht l khng gy bnh xm nhp vo c th cng gy ra p ng min dch. Hn na, c ch bo v bnh thng cn c khi gy ra mt s thng tn cho c th. Do , ngi ta a ra mt nh ngha bao hm hn i vi tnh min dch l phn ng i vi cc cht l, bao gm c vi khun v cc i phn t nh protein, cc polysaccharide, khng k phn ng l sinh l hay bnh l. Min dch hc l mn hc nghin cu tnh min dch vi ngha rng ny i vi cc hot ng phn t v t bo xy ra sau khi cc vi sinh vt v i phn

t xm nhp vo c th. Cc nh s hc k rng: Thucydides, mt ngi Hy Lp Athens, l ngi u tin vo th k th V trc Cng nguyn cp n tnh min dch chng li bnh nhim trng m lc c gi l bnh dch. Khi nim tnh min dch c l tn ti rt lu trc Trung Quc v ngi dn y c tp tc cho ngi dn ht cht bt lm t da ca ngi b u ma khi phng nga bnh ny. Cn min dch hc, vi t cch l mt mn hc hin i, li l mt ngnh khoa hc thc nghim, trong cc hin tng min dch c gii thch da trn nhng quan st thc nghim. Min dch hc, vi t cch l mt mn hc thc nghim, tin ho theo nng lc ca con ngi hiu bit v kim sot chc nng ca h thng min dch. Bng chng u tin trong lch s v nng lc ny l thnh cng ca Edward Jenner trong vic chng nga phng bnh u ma. Jenner l mt thy thuc ngi Anh, ng quan st thy rng nhng ngi vt sa b bnh u b v sau hi phc th khng bao gi mc bnh u ma na. Da vo nhn nh ny, ng ly dch t vt thng ca ngi b u b tim cho mt a tr 8 tui. a tr ny sau cho tip xc trc tip vi ngi bnh u ma th khng mc bnh v ng gi cch bo v ca mnh l "vaccination (chng nga) (ch vaccination bt ngun t ting Latinh vacca ngha l con b ci) v cho xut bn quyn sch Vaccination vo nm 1798. T bin php phng bnh nhim trng ny pht trin rng ri v cho n nay n vn l phng php phng nga hiu qu nht i vi cc bnh nhim trng (Bng 1.1). Mt vn bn c ngha quan trng i vi ngnh Min dch hc l cng b ca T chc Y t Th gii nm 1980 rng bnh u ma l cn bnh u tin trn th gii b loi tr nh vo cng tc chng nga. T nhng nm 1960, chng ta c mt s chuyn bin trong hiu bit v h thng min dch v chc nng ca n. Cc tin b v k thut nui cy t bo (k c k thut sn xut khng th n dng), ho min dch, phng php DNA ti t hp, ng vt bin i gen, ... chuyn min dch hc t ch ch yu l cc hot ng m t thnh mt ngnh khoa hc m trong cc hin tng min dch c gii thch bng nhng thut ng sinh ho v cu trc. Trong chng ny chng ti trnh by nhng c im chung ca p ng min dch cng nh gii thiu nhng khi nim to nn nhng bc ngoc trong ngnh min dch hc hin i.

Bng 1.1. Hiu qu ca vc-xin i vi mt s bnh nhim trng thng gp ti Hoa K

Bnh Bch hu Si Quai b Ho g Bi lit Rubella Un vn H. Znfluenza typ B Vim gan B

S bnh S bnh nhn nm nhn nm 2000 2000 206.939 2 (1921) 894.134 63 (1941) 152.209 315 (1968) 265.269 6.755 (1934) 21.269 0 (1952) 57.686 152 (1969) 1.560 (1923) 26 ~20.000 1.212 (1984) 26.611 6.646 (1985)

T l phn trm -99,99 -99,99 -99,99 -97,73 -100,00 -99,84 -98,44 -93,14 -75,03

1.1. Tnh min dch bm sinh v thu c S khng chng li vi sinh vt trong c th ban u l nhng phn ng ca h thng min dch bm sinh v sau l ca min dch thu c (Hnh 1.1, Bng 1.2). H min dch bm sinh (cn gi l min dch t nhin) bao gm cc c ch khng tn ti trong c th khi cha c nhim trng v sn sng p ng rt nhanh khi vi sinh vt xm nhp. Cc c ch ny ch yu phn ng chng li vi sinh vt ch khng phn ng vi cc vt l khng phi l vi sinh vt; ng thi chng phn ng theo mt c ch ging ht nhau khi vi sinh vt xm nhp ti i ti li. Cc thnh phn chnh ca min dch bm sinh bao gm: (1) cc hng ro vt l v ho hc nh da, nim mc, cc cht khng khun c tit ra trn cc b mt ny; (2) cc t bo thc bo

(t bo trung tnh, i thc bo) v t bo NK (t bo git t nhin); (3) cc protein trong mu, bao gm cc thnh phn ca h thng b th v cc cht trung gian khc ca phn ng vim; v (4) cc protein gi l cytokin c vai tr iu ho v phi hp cc hot ng ca t bo trong h min dch bm sinh. C ch hot ng ca h min dch bm sinh ch c hiu cho nhng cu trc chung ca tng nhm vi sinh vt v khng c hiu cho nhng khc bit tinh t trong tng nhm ny. H min dch bm sinh to ra nhng phn ng u tin chng li s xm nhp ca vi sinh vt. Ngc vi h min dch bm sinh, c nhng p ng min dch khc c kch thch bi s tip xc vi vi sinh vt v to ra cng tng dn nu s tip xc ny c lp i lp li. Bi v dng p ng ny ch xut hin sau khi vi sinh vt xm nhp c th nn n c gi l min dch thu c. Tnh cht c bit ca p ng min dch thu c l tnh c hiu i vi tng phn t v kh nng nh khi phn t xm nhp tr li c th to ra mt p ng mnh hn nhiu so vi ln xm nhp u tin. H min dch thu c c kh nng nhn din v phn ng li vi nhiu vt l c bn cht nhim trng hoc khng nhim trng. Ngoi ra, n cn c kh nng tuyt vi trong vic phn bit s khc nhau rt nh gia cc vt l ny v v vy m n cn c gi l min dch c hiu. Cc thnh phn ca min dch thu c l t bo lymph v cc sn phm ca chng. Nhng cht l to ra p ng min dch c hiu hoc chu tc ng ca h min dch ny c gi l khng nguyn. Theo thi quen, cc thut ng p ng min dch v h thng min dch thng dng cho p ng min dch thu c, tr khi c nhng nhn mnh ring khc n min dch bm sinh.

Hnh 1.1. Min dch bm sinh v thu c Cc c ch ca min dch t nhin cung cp sc khng ban u i vi nhim trng. p ng min dch thu c n mun hn vi s hot ho t bo lymph. Mc mnh hay yu ca p ng min dch bm sinh v thu c ph thuc tng loi nhim trng.

Bng 1.2. c im ca min dch bm sinh v min dch thu c

c im Tnh c hiu Tnh a dng Tnh nh Tnh khng p ng vi bn thn

Bm sinh i vi cu to chung ca nhm vi sinh vt t Khng C

Thu c i vi khng nguyn c hoc khng nhim trng Rt nhiu C C

Cc thnh phn tham gia Hng ro l ho Da, nim mc, T bo lymph cc ho cht nim mc; khng khng khun th nim mc Cc protein mu B th Khng th T bo Thc bo, t bo T bo lymph NK Cc thnh phn ca p ng min dch bm sinh v thu c thng xen ln vi nhau trong mt c ch khng chung ca c th thng qua nhiu loi t bo v phn t. Ring min dch bm sinh c th gip c th thot khi s tn cng ca mt s vi sinh vt, nhng nhiu vi sinh vt gy bnh c kh nng vt qua hng ro min dch ny nn s loi tr chng cn n mt c ch khng mnh hn nhiu, l min dch thu c. C hai mi lin kt quan trng gia min dch bm sinh v thu c. Th nht, min dch bm sinh c kh nng kch thch p ng min dch thu c v nh hng n bn cht ca min dch thu c. p ng ca min dch thu c c s dng nhiu c ch hiu qu ca min dch bm sinh loi tr vi sinh vt v c kh nng tng cng hot ng khng khun ca min dch thu c. Min dch bm sinh v mt di truyn thuc h thng khng c nht ca c th ch, cn min dch thu c th mi c c nh tin ho v sau. ng vt c xng sng, sc khng ca c th ch chng li vi sinh c th ch yu c m trch bi min dch bm sinh, bao gm cc thc bo, v cc phn t protein lu ng trong mu. Min dch thu c bao gm t bo lymph v khng th, xut hin u tin loi xng sng c hm v cng bit ho i vi cc loi tin ho v sau. 1.2. Cc kiu p ng min dch thu c C hai kiu p ng min dch thu c, l p ng th dch v p ng qua trung gian t bo. C hai kiu ny u c s tham gia ca rt nhiu thnh phn ca h thng min dch vi mc ch l loi tr nhiu loi vi sinh vt khc nhau ra khi c th (Hnh 1.2). Min dch dch th c thc hin qua trung gian ca nhng phn t hin din trong mu v dch nim mc c tn l khng th, c sn xut bi t bo lymph B (cn gi l t bo B). Khng th c kh nng nhn din khng nguyn vi sinh vt, trung ho tnh gy bnh v tc ng ln vi sinh vt loi tr n qua nhiu c ch hiu qu khc nhau. Min dch dch th l c ch khng ch yu chng li cc vi sinh vt ngoi bo

cng nh c t ca chng theo c ch khng th lin kt vi cc vi sinh vt hoc c t xc tin vic loi tr. Bn thn khng th l nhng phn t c chuyn mn ho, nhng tup khng th khc nhau c th to ra nhiu c ch loi b khng nguyn khc nhau. Mt s tup khng th c kh nng xc tin hot ng thc bo, mt s khc li kch thch t bo bch cu sn xut ra cc cht trung gian ca phn ng vim. Min dch qua trung gian t bo (cn gi l min dch t bo) l kiu p ng c thc hin qua trung gian ca t bo lymph T (cn gi l t bo T). Cc vi sinh vt ni bo nh virus v mt s vi khun c kh nng sng v nhn ln trong i thc bo cng nh mt s t bo ch khc, v th chng khng chu tc ng trc tip ca khng th lu ng trong mu. S khng chng li nhng vi sinh vt kiu ny l chc nng ca min dch t bo.

Hnh 1.2. Cc kiu min dch thu c Trong min dch dch th, t bo B tit ra khng th ngn chn nhim trng v loi b cc vi khun ngoi bo. Trong min dch qua trung gian t bo, t bo T hot ha i thc bo tiu dit vi khun b n vo bn trong t bo ny hoc t bo T gy c trc tip tiu dit t bo b nhim khun.

Min dch bo v chng li mt vi sinh vt c th c to ra nh kch thch ca vi sinh vt hoc nh truyn khng th hoc t bo lymph c hiu t bn ngoi vo (Hnh 1.3). Cch thc to khng th qua kch thch trc tip vi vt l c gi l min dch ch ng v c th tip xc vi vt l ng vai tr ch ng trong vic p ng vi khng nguyn. Nhng c th hoc t bo lymph cha tng c tip xc vi mt khng nguyn no c gi l nguyn vn hay nguyn (naive). Cn nhng c th c tip xc vi mt khng nguyn vi sinh vt no ri v sau c bo v chng li nhng ln tip xc khc c gi l min nhim (immune).

Hnh 1.3. Min dch ch ng v th ng Min dch ch ng c to ra khi c th ch tip xc vi vi sinh vt hoc khng nguyn vi sinh vt, trong khi min dch th ng c vay mn nh truyn khng th hay t bo lymph T c hiu. C hai loi u to ra sc khng i vi vi sinh vt nhng ch c min dch ch ng l c tnh nh min dch.

Ngi ta cng c th mang tnh min dch n cho mt c th bng cch truyn huyt thanh hoc t bo lymph t mt c th khc c gy min dch. Cch lm ny c gi l truyn min dch th ng, thng hay thc hin trn ng vt th nghim. C th nhn sau s c tnh min dch chng li khng nguyn tng ng mc d cha ln no tip xc vi khng nguyn ny. Do kiu min dch ny c gi l min dch th ng. Gy min dch th ng l mt phng php hu ch cung cp sc khng nhanh, khng phi ch cho n khi min dch ch ng xut hin. Mt v d ca min dch th ng l truyn khng th t m sang con trong thi k bo thai gip cho a tr chng li nhim trng trong thi k ch i min dch ch ng ca tr hnh thnh. Ngi ta cng dng phng php min dch th ng chng li c t vi khun gy cht ngi (v d c t un vn) bng cch truyn khng th t con vt c gy min dch bi vi sinh vt . K thut truyn min dch th ng (hay cn gi l to min dch vay mn) cng

c th thc hin vi nhng t bo v phn t khc nhau min l chng c nng lc min dch c hiu. Tht ra, thut ng min dch dch th (humoral immunity) ban u c nh ngha nh mt kiu min dch c th truyn c sang cho con vt cha nhim bng cht dch trong mu c cha khng th v khng c t bo (tc l huyt thanh hoc huyt tng m t c gi l th dch - humor). Cng vy, min dch qua trung gian t bo (cell-mediated immunity) c nh ngha l mt dng min dch c th truyn sang cho c th cha nhim di dng t bo (lymph T) ch khng phi dch th. Nm 1890, Emil von Behring v Shibasaburo Kitasato trnh din th nghim u tin v min dch dch th. H cho thy rng, nu huyt thanh ca con vt khi bnh bch hu c truyn cho con vt cha nhim th con vt ny s c kh nng khng c hiu i vi bnh bch hu. Thnh phn hiu lc trong huyt thanh lc c gi l khng c t v n trung ho tc dng bnh l ca c t bch hu. u nhng nm 1890, Karl Landsteiner v cc nh nghin cu khc chng minh rng khng phi ch c c t m nhng cht khng c ngun gc vi sinh vt khc cng c th to ra p ng min dch dch th. T cc th nghim , ngi ta a ra mt thut ng mi l khng th (antibody) ch thnh phn protein huyt thanh to ra tnh min dch dch th. Nhng cht lin kt vi khng th v to ra s sn xut khng th c gi l khng nguyn (antigen). Nm 1900, Paul Ehrlich a ra mt l thuyt mi v tnh c hiu ca phn ng khng nguyn khng th, m nhng bng chng thc nghim cho l thuyt ny ln lt c a ra trong sut 50 nm k t khi c pht hin ca Lansteiner. L thuyt ca Ehrlich v s khp nhau v mt l ho ca khng nguyn v khng th rt c gi tr vo thi k u ca min dch hc. S nhn mnh v khng th trong l thuyt ny dn n s tha nhn chung tm quan trng ca min dch dch th, min dch c trung gian bi nhng cht hin din trong cc dch c th. L thuyt t bo v min dch c Metchnikoff a ra. Trnh din ca ng v s thc bo xy ra xung quanh chic gai hng c m vo c th trong sut ca u trng sao bin c xut bn nm 1893. y c l l bng chng thc nghim u tin v vai tr p ng t bo i vi vt l xm nhp vo c th. Cc quan st ca Sir Almroth Wright vo u nhng nm 1900 cho thy rng, trong huyt thanh min dch c nhng yu t thc y s thc bo vi khun bng cch bc xung quanh vi khun, iu ny lm ngi ta tin rng khng th chun b vi khun thc bo d bt gi hn, qu trnh ny c gi l opsonin ho. Nhng ngi theo trng phi t bo ny khng chng minh c rng tnh c hiu ca min dch i vi vi sinh vt cng th hin c qua min dch t bo. L thuyt t bo trong min dch

c khng nh vo nhng nm 1950, khi George Mackaness chng t rng, s khng i vi mt loi vi sinh vt ni bo, con Listeria monocytogenes, c th vay mn bng cch truyn t bo ch khng phi truyn huyt thanh. Chng ta bit rng tnh c hiu ca min dch t bo l do lymph, t bo ny c chc nng lm nhc trng iu khin cc t bo khc nh i thc bo nhm loi b vi sinh vt. Trn lm sng, tnh min dch i vi mt vi sinh vt b nhim trc y c th o c mt cch gin tip bng cch nh lng cc sn phm ca min dch hin din trong c th (v d khng th c hiu trong huyt thanh) hoc chit xut cc cht t c th vi sinh vt v nh gi phn ng ca c th i vi cc cht ny. Mt phn ng ca c th i vi mt khng nguyn vi sinh vt no ch xy ra nu trc c th tip xc vi khng nguyn ny ri; khi c th c gi l c mn cm i vi khng nguyn . Ngi ta cho rng cc c th c mn cm c kh nng to ra p ng min dch bo v i vi vi sinh vt . 1.3. Cc c im chnh ca p ng min dch thu c Tt c p ng dch th v t bo i vi vt l c nhiu tnh cht c bn phn nh tnh cht ca t bo lymph lm trung gian cho phn ng ny (Bng 1.3).

Bng 1.3. Cc c im chnh ca p ng min dch thu c

c im c hiu a dng Nh Chuyn mn ho T gii hn

ngha chc nng m bo cc khng nguyn khc nhau to ra p ng c hiu ring cho chng Cho php h thng min dch p ng c nhiu loi khng nguyn Dn n p ng mnh hn i vi khng nguyn tng tip xc To ra p ng ti u chng li nhiu loi vi sinh vt khc nhau Cho php h thng min dch p ng c vi cc khng nguyn mi xm

Khng phn ng vi bn thn

nhp Ngn nga cc tn thng i vi c th ch trong sut qu trnh phn ng vi khng nguyn l

1.3.1. Tnh c hiu v a dng p ng min dch c hiu cho tng khng nguyn khc nhau v c ngay cho tng thnh phn cu trc ca khng nguyn nh protein, polysaccharide hoc i phn t (Hnh 1.4). Nhng thnh phn ny ca khng nguyn c gi l quyt nh khng nguyn hay epitop. Tnh c hiu ny c c l nh trn mng ca cc t bo lymph ring l c nhng th th ring nhn din nhng cu trc khng nguyn khc nhau. Trong c th c gy min dch c nhiu cln t bo lymph vi tnh c hiu khc nhau tn ti, chng c th nhn din v p ng li tt c khng nguyn ngoi lai. Khi nim ny l nn tng ca l thuyt chn cln m chng ta s cp n v sau ny.

Hnh 1.4. Tnh c hiu, nh, v t gii hn ca p ng min dch Khng nguyn X v Y to ra s sn xut cc khng th khc nhau (tnh c hiu). p ng ln th hai i vi khng nguyn X th nhanh hn v mnh hn (nh). Mc khng th gim dn theo thi gian sau mi ln gy min dch (t gii hn). Ngi ta cng thy c hin tng tng t th ny i vi min dch t bo. Tng s tnh c hiu ca t bo lymph trong mt c th l mt con s cc k ln v c gi l kho lymph (lymphocyte repertoire). Ngi ta c tnh rng h thng min dch ca mt c th c th phn bit t 107 n 109 quyt nh khng nguyn khc nhau. iu ny to nn tnh a dng ca kho lymph. Mt h qu c th thy l cc din kt hp khng nguyn ca khng th v th th khng nguyn trn t bo lymph cng c cu trc rt a dng tng ng vi kho lymph ny. 1.3.2. Nh min dch S tip xc ca h min dch vi khng nguyn l lm tng cng p ng vi khng nguyn khi n xm nhp c th cc ln sau. p ng cc ln lp li v sau i vi mt khng nguyn c gi l p ng min dch th cp. p ng ny thng nhanh hn, mnh hn v khc v cht so vi p ng s cp khi c th tip xc khng nguyn ln u tin (xem Hnh 1.4). Nh min dch c c mt phn l do c mi ln tip xc vi c th th khng nguyn m rng cln lymph c hiu cho khng nguyn . ng thi, s kch thch t bo lymph nguyn vn ca khng nguyn to ra cc t bo nh tn ti lu di. T bo nh c tnh cht c bit lm cho chng loi b khng nguyn hiu qu hn so vi t bo lymph nguyn vn. V d, t bo lymph B nh sn xut khng th lin kt vi khng nguyn vi i lc mnh hn so vi t bo B cha tng tip xc vi khng nguyn . T bo T nh cng c kh nng tr v ni nhim trng nhanh hn t bo T nguyn vn (tc cha tng tip xc khng nguyn). 1.3.3. Chuyn mn ho H thng min dch p ng mt cch c bit v khc nhau i vi tng vi sinh vt sao cho c th to hiu qu ti a cho c ch khng. Nh vy, min dch dch th v min dch t bo c hnh thnh mt cch khc nhau di s kch thch ca nhng loi vi sinh vt khc nhau hoc cc giai on nhim trng khc nhau (ngoi bo v ni bo) ca mt vi sinh vt bo v c th ch chng li loi vi sinh vt vo giai on nhim trng . V ngay trong tng

kiu min dch dch th hay t bo th bn cht ca khng th hay t bo T c to ra cng khc nhau tuy loi vi sinh vt kch thch. 1.3.4. T gii hn Tt c p ng min dch bnh thng s phai nht dn theo thi gian tr li h min dch trng thi ngh ban u, tnh trng ny gi l hng nh ni mi (homeostasis). Tnh trng cn bng dch th c duy tr ch yu l v p ng min dch c khi ng bi khng nguyn v nhm n loi tr khng nguyn, v nh vy tc l loi tr nguyn nhn gy hot ho t bo lymph. Ngoi ra, khng nguyn v p ng min dch cn kch thch c ch iu ho nhm c ch chnh p ng ny. 1.3.5. Khng phn ng vi bn thn Mt trong nhng tnh cht quan trng ca h min dch ca ngi bnh thng l kh nng nhn bit, p ng v loi b khng nguyn l (khng phi ca bn thn) v khng phn ng li gy hi cho c th (bn thn). Tnh cht khng p ng min dch ny cn c gi l dung np. Dung np i vi khng nguyn bn thn, tc t dung np, c duy tr bi nhiu c ch. Nhng c ch ny bao gm loi b t bo lymph c mang th th c hiu cho khng nguyn bn thn v cho php t bo lymph tiu dit cc khng nguyn t thn c kh nng to ra phn ng chng li bn thn. Nhng bt thng v kh nng t dung np c th dn n p ng min dch i vi khng nguyn bn thn (t khng nguyn) v hnh thnh cc bnh t min. Cc tnh cht trn y ca min dch thu c rt cn thit duy tr chc nng khng bnh thng ca c th ch.

1.4. Cc thnh phn t bo ca h thng min dch thu c Cc t bo chnh ca h min dch l t bo lymph, t bo trnh din khng nguyn, v t bo hiu qu. T bo lymph l nhng t bo c kh nng nhn din mt cch c hiu khng nguyn l v to phn ng chng li chng. Do vy, lymph bo l t bo trung gian ca c min dch dch th

v min dch t bo. C nhiu tiu qun th t bo lymph khc nhau v c cch nhn din khng nguyn ln chc nng ca chng (Hnh 1.5). T bo lymph B l t bo duy nht c th sn xut khng th. Chng nhn din khng nguyn ngoi bo (k c khng nguyn trn b mt t bo) v bit ho thnh t bo tit khng th, do chng tc dng nh t bo trung gian ca min dch dch th. T bo lymph T nhn din khng nguyn ca vi sinh vt ni bo v c chc nng tiu dit nhng vi sinh vt ny hoc nhng t bo b nhim trng. Th th khng nguyn ca chng l nhng phn t mng khc vi khng th nhng c cu trc lin quan. T bo T c tnh c hiu rt cht ch i vi khng nguyn. Chng ch nhn din nhng phn t peptid gn vi mt protein bn thn c m ho bi nhng gen trong phc h ha hp m ch yu (MHC) v c th hin trn b mt ca nhng t bo khc. Nh vy, t bo T nhn din v phn ng vi khng nguyn gn trn b mt t bo ch khng phi khng nguyn ho tan. T bo T c nhiu nhm mang chc nng khc nhau. c bit nhiu nht l t bo T gip , T gy c. Khi p ng vi khng nguyn, t bo T gip tit ra nhng protein gi l cytokin c chc nng kch thch s tng sinh v bit ho ca t bo T v mt s t bo trong c t bo B, i thc bo v cc bch cu khc. T bo T gy c git cc t bo sn xut ra khng nguyn l nh cc t bo b nhim virus hay nhng vi khun ni bo khc. Mt s t bo T c gi l T iu ho c chc nng c ch p ng min dch. Bn cht v vai tr sinh l ca t bo T iu ho cha c bit y . C mt nhm t bo lymph th ba l t bo git (NK), y l nhng t bo tham gia vo h thng min dch bm sinh chng li nhim trng virus v cc vi sinh vt ni bo khc. S khi ng v pht trin p ng min dch thu c bao gi cng i hi khng nguyn phi c bt gi v trnh din cho t bo lymph. T bo chu trch nhim lm vic ny c gi l t bo trnh din khng nguyn (APC). T bo trnh din khng nguyn c chuyn mn ho cao nht l t bo hnh sao (dendritic), chng bt gi nhng vi sinh vt t bn ngoi xm nhp vo, vn chuyn nhng khng nguyn ny n cc c quan lymph v trnh din khng nguyn cho nhng t bo T khi ng p ng min dch. S hot ho t bo lymph bi khng nguyn dn n s hnh thnh nhiu c ch loi b khng nguyn. S loi b khng nguyn i hi s tham gia ca nhng t bo gi l t bo hiu qu. T bo lymph hot ho, thc bo n nhn, v mt s bch cu khc c th lm chc nng t bo hiu qu trong nhng p ng min dch khc nhau.

T bo lymph v nhng t bo h tr ca h min dch c tp trung ti cc c quan lymph; chng tng tc vi nhau to ra p ng min dch. T bo lymph cng hin din trong mu. T mu chng c th theo mu tun hon n cc m lymph v cc v tr ngoi bin ni khng nguyn thng xm nhp loi tr chng.

1.5. Cc giai on ca p ng min dch thu c Qu trnh p ng min dch thu c c th chia thnh nhiu giai on

khc nhau: nhn din khng nguyn, hot ho t bo lymph, v giai on hiu qu (loi tr khng nguyn). Sau l s tr li hng nh ni mi v duy tr tnh nh min dch (Hnh 1.6). Tt c p ng min dch u c khi u bng nhn din khng nguyn c hiu. S nhn din ny dn n hot ho t bo lymph v sau l hnh thnh cc c ch hiu qu lm chc nng loi b khng nguyn. Sau khi khng nguyn c loi b, p ng min dch du i v tr li tnh trng hng nh ni mi.

Hnh 1.6. Cc giai on ca p ng min dch thu c Ba giai on u c tn l nhn din khng nguyn, hot ho t bo lymph v hiu qu (loi b khng nguyn). p ng tt dn v cc t bo lymph c khng nguyn kch thch s cht dn do hin tng cht lp trnh (apoptosis), nhng t bo c hiu khng nguyn cn li l t bo nh. Thi gian ca mi giai on thay i tu theo bi cnh p ng. Trc y tng trng cho cng ca p ng. M hnh ny p dng cho c min dch dch th v min dch t bo.

1.5.1. Nhn din khng nguyn

Mi c th s hu mt lng t bo lymph vi rt nhiu cln khc nhau. Mi cln mang sn nhng yu t nhn din v p ng vi mt quyt nh khng nguyn nht nh. Khi khng nguyn xm nhp c th n tm n cln lymph tng ng v hot ho n (Hnh 1.7). Quan nim c bn ny c gi l thuyt chn cln (clonal selection hypothesis), ln u tin c Niels Jerne a ra vo nm 1955 v c Macfarlane Burnet lm sng t vo nm 1957. y l gi thuyt gii thch ti sao h thng min dch li c th p ng vi mt s lng rt ln cc loi khng nguyn khc nhau. Theo gi thuyt ny, cc cln lymph c hiu khng nguyn c sn trong c th trc khi tip xc vi khng nguyn. Nhng t bo trong cng cln mang th th khng nguyn ging ht nhau v khc vi t bo ca cln khc. Mc d rt kh xc nh gii hn trn ca s lng quyt nh khng nguyn m h min dch ca mt c th ng vt c v c th nhn din c, nhng ngi ta thng cho rng con s ny l vo khong t 107 n 109. y l con s c lng hp l i vi s lng protein th th khng nguyn c sn xut v do ngi ta cho rng s lng cln t bo lymph hin din trong c th cng nh th. Khng nguyn l s tng tc vi cln t bo lymph c hiu cho khng nguyn tn ti sn trong m lymph to ra p ng min dch.

Hnh 1.7. Thuyt chn cln Mi khng nguyn (x hoc y) chn mt cln lymph c hiu c sn v kch thch s tng sinh, bit ho ca cln . S ny ch trnh by qu trnh lymph B pht trin thnh t bo hiu qu v tit ra khng th, nhng nguyn l ny cng p dng cho c t bo T.

Nhng nguyn l c bn ca thuyt chn cln dn c chng minh mt cch thuyt phc qua nhiu th nghim v to nn nn tng cho quan nim hin nay v s nhn din khng nguyn ca t bo lymph c hiu.

1.5.2. Hot ho t bo lymph S hot ho t bo lymph i hi 2 tn hiu khc nhau: tn hiu th nht l khng nguyn v tn hiu th hai l cc sn phm vi sinh vt hoc l cc thnh phn ca p ng min dch bm sinh i vi vi sinh vt (Hnh 1.8). tng ny c gi l thuyt hai tn hiu i vi s hot ho lymph bo. Yu cu v khng nguyn (tc tn hiu 1) nhm m bo tnh c hiu ca p ng min dch. Cn yu cu v kch thch ph do sn phm vi khun hoc ca p ng bm sinh i vi vi khun nhm m bo phn ng ch c to ra khi cn thit (tc chng vi khun hoc cht c hi khc) ch khng chng li cc cht v hi bao gm khng nguyn bn thn.

Hnh 1.8. Yu cu hai tn hiu i vi hot ho lymph bo S nhn din khng nguyn ca lymph bo cung cp tn hiu 1 cho s

hot ho, v cc thnh phn ca vi sinh vt hoc cc cht to ra trong qu trnh p ng min dch bm sinh cung cp tn hiu 2. Trong hnh ny, t bo lymph l t bo B, nhng i vi t bo T cng c nguyn l nh vy p ng ca lymph bo i vi khng nguyn v tn hiu th hai bao gm s tng hp cc protein mi, tng sinh t bo, v bit ho thnh t bo hiu qu v t bo nh. 1.5.3. Giai on hiu qu ca p ng min dch: loi b khng nguyn Trong sut giai on hiu qu ca p ng min dch, cc lymph bo c khng nguyn hot ho s to ra nhng chc nng hiu qu tin n vic loi b khng nguyn. Khng th loi b khng nguyn ngoi bo v t bo T loi b khng nguyn ni bo. Chc nng ny ca khng th v t bo T thng yu cu s tham gia ca cc t bo hiu qu khc khng thuc h lymph v c c ch khng ca min dch bm sinh. Nh vy, cng nhng c ch min dch bm sinh hot ng nh phng tuyn u tin nhng v sau li cn tham gia vo phng tuyn th hai ca min dch thu c loi b khng nguyn ra khi c th. Tht ra, nh ni trn, mt chc nng quan trng ca p ng min dch thu c l nhm tng cng c ch hiu qu ca min dch bm sinh v hng nhng c ch hiu qu ny vo cc m hoc t bo cha khng nguyn l.

1.5.4. Tnh hng nh ni mi: gim dn p ng min dch Vo cui p ng min dch, h thng min dch tr li trng thi ngh c bn do phn ln cc t bo tin thn (progeny) ca lymph b khng nguyn kch thch cht do hin tng cht lp trnh (apoptosis). Cht lp trnh l mt dng cht sinh l c chun b trc, trong nhn t bo b c li v v ra tng mnh, mng bo tng ni bt, khng cn s tch bit ca lp lipid mng v t bo cht nhanh chng b thc bo m cc cht ni bo khng cn b gii phng ra ngoi (qu trnh cht ny ngc vi kiu cht hoi t, trong nhn v mng bo tng b phn gii v cc cht ni bo b v ra ngoi to ra mt phn ng vim ti ch). Mt lng ln t bo lymph b khng nguyn kch thch s cht i theo kiu lp trnh. Gii thch iu ny, ngi ta cho rng c l do s tn ti ca lymph bo ph thuc vo khng nguyn v cc yu t pht trin do khng nguyn khi ng nn khi p ng min dch loi b ht khng nguyn th t bo lymph khng cn nhn c nhng kch thch cn thit cho s sng.

CC C QUAN CA H THNG MIN DCH 2.1. Cc m lymph M lymph c phn loi thnh c quan lymph trung ng (hay c quan lymph s cp) l ni m t bo lymph ln u tin th hin th th khng nguyn v trng thnh v mt chc nng v c quan lymph ngoi bin (hay c quan lymph th cp) l ni xy ra p ng ca t bo lymph vi khng nguyn l. C quan lymph trung ng ca ng vt c v bao gm tu xng, ni sn xut ra ton b t bo lymph, v tuyn c, ni t bo T trng thnh v t n giai on pht trin chc nng y . C quan v m lymph ngoi bin bao gm hch bch huyt, lch, h thng min dch da v h thng min dch nim mc. Ngoi ra, ngi ta cn tm thy mt s t bo lymph trong cc m lin kt v tt c cc c quan tr h thn kinh trung ng.

2.1.1. Tu xng ngi trng thnh, tu xng l ni sn sinh tt c cc t bo mu lu ng k c t bo lymph non. Tu xng cng l ni trng thnh ca t bo B. Trong qu trnh pht trin bo thai, s sn xut t bo mu, gi l qu trnh to mu, xut hin u tin trong cc o mu ca ti phi v trong nhu m cnh ng mch ch v sau th ti gan v lch. Chc nng ny c chuyn giao dn dn cho tu xng v c bit l cc xng dt sao cho n tui dy th th chc nng to mu ch yu xy ra xng c, t sng, xng chu v xng sn. Tu l loi tu ca cc xng ny c tm thy trong mt cu to li dng m xp nm gia cc b di. Khong khng gia cc cu to ny c lm y bi t bo m, nguyn bo si, v t bo tin thn ca t bo mu. Nhng t bo tin thn ny s pht trin n trng thnh v i ra khi tu qua mt h thng dy c cc

xoang mch vo h tun hon. Khi tu xng b tn thng, hoc khi c cc nhu cu to nhiu t bo mu mi th gan v lch cng c huy ng lm chc nng to mu. Tt c t bo mu u xut pht t mt loi t bo gi l t bo mm, nhng t bo ny ri s phn ho to ra nhiu dng t bo mu khc nhau (bao gm dng tu, dng i nguyn hng cu, dng ht, dng lymph) (Hnh 2.1). T bo mm khng c cc du n ca t bo bit ho v thay vo l 2 protein mng c tn l CD34 v khng nguyn-1 ca t bo mm (Sca-1). Nhng du n ny dng nhn din v lm giu t bo mm t cc hn dch tu xng dng cho ghp tu. S tng sinh v trng thnh ca t bo mu tin thn trong tu xng c kch thch bi cc cytokin. C nhiu cytokin c tn gi l yu t kch thch colony (colony-stimulating factor) v ban u ngi ta kho st chng qua chc nng kch thch s pht trin ca nhiu colony dng bch cu v dng hng cu trong tu xng. Cc cytokin to mu c sn xut bi t bo m v i thc bo trong tu xng to nn mt mi trng to mu thun li. Chng cng c sn xut bi t bo T c khng nguyn kch thch hoc cc i thc bo b cytokin hay vi sinh vt kch thch to nn mt c ch b sung cho cc bch cu b tiu hao do phn ng min dch hoc vim.

Hnh 2.1. S ca hot ng to mu S pht trin ca cc dng t bo mu c tm tt trong cy to mu ny. Ngoi cc t bo mm v cc th h t bo tip theo do chng sinh ra, tu xng cn cha nhiu Z tng bo sn xut khng th. Nhng tng bo ny c to ra trong m lymph ngoi bin (do s kch thch ca khng nguyn ln t bo B) v di chuyn vo tu xng, chng s sng y v sn xut khng th trong nhiu nm. 2.1.2. Tuyn c Tuyn c l ni trng thnh ca t bo T. Tuyn c l mt c quan c hai thu nm trung tht trc. Mi thu c phn chia thnh nhiu tiu thu ngn cch nhau bi cc vch si v mi tiu thu c vng v bn ngoi v vng tu bn trong (Hnh 2.2). Vng tu cha dy c t bo T lymph v vng tu th t t bo hn nhng cng ch yu l t bo lymph. Ri rc trong tuyn c l cc t bo biu m khng phi lymph ( l nhng t bo c nhiu bo tng), i thc bo c ngun gc tu xng v t bo hnh sao. Mt s t bo hnh sao trong tuyn c c mang cc du n nh CD8a l du n c trng ca t bo lymph nn c gi l t bo hnh sao dng lymph phn bit vi t bo hnh sao dng tu trnh by phn trn. vng tu c nhng cu trc gi l tiu th Hassall c cu to bi nhng vng xon t bo biu m m c l l vt tch ca cc t bo thoi ho. Tuyn c c cung cp mch mu rt di do v c nhng mch i dn n h thng bch mch vng trung tht. Tuyn c c hnh thnh trong qu trnh lm vo ca ngoi b (ectoderm) trong thi k bo thai to nn c v ngc. Trong mt dng chut tri lng c bit, mt t bin gen lm cho chng mt kh nng bit ho cc t bo biu m l t bo cn thit hnh thnh tuyn c v cc nang to lng. Kt qu l chut ny khng c t bo T v khng c lng. ngi, nhng tr c hi chng DiGeorge cng khng c t bo T do t bin gen cn thit cho s hnh thnh tuyn c.

Hnh 2.2. Hnh thi tuyn c A. Hnh nh knh hin vi quang hc ca mt thu tuyn c cho thy c vng tu v vng v. T bo bt thuc nhum xanh gi l t bo tuyn c l lymph bo T ang trng thnh . B. S tuyn c cho thy thu c chia thnh nhiu tiu thu ngn cch bi cc b si.

T bo lymph trong tuyn c, cn c gi l t bo tuyn c, l t bo T cc giai on pht trin khc nhau. Ni chung, hu ht t bo T non u i vo v tuyn c qua h thng mch mu. S trng thnh xy ra trong vng

v, v khi t bo tuyn c trng thnh chng s di c qua vng tu, do vng tu cha ch yu l t bo T trng thnh. Ch c t bo T trng thnh mi i ra khi tuyn c vo mu v m lymph ngoi bin. 2.1.3. Hch bch huyt v h thng bch mch Hch bch huyt l nhng c quan nh dng nt ca m lymph c tm thy dc theo h thng bch mch khp c th. Mt hch bch huyt c vng v bn ngoi v vng tu bn trong. Mi hch c bao bc bi mt nang si c nhiu mch bch huyt n xuyn qua a bch huyt vo vng di v tc vo cc xoang nm st mt ngoi ca hch. Bch mch thm qua vng v vo vng tu v ri hch qua cc bch mch i vng rn hch. Bn di nhng tiu mao mch ca lp v l nhng m t bo tp trung dy c c gi l nang. Mt s nang c gia mt trung tm mm bt thuc nhm nht hn. Nhng nang khng c trung tm mm c gi l nang s cp, cn nhng nang c trung tm mm c gi l nang th cp. Vng v xung quanh nang c t chc thnh nhng khong khng gian hnh di cha t bo lymph, t bo hnh sao v thc bo n nhn; nhng t bo ny c b tr xung quanh nhng xoang bch mch v mu. T bo lymph v t bo trnh din khng nguyn trong nhng khong khng gian ny thng nm cnh nhau nhng khng to nn nhng cu ni lin bo v iu ny cn thit t bo lymph c th di chuyn v lu thng trong mu, h bch mch hoc cc m. Bn di vng v l vng tu c cu to bi nhng di tu dn n nhng xoang tu. Nhng di ny cha i thc bo v tng bo. Mu c dn vo hch qua mt ng mch n i vo rn hch ri chia nhnh nh dn thnh cc mao mch n vng v ngoi. Mu i khi hch qua mt tnh mch duy nht vng rn. Cc loi t bo lymph khc nhau c b tr nhng vng ring bit trong hch bch huyt (Hnh 2.3). Cc nang l vng ca t bo B. Nang s cp cha ch yu l t bo B trng thnh v cn nguyn vn. Cc trung tm mm c to ra khi c p ng khng nguyn. l ni xy ra tng sinh t bo B, la chn t bo B sn xut khng nguyn c tnh c hiu cao, v sn xut ra t bo B nh. Cc si tua bo tng ca t bo hnh sao vng nang an xen vo nhau to ra mt cu trc hnh li dy c trong trung tm mm. T bo lymph T c b tr ch yu bn di v gia cc nang, trong vng v. a s (khong 70%) t bo T l t bo T gip CD4+,

trn ln vi mt s ri rc t bo CD8+. T bo hnh sao cng tp trung vng t bo T trong hch bch huyt. S chia tch v mt gii phu ca cc loi t bo lymph trong hch bch huyt l qu trnh ph thuc vo cytokin (Hnh 2.3). T bo lymph T v B nguyn vn c a vo hch qua ng mch. Nhng t bo ny ri tun hon v i vo vng m ca hch qua mt loi mch mu c bit gi l tiu tnh mch giu ni m nm vng v. T bo T nguyn vn c mang mt th th dnh cho mt cytokin hp dn ho hc gi l chemokin; th th ny c tn l CCR7. CCR7 ch nhn din nhng chemokin c sn xut trong vng t bo T ca hch bch huyt, v nhng chemokin ny c chc nng thu ht t bo T nguyn vn vo vng t bo T ny. T bo hnh sao cng mang CCR7, v l l do v sao chng di c vo cng mt ni vi t bo T nguyn vn trong hch. T bo B nguyn vn mang th th ca mt chemokin khc l CXCR5 c chc nng nhn din mt chemokin ch c sn xut trong nang. V th m t bo B c thu ht vo nang l vng ca t bo B trong hch bch huyt. C mt chemokin khc c tn l lymphotoxin c kh nng kch thch s sn xut chemokin cc vng khc nhau trong hch, nht l vng nang. Ngi ta xc nh chc nng ca cc cytokin khc nhau nh vo cc th nghim trn chut.

Hnh 2.3. S chia tch cc vng ca t bo B v T trong hch A. S v cc ng xm nhp ca t bo T v B vo hch bch huyt.

1.

Trong tiu bn ny ca hch bch huyt, t bo B trong cc nang c nhum xanh, cn t bo T vng v cn nang th nhum (theo phng php nhum min dch hunh quang).

S phn cch v mt gii phu ca t bo T v B l nhm m bo cho mi t bo c tip xc trc tip vi t bo trnh din khng nguyn thch hp (v d t bo T th tip xc vi t bo hnh sao cn t bo B th vi t bo hnh sao vng nang). Hn na, s phn cch chnh xc ny gip cho cc qun th t bo T v B c gi ring r nhau cho n khi cn tng tc thc hin chc nng. Sau khi c khng nguyn kch thch, t bo T v B mt s ngn cch v mt gii phu v di chuyn v pha nhau. T bo T hot ho cui cng ri c th i ra khi hch vo tun hon, trong khi t bo B tin vo cc trung tm mm hoc vng tu, t chng s tit ra khng th.

Hnh 2.4. H thng bch mch Hnh bn phi l s h thng bch mch v cc hch bch huyt ch yu. Hnh bn tri minh ho cch khng nguyn c bt gi v chuyn n

hch bch huyt to ra p ng min dch.

Khng nguyn c vn chuyn n hch ch yu qua h thng bch mch. H bch mch m trch chc nng thu thp v vn chuyn khng nguyn t ni xm nhp n hch bch huyt (Hnh 2.4). Da, biu m v nhng c quan c nhu m cha rt nhiu mao mch bch huyt l ni hp th v vn chuyn dch gian bo (thot ra t bo tng) i khi cc ni ny. Dch gian bo c hp th vo c gi l bch huyt, n s di chuyn dn qua cc mao mch ln hn cui cng vo mt mch bch huyt ln nht gi l ng ngc. Bch huyt t ng ngc c vo tnh mch ch trn tr li h tun hon. Mi ngy c nhiu lt bch huyt c vo h tun hon, do tc h bch mch s nhanh chng dn n ph cc m. Vi sinh vt thng xm nhp vo c th qua da, ng tiu ho v h hp. Tt c cc m ny u c bao ph bi mt lp biu m cha nhiu t bo hnh sao. T bo hnh sao bt gi khng nguyn vi sinh vt v di chuyn vo bch mch. Cc hch bch huyt c b tr dc theo h bch mch v hot ng nh nhng c quan lc mu vt trong bch huyt trc khi bch huyt vo h tun hon. Nh vy khi khng nguyn b bt gi n s c chuyn n hch bch huyt. Nhng khng nguyn khng phi l t bo cng c th c vn chuyn trong bch mch. Mch bch huyt a bch huyt n hch c gi l bch mch n, cn bch mch dn bch huyt ra khi hch c gi l bch mch i. Bi v cc hch bch huyt to thnh chui dc theo bch mch nn mt mch i ca hch ny c th l mch n ca hch kia. Khi bch huyt i vo mt hch bch huyt qua h thng bch mch, n s thm vo vng m ca hch. Cc t bo hnh sao mang khng nguyn s i vo vng t bo T v li vng ny. Cc khng nguyn ho tan n theo bch mch c th c t bo hnh sao hoc i thc bo hin din trong vng m ca hch thu thp. Kt qu l khng nguyn c tp trung vi m cao hn hch trnh din cho t bo T c hiu. 2.1.4. Lch

Hnh 2.5. Hnh thi hc ca lch A. trng. S cu to ca lch vi cc vng t bo T v B to nn nhu m

B. Hnh nh knh hin vi quang hc ca tiu bn lch vi ng mch c b si v nang lymph.

1.

Hnh nh nhum ho min dch ca tiu bn lch. Vng t bo T mu

 v t bo B mu xanh. Lch l v tr ch yu ca p ng min dch i vi khng nguyn n t mu. Lch l mt c quan nng 150gam ngi ln, nm trong bng, vng h sn tri. Lch c ti mu bi mt ng mch duy nht l ng mch lch. Khi i vo lch ng mch chia nhiu nhnh nh dn; cc nhnh ny c bao bc v nng bi cc b si (Hnh 2.5). Cc tiu ng mch nh c bao bc bi t bo lymph, l vng t bo T ca lch. Do v tr gii phu ca n, cc nh hnh thi hc gi vng ny tm lymph quanh tiu ng mch. Cc nang lymph (mt s c trung tm mm) c gn lin vi vng t bo T ging nh trong hch. Nang lymph l vng t bo B. Cc nang ny c bao bc bi mt vng t bo lymph v i thc bo gi l vng vin. Nhng m dy c t bo lymph ny to nn m lch trng. Cc tiu ng mch cui cng vo cc xoang mch nm ri rc trong lch. Cc xoang ny cha ch yu l hng cu, i thc bo, t bo hnh sao, mt t t bo lymph v tng bo. Cc xoang ny to nn m tu ca lch. T cc xoang mu s v tnh mch lch sau i khi lch qua h thng tun hon ca. Cc loi t bo lymph c phn b tch bit trong lch ging nh trong hch v c ch ca s tch bit ny ging nhau c hai c quan (Hnh 2.3). Khng nguyn v t bo lymph i vo lch qua cc xoang mch mu. Khi chemokin c sn xut th t bo T c thu ht n vng t bo T nm bn cnh cc tiu ng mch, cn t bo B th i vo cc nang. Lch l mt c quan lc mu quan trng. Cc i thc bo trong m lch chu trch nhim lm sch cc vi sinh vt v vt l khc c trong mu; ng thi lch l ni ch yu thc hin vic thc bo cc vi sinh vt c gn khng th (tc l opsonin ho). Nhng c th mt lch rt d b nhim trng i vi cc vi khun c v bc nh ph cu, mng no cu v nhng vi khun ny thng c loi b nh s opsonin ha v thc bo v khi mt lch th chc nng ny khng thc hin c. 2.1.5. H thng min dch da Da c cha mt h thng min dch c chuyn mn ho bao gm t bo lymph v t bo trnh din khng nguyn. Da l c quan rng nht trong c th to nn hng ro vt l quan trng nht ngn cch c th vi vi sinh vt v cc vt l ca mi trng bn ngoi. Da cn l mt b phn tch cc

ca h thng bo v c th c kh nng to ra phn ng vim v p ng min dch ti ch. Nhiu khng nguyn l i vo c th qua ng da, do da cng l ni khi ng nhiu p ng min dch ton thn khc. Qun th t bo chnh trong lp biu m l t bo sng (keratinocyte), t bo hc t (melanocyte), t bo Langerhans biu m v t bo T trong biu m (intraepithelial T cell) (Hnh 2.6). T bo sng v t bo hc t hnh nh khng c vai tr quan trng trong min dch thu c, mc d t bo sng c th sn xut nhiu cytokin ng gp cho phn ng min dch bm sinh v phn ng vim da. T bo Langerhanx nm pha trn lp mng cn bn ca biu m, y l nhng t bo hnh sao cha trng thnh ca h thng min dch da. T bo Langerhans to nn mt mng li gn nh lin tc cho php bt gi hu nh ton b nhng khng nguyn no xm nhp vo c th qua da. Khi b kch thch bi cc cytokin tin vim, t bo Langerhans s co cc si tua ca mnh li, mt tnh kt dnh vi t bo biu m v di chuyn vo lp b. Sau chng theo ng bch mch tr v nh ca chng l cc hch bch huyt, qu trnh ny c kch thch bi cc chemokin ch tc ng c hiu ln t bo Langerhans.

Hnh 2.6. Cc thnh phn t bo ca h thng min dch da

Thnh phn ch yu ca h thng min dch da trong s ny l t bo sng, Langerhans, v lymph trong biu m, tt c u nm trong lp biu m; v cc t bo cn li bao gm t bo T v i thc bo th nm trong lp b. T bo lymph trong biu m chim ch 2% t bo lymph lin quan n da (s t bo lymph cn li nm lp b), v chng a s l t bo T CD8+. T bo T trong biu m c th mang mt b th th khng nguyn c tnh hn ch cao hn t bo lymph T a s cc m ngoi da. chut nht (v mt s loi khc), nhiu t bo lymph trong biu m l t bo T mang mt loi th th khng nguyn to bi chui g v d thay v chui a v b thng thng nh t bo T CD4+ v CD8+. Lp b c cha t bo lymph T (c CD4+ v CD8+), ch yu xung quanh cc mch mu, v ri rc trong lp b l i thc bo. iu ny cng tng t nh cc m lin kt cc c quan khc. T bo T thng mang cc du n kiu hnh c trng cho t bo nh hoc t bo hot ho. Ngi ta cng cha r y l nhng t bo thng xuyn c tr trong lp b hay ch li thong qua khi dng mu v bch mch mang chng n y. Nhiu t bo T lp b cn mang mt epitop hydrat cc-bon c tn l khng nguyn-1 lymph bo da, khng nguyn ny c tham gia vo qu trnh di chuyn c hiu ca t bo v da. 2.1.6. H thng min dch nim mc Trong lp nim mc ca h tiu ho v h hp c t tp ca nhiu t bo lymph v v t bo trnh din khng nguyn c vai tr khi ng p ng min dch i vi khng nguyn ng tiu ho (n vo) v h hp (ht vo). Cng ging nh da, lp biu m nim mc l hng ro quan trng ngn cn s xm nhp ca vi sinh vt. Nhng hiu bit ca chng ta v min dch nim mc da ch yu vo nhng nghin cu ng tiu ho, cn nhng hiu bit v min dch nim mc h hp th rt t mc d y cng l ng xm nhp rt thng xuyn ca vi sinh vt. Tuy nhin, hnh nh cc kha cnh ca p ng min dch ging nhau c hai m lymph nim mc ny.

Hnh 2.7. H thng min dch nim mc S cc thnh phn t bo ca h thng min dch nim mc. 2. Hnh nh knh hin vi quang hc ca m lymph nim mc rut tha ngi. Ngi ta tm thy nhng m t bo lymph ging nhau nm ri rc dc theo ng tiu ho v ng h hp.
1.

Trong nim mc ca ng tiu ho, rt nhiu t bo lymph tp trung ba khu vc: trong lp biu m, phn tn rng ri cc lamina propria, v nhng tm Peyer (tc l nhng lamina propria c t chc li) (Hnh 2.7). T bo ti mi khu vc c c im kiu hnh v chc nng khc nhau. a s lymph trong biu m l t bo T. ngi, phn ln nhng t bo ny l

CD8+. chut nht, khong 50% t bo lymph trong biu m mang th th t bo T (TCR) dng gd, tng t nh lymph bo trong biu m da. ngi ch 10% t bo lymph trong biu m l gd, nhng t l ny vn cn cao hn t l t bo gd trong cc m khc. T bo lymph trong biu m mang TCR ab v gd c tnh a dng v th th khng nguyn rt thp. Tt cc nhng pht hin va cp u ph hp vi kin cho rng lymph bo trong biu m rt hn ch v tnh c hiu, khc vi hu ht vi cc t bo T khc. Cc lamina propria trong ng tiu ho cha nhiu loi t bo khc nhau, bao gm lymph T, m a s l CD4+, c kiu hnh ca t bo hot ho. Ngi ta nhn thy rng u tin t bo T i ra khi rut non nhn din v p ng vi khng nguyn trong hch mc treo ri quay tr li rut non v tp trung lamina propria. iu ny cng ging nh ngun gc gi nh ca t bo T trong lp b ca da. Lamina propria cn cha nhiu t bo B hot ho v tng bo cng nh i thc bo, t bo hnh sao, t bo i toan v dng bo (t bo mast). Bn cnh nhng t bo lymph nm ri rc khp ni trong nim mc rut, h thng min dch nim mc cn cha nhng m lymph c t chc ho, m ni bt nht l cc tm Peyer ca rut non. Cng ging nh cc nang lymph lch v hch, vng trung tm ca nhng nang nim mc ny l vng giu t bo B. Cc tm Peyer cn cha mt lng nh t bo T CD4+, ch yu l nm vng lin nang. chut nht trng thnh, 50% 70% lymph bo ca tm Peyer l t bo B, v 10% - 30% l t bo T. C mt s t bo biu m nm ph ln tm Peyer, l nhng t bo M (mng) c chuyn mn ho. T bo M khng c vi mao, bt gi vt l mt cch ch ng v vn chuyn cc i phn t t lng rut non vo m di biu m. Cc t bo M ny ng vai tr quan trng trong vic a khng nguyn n cho cc tm Peyer. (Lu rng t bo M khng c chc nng ging nh t bo trnh din khng nguyn). Cc nang ging nh tm Peyer hin din rt nhiu trong rut tha, cn trong ng tiu ho v h hp th t thi. Hch hnh nhn c cng l cc cu to nang lymph nim mc tng t nh tm Peyer. p ng min dch i vi khng nguyn ng ming c mt s im khc bit c bn vi p ng i vi khng nguyn xm nhp vo c th theo cc ng khc. Hai im khc bit ni bt l: mc sn xut khng th IgA rt cao trong m nim mc, v min dch ng ming i vi khng

nguyn protein c xu hng to ra dung np t bo T hn l hot ho t bo T.

2.2. Cc con ng v c ch ti tun hon v homing ca t bo lymph T bo lymph lin tc di chuyn trong mu v bch mch, t m lymph ngoi bin (th cp) ny n m lymph ngoi bin khc v n a im vim ngoi bin (Hnh 2.8). S di chuyn ca t bo lymph gia cc v tr ny c gi l s ti tun hon lymph bo, v hin tng nhng tiu qun th lymph c bit c chn lc i vo nhng m nht nh m khng i vo cc m khc c gi l hin tng homing (v nh) ca t bo lymph. Hin tng ti tun hon gip cho lymph bo thc hin nhng chc nng quan trng ca mnh trong p ng min dch thu c. Trc ht, n gip cho mt t bo lymph c th tm ra khng nguyn tng ng ca mnh d khng nguyn bt c ni no trong c th. Th hai, n m bo cho mt tiu qun th lymph c th c a n mt vi mi trng thch hp trong m to ra p ng min dch ch khng a n mt ni m chng khng to c hiu qu no c. V d, con ng ti tun hon ca t bo lymph nguyn vn khc vi con ng ca t bo hiu qu v t bo nh, v s khc bit ny rt quan trng cho tng giai on khc nhau ca p ng min dch. Ni mt cch c th, t bo lymph nguyn vn ti tun hon qua cc c quan lymph ngoi bin, t bo lymph hiu qu th di chuyn n cc m ngoi bin ni c nhim trng v vim. Nhng iu c ni y lin quan ch yu n t bo T v nhng hiu bit v ti tun hon t bo B cn rt hn ch. S ti tun hon v di chuyn ca lymph bo n nhng m nht nh c trung gian bi cc phn t kt dnh hin din trn t bo lymph, t bo ni m v gian cht ngoi bo, cng nh trung gian ca cc chemokin trong lp t bo ni m v trong cc m. S kt dnh hoc khng ca t bo lymph vi t bo ni m nm cc tiu tnh mch sau mao mch trong mt m no s quyt nh t bo lymph c i vo m hay khng. S kt dnh v tch ri cc thnh phn gian cht ngoi bo trong mt m s quyt nh t bo lymph li bao lu trong vng ngoi bo trc khi vo bch mch vo mu. Cc phn t kt dnh trn b mt lymph bo c gi l th th homing (homing receptor), cn u kt ni tng ng (ligand) ca chng trn t bo ni m c gi l addressin. Th th homing trn t bo

lymph bao gm ba h phn t: selectin, integrin v siu h (superfamily) Ig. Nhng th th homing ny hon ton khc vi th th khng nguyn, v quy trnh ti tun hon c lp vi khng nguyn. Vai tr duy nht ca nhn din khng nguyn trong ti tun hon lymph bo l lm tng i lc (affinity) ca integrin trn lymph bo i vi cc u ni tng ng ca chng dn n s duy tr ca cc t bo ti ni hin din ca khng nguyn.

2.2.1. Ti tun hon lymph bo nguyn vn qua cc c quan ngoi bin T bo T nguyn vn c xu hng homing v ti tun hon qua cc c quan lymph ngoi bin chng s nhn dng v p ng vi khng nguyn. Lung t bo lymph di chuyn qua hch rt ln; ngi ta c tnh mi ngy c khong 25x109 t bo i qua hch (tc trung bnh mt lymph bo i qua mi hch mt ln trong ngy). Khng nguyn c tp trung trong hch v lch, chng c trnh din bi t bo trnh din khng nguyn hoc t bo hnh sao trng thnh kch thch p ng t cc t bo T nguyn vn. Nh vy vic di chuyn ca t bo lymph nguyn vn ngang qua cc hch lymph v lch l nhm tng c hi ti a cho vic tm gp khng nguyn tng ng v khi ng p ng min dch thu c.

Hnh 2.8. Cc con ng ti tun hon ca lymph bo T T bo T nguyn vn c xu hng ri mch mu vo hch khu vc tiu tnh mch giu ni m. T bo hnh sao mang khng nguyn s i vo hch qua ng bch huyt. Nu t bo T nhn din khng nguyn, chng c hot ho v tr v mu qua bch mch, v ng ngc, tnh mch ch trn v vo tim tr li tun hon ng mch.

Hnh 2.9. Tiu tnh mch giu ni m A. Hnh nh knh hin vi quang hc ca tiu tnh mch giu ni m trong hch bch huyt. B. Th hin ca u lin kt L-selectin trn tiu tnh mch giu ni m. C. Hnh nh t bo lymph gn mt cch chn lc vo t bo ni m ca tiu tnh mch giu ni m. D. Hnh nh knh hin vi in t (qut) ca t bo lymph gn vo

tiu tnh mch giu ni m. Khi i vo hch, t bo lymph nguyn vn s ri h tun hon mt vng mch mu c cu to gii phu c bit gi l tiu tnh mch giu ni m (high endothelial venule) (Hnh 2.9). Tiu tnh mch giu ni m cn c th gp trong m lymph nim mc (ti tm Peyer ca rut) nhng khng c trong lch. T bo T nguyn vn di chuyn t h tun hon vo vng m ca hch tri qua mt chui nhiu bc tng tc gia t bo v t bo ni m trong tiu tnh mch giu ni m. Chui tng tc ny, cng ging nh trong qu trnh di chuyn ca bch cu vo cc m ngoi bin, bao gm ban u l bc tng tc i lc thp qua trung gian ca selectin, v sau l bc tng cng i lc integrin ca t bo T do chemokin lm trung gian, v cui cng l bc dnh cht t bo T vo tiu tnh mch giu ni m qua trung gian ca integrin. T bo lymph nguyn vn mang mt th th homing thuc h selectin c tn l L-selectin (CD62L). Cc tiu tnh mch giu ni m c cha nhng glycosaminoglycan sulfat c gi bng tn chung l addressin hch ngoi bin (peripheral node addressin, PNAd); y l nhng u lin kt (ligand) ca L-selectin. Cc gc ng lin kt vi L-selectin c th c gn vi nhiu sialomucin khc nhau trn t bo ni m ca nhiu m khc nhau. V d, trn tiu tnh mch giu ni m ca hch bch huyt, PNAd c th lm cho bc l nh hai sialomucin gi l GlyCAM-1 (phn t kt dnh t bo s 1 mang glycan) v CD34. Trong cc tm Peyer ca ng tiu ho, u kt ni L-selectin l mt phn t c tn l MadCAM-1 (phn t kt dnh t bo s 1 mang addressin nim mc). Nh vy, nhng phn t khc nhau mang u lin kt ng i vi L-selectin c th ng vai tr quan trng trong vic t tp t bo T nguyn vn n lp ni m ca nhng m khc nhau. S lin kt ca L-selectin vo u lin kt ca n l mt tng tc c i lc yu v d t do lc ct ca dng huyt ng. Kt qu l cc t bo T dnh vo tiu tnh mch giu ni m vi lc dnh lng lo trong mt vi giy, ri li tch ra, dnh vo v ln trn b mt ni m. Trong lc , cc chemokin c sn xut trong hch c th xut hin trn b mt ca t bo ni m gn glycosaminoglycan. T bo T ln trn lp ni m c th gp cc chemokin ny v gia tng lc kt dnh, c th co dn thnh dng vn ng v trn qua khe h gia cc t bo ni m vo vng m ca hch. T bo lymph i khi tiu tnh mch giu ni m nh vo chnh nng chemokin. Nh cp trc y, t bo T nguyn vn c mang th th CCR7 v di chuyn vo vng t bo T l vng sn xut ra chemokin c i tnh vi CCR7; cn t bo B mang CXCR5 nn di chuyn vo vng nang l ni sn xut chemokin lin kt vi CXCR5. Vai tr quan trng ca L-selectin v chemokin trong hin tng homing ca t bo lymph v cc m lymph th cp c nhiu

tc gi chng minh bng thc nghim. Hin nay, ngi ta cn t bit v bn cht ca th th homing hay addressin tham gia vo qu trnh ti tun hon t bo lymph ngang qua lch, mc d bit rng t l ca lng lymph bo qua lch trong 24 gi bng mt na tng s t bo lymph. Phn t MadCAM-1 trn b mt t bo ni m nm cc xoang mch xung quanh vng t bo T ca lch hnh nh c lin quan n hin tng homing ca t bo T nguyn vn. Lch khng c cc tiu tnh mch giu ni m c th nhn ra bng hnh thi hc, v c l hin tng homing ca lymph bo v lch khng c tnh chn lc nh cc lymph bo homing v hch. T bo nguyn vn i vo hch c th c hot ho bi nhng khng nguyn c vn chuyn n hch. Sau mt vi gi tip xc vi khng nguyn ngoi bin, lng mu n mch c th c huy ng tng ln hn 20 ln nhm lm tng s lng t bo lymph nguyn vn n v tr c khng nguyn. ng thi, lc ny lng mu ra khi hch gim i. Nhng thay i ny l do mt phn ng vim chng li vi sinh vt hay chng li t cht i cng khng nguyn. T bo T nguyn vn i vo vng t bo T ca hch s r sot ton b t bo hnh sao trong vng ny tm ra khng nguyn v nhn din chng. Khi nhn din khng nguyn, t bo T chu s tng sinh pht trin cln, ri bit ho thnh t bo hiu qu hoc t bo nh sau bc vo cc con ng ti tun hon khc nhau. Nu t bo T khng nhn din khng nguyn chng s i ra khi hch theo bch mch i vo h tun hon v ri homing ti mt hch khc. 2.2.2. S di c ca lymph bo hiu qu v lymph bo nh n ni c vim T bo T hiu qu v T nh i ra khi hch v c xu hng mun di c n cc m ngoi bin ni c nhim trng; ti chng s lm nhim v loi b vi sinh vt, l giai on hiu qu p ng min dch thu c. S bit ho ca t bo T nguyn vn thnh t bo hiu qu trong c quan lymph ngoi bin ko theo s thay i ca nhiu phn t kt dnh. S th hin ca L-selectin gim xung, nhng s lng mt s integrin, cc u lin kt ca E- v P-selectin v CD44 th gia tng. S bit ho ca t bo T hiu qu cng gy ra mt th th chemokin CCR7. Do , t bo hiu qu khng cn c gi li trong hch na, chng s theo bch mch i vo h tun hon. Ti v tr nhim trng, phn ng min dch bm sinh sn xut ra nhiu cytokin. Mt s cytokin ny tc ng ln ni m mch mu ti ch kch thch th hin cc u lin kt i vi integrin v E- cng nh P-selectin. ng thi

chng cng kch thch tit mt s chemokin tc ng ln t bo T. Nhng chemokin ny lm tng i lc lin kt ca integrin trn t bo T vo cc u lin kt ca n. Nh vy, t bo T bm cht vo t bo ni m v chui ra khi thnh mch n v tr nhim trng. Bi v cc integrin v CD44 cng lin kt vi cc protein ca c cht ngoi bo nn t bo T hiu qu c lu gi li ti cc ni ny. Do t bo hiu qu c th thc hin chc nng loi b nhim trng ca chng. T bo T nh rt a dng v cch thc th hin cc phn t kt dnh v xu hng di c n nhng m khc nhau. Mt s t bo nh di chuyn n m da v nim mc; mt s phn t kt dnh ng vai tr quan trng trong qu trnh ny. V d, mt s t bo nh mang integrin (a 4b6) l phn t c th tng tc vi addressin MadCAM ca t bo ni m nim mc v nh th kch thch qu trnh homing ca t bo T nh v m lymph nim mc. T bo T nh trong biu m ng tiu ho mang mt integrin khc (aEb7) l phn t c th kt ni vi phn t E-cadherin trn t bo biu m, v cho php t bo T lu li nh nhng lymph bo trong biu m. Nhng t bo T nh khc c xu hng di c v da mang mt u kt ni cacbon hyrat c tn l CLA-1 (cutaneous lymphocyte antigen-1) c kh nng kt ni vi E-selectin. Li cn nhng t bo nh khc mang L-selectin v CCR7, v nhng t bo ny c xu hng di chuyn n hch bch huyt, chng c th m rng cln nhanh chng nu gp khng nguyn thch hp.

2.2.3. Ti tun hon ca lymph bo B V nguyn tc, s di chuyn ca t bo lymph B n cc m khc nhau cng ging nh s di chuyn ca t bo T v c iu ho bi c ch phn t tng t. T bo B nguyn vn di chuyn n hch, c th l n cc nang nh vo s dng cc th th L-selectin v chemokin CXCR5. Khi c hot ho, t bo B mt i phn t b mt CXCR5 v i khi nang vo vng t bo T ca c quan lymph. T bo T hot ho c mang cc integrin v dng chng di chuyn n cc m ngoi bin. Mt s tng bo sn xut khng th di chuyn vo tu xng; phn t no tham gia vo vic ny th cha r. Cc t bo tit khng th khc li trong c quan lymph v khng th do chng sn xut s i vo tun hon tm khng nguyn trong khp c th.

KHNG TH Mt trong nhng thng bo thc nghim u tin v p ng min dch thu c l s trnh by v min dch dch th chng li c t vi khun. Vo nhng nm u ca thp k 1900, bnh nhn b nhim trng bch hu c th b nguy him tnh mng nhng c th iu tr c bng cch tim huyt thanh ca nhng nga c gy min dch vi c t bch hu. Th dng min dch ny c gi l min dch dch th v c trung gian bi mt h glycoprotein c tn l khng th. Khng th, phn t MHC (phc h ho hp m ch yu), v th th khng nguyn ca t bo T l ba loi phn t tham gia vo vic nhn din khng nguyn trong min dch thu c. Trong ba loi phn t ny th khng th lin kt vi nhiu cu trc khng nguyn nht, c kh nng tt nht trong vic phn bit cc khng nguyn khc nhau, v lin kt vi khng nguyn vi lc mnh nht. Khng th cng l phn t c nghin cu nhiu nht trong ba phn t lin kt khng nguyn ny.

3.1. Phn b t nhin v sn xut khng th Khng th c phn b trong cc dch sinh hc khp c th v c tm thy trn b mt mt s t bo. Lymph bo B l t bo duy nht sinh tng hp c phn t khng th. Trong t bo B, khng th hin din trong cc b phn lin kt vi mang trong bo tng (nh h li ni bo v h Golgi) v trn b mt t bo ni m chng c xem nh l mt protein mng. Dng tit ca khng th hin din trong huyt tng, dch nim mc, v dch gian bo ca cc m. Khng th do t bo B tng hp v sn xut s gn ln b mt ca mt s t bo hiu qu min dch nh thc bo n nhn, t bo NK (git t nhin), v dng bo l nhng t bo c th th c hiu dnh cho phn t khng th. Khi mu hay huyt tng to thnh cc ng, khng th nm trong khi dch cn li gi l huyt thanh. Huyt thanh c cha khng th chng li mt khng nguyn nht nh no c gi l khng huyt thanh. (Do , nhng nghin cu v khng th v tng tc ca n vi khng nguyn c gi mt cch kinh in l huyt thanh hc). Nng ca khng th trong huyt thanh chng li mt khng nguyn c bit no thng c o bng cch tnh xem n pha long no th phn ng gia khng nguyn v khng th khng cn thy c na. pha long c gi l hiu gi

khng th. Mt ngi ln kho mnh nng 70 kg sn xut khong 3 g khng th mi ngy. Khong 2/3 trong s ny l khng th c tn l IgA c sn xut bi t bo B trong thnh rut v ng h hp v sau chuyn vo lp dch nim mc ca nhng ni ny. Mt lng ln IgA c sn xut chng t cc c quan ny c b mt nim mc rt ln. Sau khi tip xc vi mt khng nguyn no , p ng to khng th ban u a s xy ra cc m lymph, ch yu l lch, hch bch huyt v m lymph nim mc; nhng nhng t bo to ra khng th lu di th c th nm cc m khc, nht l ty xng. Nhng khng th i vo tun hon th c thi gian na i sng rt ngn. Loi khng th c nhiu nht trong huyt thanh l IgG ch c thi gian na i sng l 3 tun.

3.2. Cu trc phn t ca khng th Cc nghin cu trc y v khng th ch yu l ly khng th t mu cc c th c gy min dch ri sau tinh ch kho st. Nhng cch ny th khng th dng xc nh cu trc ca khng th mt cch chnh xc, bi v huyt thanh cha qu nhiu loi khng th c sn xut bi nhiu cln t bo B p ng vi nhiu quyt nh khng nguyn (epitp) khc nhau (v c gi l khng th a cln). C hai pht hin t ph to iu kin c th kho st cu trc khng th mt cch chnh xc. Pht hin th nht l bnh nhn a u ty c mt khi u tng bo tit ra khng th n cln vi lng ln trong mu v nc tiu c th xc nh tnh cht ha sinh ca chng. Pht hin th hai, quan trng hn, l k thut to ra khng th n cln c Georges Kohler v Cesar Milstein m t nm 1975. H tm c cch lm cho t bo sn xut khng th bt t bng k thut to u lai (hybridoma); nhng u lai ny cho php sn xut khng th chng li ch mt tnh c hiu khng nguyn nh trc. Vic to ra c qun th t bo sn xut khng th thun nht ny gip cho cc nh nghin cu xc nh c trnh t acid amin ca tng phn t khng th. 3.2.1. c im chung ca cu trc khng th Cc glycoprotein huyt tng hoc huyt thanh trc y thng c phn chia theo tnh cht ha tan ca chng thnh albumin v globulin v phn

chia su hn da theo tnh in di ca chng. Hu ht khng th c tm thy trong thnh phn in di nhanh th ba ca globulin v c gi l gamma globulin (gamma l ch ci th ba trong mu t Hy Lp). Mt tn thng gi na ca khng th l immunoglobulin (globulin min dch), vit tt l Ig. Trong quyn sch ny hai thut ng immunoglobulin v khng th thng c dng vi cng mt ngha. Tt c mi phn t khng th u c chung mt cu trc c bn ging nhau, v s khc bit ch thy v tr kt hp khng nguyn. S khc bit ca vng kt hp khng nguyn gip cho khng th lin kt d dng vi khng nguyn v mt cu trc. Trong mi c th c khong t 107 n 109 phn t khng th khc nhau mang nhng vng kt hp khng nguyn khc nhau. Cc chc nng hiu qu v tnh cht ha l ca khng th thng do phn khng lin quan n khng nguyn m trch v nhng phn ny thng khng khc nhau my gia cc khng th. Mi phn t khng th c mt cu trc li i xng c cu to bi hai chui nng v hai chui nh ging ht nhau (Hnh 3.1). Mi chui nh c trng lng phn t khong 24 kD, v mi chui nng khong 55-70 kD. Mt chui nh c lin kt ng ha tr vi mt chui nng bng mt cu disulphua v cc chui nng cng ni vi nhau bng nhng cu disulphua. C chui nh v nng u cha nhng chui n v ng nht v lp i lp li. Mi n v c di 110 acid amin cun li mt cch c lp thnh nhng bi gi l lnh vc Ig (Ig domain). Mt lnh vc Ig cha hai tm gp b, mi lp c 3-5 chui polypeptid. C nhiu protein quan trng khc trong h thng min dch cng cha nhng lnh vc c cu to m-tp tm gp tng t nh vy v c cc chui acid amin ging nh Ig. Tt c nhng phn t cha cu to theo m-tp ny c t chung mt tn l siu h Ig (Ig superfamily), v tt c nhng gen m ha cho cc lnh vc Ig ca nhng phn t ny c cho l u tin ha t mt gen t tin.

Hnh 3.1. Cu trc ca mt phn t khng th A. S cu trc ca mt phn t IgG. Din kt hp khng nguyn c to bi lnh vc thay i ca chui nh (VL) v chui nng (VH) nm cnh nhau. Cc vng C ca chui nng tn cng ti phn ui. B. S cu trc ca phn t IgM gn trn mng t bo lymph B. IgM c nhiu hn IgG mt lnh vc vng C chui nng (CH) v tn cng bng mt on C cm xuyn qua mng t bo. C. Cu trc ca IgG ngi c v nh php chp tinh th bng tia X. Trong s ny chui nng c v bng mu xanh nc bin v , cn chui nh c mu lc.

C chui nng v nh u mang mt u tn cng amin lun thay i (gi l vng bin i hay vng V) tham gia vo vic nhn din khng nguyn v mt u tn cng cacboxyl hng nh (gi l vng hng nh hay vng C); vng hng nh ca chui nng lm trung gian cho cc chc nng hiu qu. Trn chui nng, vng V ch c 1 lnh vc Ig, nhng vng C th c 3-4 lnh vc Ig. Mi chui nh ch cu to bi 1 lnh vc Ig vng V v 1 lnh vc Ig vng C. Vng bin i ca mi phn t khng th gip phn bit khng th

c sn xut bi mt cln t bo B ny vi khng th c sn xut bi mt cln t bo B khc. Vng bin i ca chui nng (c gi l VH) nm st bn cnh vng V ca chui nh (c gi l VL) to nn din kt hp khng nguyn (Hnh 3.1). Bi v n v cu to c bn ca mi phn t khng th cha 2 chui nng v 2 chui nh nn n c 2 din kt hp khng nguyn. Cc lnh vc ca vng C tch bit vi din kt hp khng nguyn v khng tham gia vo qu trnh nhn din khng nguyn. Cc vng C ca chui nng c kh nng tng tc vi cc phn t v t bo hiu qu khc ca h min dch nn do m trch hu ht cc chc nng sinh hc ca khng th. Ngoai ra, u tn cng cacboxyl ca cc chui nng c tc dng gn cc phn t khng th mng vo mng t bo B. Vng C ca chui nh khng tham gia vo cc chc nng hiu qu v cng khng dnh vo mng t bo. 3.2.2. c im cu trc ca vng bin i v mi lin quan vi s lin kt khng nguyn Mi mt khng th thng mang 3 on ngn acid amin vng V (ca c chui nng v chui nh) rt ring cho khng th v c gi l vng siu bin. Nhng vng siu bin ny c di khong 10 acid amin v c gi yn ti v tr ca n chui peptid to nn lnh vc ca vng V. Trong mi phn t khng th, 3 vng siu bin ca vng VL v 3 vng siu bin ca vng VH c ko li vi nhau to nn mt cu trc khng gian ba chiu, l din kt hp khng nguyn. Bi v cu to ny c to ra sao cho khp vi cu trc khng gian ba chiu ca phn t khng nguyn tng ng nn nhng vng siu bin ny cn c gi l vng xc nh tnh b khuyt (complementarity-determined regions, CDR). Trn mi chui acid amin ca VL hoc VH, cc vng ny c t tn l CDR1, CDR2 v CDR3. Vng CDR3 ca c VL v HL l vng c bin i cao nht trong s 3 vng va k. C nhng c ch di truyn to ra tnh a dng cao hn CDR3 so vi CDR1 v CDR2. Nghin cu hnh nh tinh th ca khng th cho thy cc CDR to ra nhng cung ha hc a ra b ngoi khng th sn sng tng tc vi khng nguyn. S khc bit v trnh t acid amin trong cc CDR ca cc phn t khng th khc nhau to ra cu trc ha hc ring bit cho chng v c th hin ra b mt ca khng th to nn tnh c hiu i vi khng nguyn. 3.2.3. c im cu trc ca vng hng nh v mi lin quan vi chc nng hiu qu Cc phn t khng th c th c chia thnh nhiu lp khc nhau da trn s khc bit v cu trc vng C ca chui nng. Cc lp khng th cn

c gi l isotyp v gm c 5 lp c t tn l: IgA, IgD, IgE, IgG, v IgM. ngi, cc isotyp IgA v IgG c th c chia thnh cc tiu lp v t tn l: IgA1, IgA2, IgG1, IgG2, IgG3, IgG4. ( chut nht, loi ng vt thng c dng trong nghin cu min dch hc, th lp IgG c chia thnh cc tiu lp IgG1, IgG2a, IgG2b, v IgG3.) Vng C ca chui nng ca tt c cc phn t khng th trong mt lp hoc tiu lp u c chung mt trnh t acid amin. Trnh t ny khc vi trnh t ca lp khc hay tiu lp khc. Cc chui nng c t tn theo ch ci Hy Lp tng ng vi isotyp khng th: IgA1 cha chui nng a1; IgA2 cha a2; IgD cha d; IgE cha e; IgG1 cha g1; IgG2 cha g2; IgG3 cha g3; IgG4 cha g4 v IgM cha m. Trong khng th ca IgM v IgE ngi, vng C cha 4 lnh vc Ig ni tip nhau. Vng C ca IgG, IgA, v IgD ch cha 3 lnh vc Ig. Nhng lnh vc ny c k hiu l CH v c nh s t u tn cng amin n u tn cng cacboxyl (v d CH1, CH2, .v.v.). Trong mi isotyp, cc vng ny c k hiu c th hn (v d Cg1, Cg2 trong IgG). Khng th c th c tc dng nh mt khng nguyn khi n c a vo mt c th l v kch thch c th to khng - khng th. Bng cch gy min dch mt con vt bng khng th ly t mt con vt khc loi, chng ta c th sn xut ra cc khng - khng th c hiu cho mt lp hoc tiu lp Ig, v khng th kiu ny thng c dng thng xuyn trong cc nghin cu lm sng hoc thc nghim v p ng min dch dch th. Nhng lp v tiu lp khng th khc nhau s to nn nhng chc nng hiu qu khc nhau. Nguyn nhn l v hu ht cc chc nng hiu qu u qua trung gian ca s kt hp vng C chui nng vo th th ca n ln cc loi t bo nh i thc bo, t bo NK, t bo mast, hoc kt hp vi cc loi protein huyt tng khc nhau nh protein b th. Cc lp v tiu lp khng th khc nhau vng C nn cng khc nhau v chc nng hiu qu. Chui nh ca khng th c hai lp v c gi l k v l phn bit nh vng hng nh tn cng bng cacboxyl. Mt phn t khng th c th c hoc l 2 chui nh k hoc l 2 chui nh l, v khng bao gi c mi loi mt chui. Trnh t acid amin ca vng C chui nh k (Ck) khc vi trnh t ca vng C chui nh l (Cl), nhng trnh t Ck ca tt c cc phn t khng th u ging ht nhau, v trnh t Cl cng vy. Mc d c khc nhau v trnh t acid amin nhng Ck v Cl hon ton ng nht v mt cu trc, v u gp vo trong cng mt lnh vc Ig. ngi, khong 60% phn t khng th c chui nh k v 40% c chui l. Ngi ta tm thy t l ny thay i rt r trn bnh nhn u t bo B n cln bi v cc cln t bo ung th sn xut nhng phn t khng th vi cng mt lp chui nh m thi. V ngi ta dng t l t bo mang k v t bo mang l chn on u lymph t bo

B. chut, lng khng th cha k nhiu gp 10 ln lng khng th cha l. Khc vi lp chui nng, cc lp chui nh khng to ra iu g khc nhau v chc nng ca khng th. Khng th c th xut hin di dng cht tit (dng tit) hoc nm trn mng t bo (dng mng). Dng khng th ny khc vi khng th huyt thanh v trnh t acid amin u tn cng cacboxyl ca vng C chui nng. Dng tit gp trong mu v cc dch ngoi bo. i vi dng ny, trnh t acid amin ca vng CH c tn cng bng cc acid amin a nc v tch in. y l cu trc c trng cho cc protein gn trn mng t bo. Cc khng th IgG v IgE c tit ra di dng n phn t tc dng n v khng th c bn (bao gm 2 chui nng v 2 chui nh). Ngc li, cc khng th IgM v IgA th thng to nn nhng phc hp a phn t tc bao gm t 4 chui nng v 4 chui nh tr ln. Cc khng th a phn t IgM v IgA cn cha mt polypeptid ph vi trng lng phn t 15 kD gi l chui J (lin kt), gn vi cc phn t khng th bi cc cu ni disulphua v c chc nng lm bn vng cc phc hp a phn t ny. 3.2.4. S tng hp v biu hin ca phn t Ig Cc chui nng v nh ca Ig c tng hp trong cc ribosom nm trn b mt ca h li ni bo. S kt hp ng ha tr ca cc chui nng v cc chui nh c thc hin nh cc cu ni disulphua v cng xy ra trong h li ni bo. Sau khi c hnh thnh phn t Ig c chuyn n th Golgi t chuyn ra mng t bo trong cc nang nh v sau c tit ra khi t bo qua mt qu trnh gi l thot bo (exocytosis). Cc protein khc cn gn vo Ig nh cc chui J cng ng thi c thc hin trc khi bi tit ra khi t bo. Trong nhng t bo sn xut khng th lp IgA v IgM th s sao chp ca gen chui nng v gen chui nh c thc hin ng thi vi s sao chp gen chui J. S trng thnh ca cc t bo B trong ty xng thng i km vi s thay i biu hin gen Ig dn n sn xut cc phn t Ig di cc dng khc nhau (Hnh 3.2). Cc t bo sm nht ca dng lymph B c gi l t bo tin B sn xut ra cc dng mng ca chui nng m, nhng a s cc protein li trong bo tng. Hu ht cc chui nng m ni bo trong t bo tin B u t phn hy ngay trong t bo. Ch mt lng nh cc phn t ny c biu hin mng t bo v kt hp vi nhng protein c tn l chui nh thay th to nn th th ca t bo tin B. Cc t bo B trng thnh hoc cha trng thnh u sn xut cc chui nh k hoc l lin kt vi

chui nng m to nn phn t IgM. S t hp ny bo v cho chui nng khi b phn hy trong ni bo v cho php IgM biu hin trn b mt t bo. T bo B trng thnh c biu hin ca IgM v IgD trn b mt. Cc th th Ig mng ny c chc nng nhn din khng nguyn v khi ng qu trnh hot ha t bo B. Th th khng nguyn ca t bo B lin kt khng ng ha tr vi hai protein mng khc l Iga v Igb to nn cc phc hp phn t v iu ny rt cn i vi vic th hin IgM v IgD b mt. Khi t bo B c khng nguyn hoc cc kch thch khc hot ha, chng bit ha thnh cc t bo sn xut khng th. Qu trnh ny thng phi hp vi s bin i cc th dng sn xut Ig. Mt trong nhng bin i l s chuyn t Ig mng sang Ig tit. Mt bin i th hai l xut hin cc biu hin khc ca isotyp chui nng ngoi IgM v IgD. Qu trnh ny gi l chuyn mch isotyp chui nng.

Hnh 3.2. S bc l Ig trong qu trnh trng thnh t bo B Cc giai on trng thnh t bo B thng i km vi cc bin i trong sn xut chui nng v chui nh ca Ig. 3.3. S kt hp khng nguyn khng th 3.3.1. Cc c im lin quan n qu trnh nhn din khng nguyn Phn t khng th c nhiu c im cu trc rt quan trng i vi qu trnh nhn din khng nguyn cng nh thc hin chc nng hiu qu. Cc c im ny nm ch yu vng V ca phn t khng th. 3.3.1.1. Tnh c hiu (specificity)

Khng th bao gi cng kt hp rt c hiu cho khng nguyn tng ng ca mnh. Ch cn mt khc bit nh v cu trc ha hc l c th lm cho s kt hp khng nguyn-khng th b tr ngi. Tnh c hiu tinh t ca phn t khng th hin din trn tt c cc lp phn t. V d, khng th c th phn bit hai quyt nh khng nguyn khc nhau ch mt v tr acid amin c th hin rt t trn cu trc cp hai. Bi v cu to sinh ha ca tt c sinh vt sng u c bn l tng t nhau, nn tnh c hiu cao ny rt cn khng th to c p ng vi mt khng nguyn ca mt vi khun m khng to p ng vi phn t c cu trc tng t ca c th mnh hay ca vi khun khc. Tuy vy, cng c trng hp mt s khng th c sn xut chng li mt khng nguyn li c th lin kt vi mt khng nguyn khc c cu trc lin quan. iu ny c gi l phn ng cho. Khng th c to ra chng vi khun i khi li cho phn ng cho vi t khng nguyn ca c th mnh v c th gy ra mt s bnh l min dch. 3.3.1.2. Tnh a dng (diversity) Nh trnh by phn trc, mt c th c kh nng to ra mt s lng ln (n 109) khng th c tnh c hiu khc nhau. S hin din ca lng ln khng th vi tnh c hiu khc nhau ny c gi l tnh a dng ca khng th v ton b su tp khng th vi tnh c hiu khc nhau ny c gi l h cha (repertoire) khng th. C ch di truyn ca tnh a dng ny nm t bo lymph. Chng c thc hin trn c s s ti t hp ngu nhin ca mt s b trnh t DNA di truyn vo cc gen chc nng m ha cho vng V ca chui nng v chui nh. Mt c s khc ca tnh a dng l s thm ngu nhin cc trnh t nucleotide khng theo khun mu vo cc gen on V. Hng triu dng cu trc khc nhau tp trung ch yu vo vng siu bin ca c chui nng v chui nh to nn tnh c hiu i vi khng nguyn. 3.3.1.3. i lc (affinitive) v i tnh (avidity) Kh nng trung ha c t v vi sinh vt ca khng th lun ph thuc vo s gn kt cht ch ca chng vo khng th. S gn kt ny c c l do i lc v i tnh cao ca s tng tc. C ch to ra i lc cao ca khng th l do nhng bin i tinh vi ti vng V ca phn t khng th trong giai on p ng dch th. Nhng bin i ny c to ra do qu trnh t bin thn ca t bo lymph B sau khi c khng nguyn kch thch. Kt qu l

hnh thnh nhng cu trc mi ca lnh vc V, trong s c nhng cu trc gn kt c i lc cao hn nhiu so vi cu trc ban u ca cc lnh vc V (Hnh 3.3). Nhng t bo B sn xut khng th c i lc cao rt d c khng nguyn kch thch v tr nn t bo B ch o i vi nhng ln tip xc khng nguyn v sau. Qu trnh ny c gi l s trng thnh v i lc c kh nng lm tng dn i lc trung bnh ca khng th i vi khng nguyn trong vic to ra p ng dch th. V d, nu mt khng th trong p ng min dch tin pht i vi mt khng nguyn c h s i lc lin kt Kd l 10-7 n 10-9 M th trong p ng th pht i vi khng nguyn i lc s gia tng v h s Kd by gi s l 11-11 M hay thm ch nh hn.

3.3.2. Cc c im lin quan n chc nng hiu qu Cc chc nng hiu qu ca khng th thng lin quan n on Fc ca phn t khng th, do nhng isotyp khc nhau on Fc s to ra chc nng hiu qu khc nhau. V d, phn t IgG thng gn vi t bo vi khun chuyn vi khun n cho t bo trung tnh hoc i thc bo tiu dit. iu ny thc hin c l nh phn t IgG c gn khng nguyn nh c on Fc m c th lin kt vi chui nng g ca mnh vi phn t th th c hiu cho on Fc nm trn b mt ca t bo trung tnh v i thc bo. Ngc li, phn t IgE gn vo c th giun trn chuyn chng n cho t bo i toan tiu dit v trn t bo ny c nhiu th th c hiu dnh cho IgE. Mt c ch hiu qu khc ph thuc Fc trong min dch dch th l s hot ha h thng b th theo con ng c in. H thng b th to ra cc ha cht trung gian ca phn ng vim v thc y qu trnh thc bo cng nh ly gii t bo ch. Qu trnh ny c bt u vi s lin kt ca mt protein b th c tn l C1q vo on Fc ca phn t khng th IgG hoc IgM trong phc hp khng nguyn khng th. FcR v v tr kt hp b th ca khng th u nm khu vc C ca chui nng ca tt c cc isotyp. Tt c cc hiu qu chc nng ca khng th u ch c thc hin khi khng th lin kt vi khng nguyn ch khng phi dng Ig t do. Nguyn nhn l cn phi c t nht 2 on Fc nm k cn nhau c th tc ng vo cc h thng hiu qu nh cc protein b th v FcR ca ai thc bo. Yu cu phi c nhng phn t lin k ny m bo cho chc nng hiu qu c thc hin mt cch c hiu n ng khng nguyn ch v loi b chng v cng l nhm lm cho cc khng th lu ng t do trong mu

khng tc ng tha vo h thng hiu qu.

Hnh 3.3. Cc thay i ca cu trc khng th trong qu trnh p ng min dch dch th Trong qu trnh trng thnh i lc, t bin c th xy ra vng V dn n thay i tnh c hiu trong khi chc nng hiu qu ph thuc vng C khng thay i g. T bo B hot ha c th chuyn cc phn t Ig mng sang Ig tit. Ig tit c th c t bin gen hoc khng. Trong qu trnh chuyn mch isotyp, c bin i vng C trong khi vng V khng c g thay i. Vic chuyn mch isotyp c th gp c Ig mng ln Ig tit. S thay i ca isotyp khng th trong qu trnh p ng dch th s nh hng vic p ng min dch hot ng loi b khng nguyn ni no v u. Sau khi c khng nguyn kch thch, mt cln t bo B s sn xut

khng th vi cc isotyp khc nhau nhng c cng lnh vc V tc la c hiu cng 1 khng nguyn. Cc t bo B cha tip xc khng nguyn s ng thi sn xut IgM v IgD c tc dng nh l th th b mt i vi khng nguyn. Khi t bo B tip xc vi mt vi khun chng hn th trong t bo s xy ra mt qu trnh gi l chuyn mch isotyp (isotype switching) trong typ ca vng CH do t bo B sn xut b chuyn i nhng cn vng V v tnh c hiu th khng thay i (Hnh 3.3). V qu trnh chuyn mch isotyp m cc t bo tin thn ca t bo B sn xut IgD v IgM sn xut c cc isotyp khc c kh nng tiu dit khng nguyn tt hn. V d, khng th chng vi khun v virus ch yu l typ IgG l typ c xu hng thc y qu trnh thc bo vi khun, cn typ chuyn i ph vi giun trn th ch yu l IgE l typ c kh nng ph hy k sinh trng ny. Vng C trn chui nng ca khng th cng quyt nh v tr phn b ca phn t khng th cc m. IgA thng l isotyp duy nht c th c bi tit qua lp thng b ca nim mc v do IgA l lp khng th ch yu ca cc dch tit k c sa. Tr s sinh c bo v khi cc bnh nhim trng nh khng th IgG c truyn t m sang trong qu trnh mang thai v trong giai on sm ca thi k b m. S truyn ny c thc hin qua trung gian ca mt th th Fc c bit c trong bnh nhau (gip khng th i vo tun hon phi) v trong ng tiu ha ca tr s sinh (gip hp th khng th t sa m). KHNG NGUYN 4.1. Cc tnh cht ca khng nguyn p ng to khng nguyn nh ta bit s xy ra khi c mt vt l t nhp vo c th v tip xc vi h thng min dch. Vt l c gi l cht gy khng th (antibody generator) hay khng nguyn (antigen). Tuy nhin, khng phi vt l no vo c th cng c tnh cht khng nguyn. Khng nguyn c hai tnh cht sau: (1) kch thch c c th to ra p ng min dch, tnh cht ny gi l tnh sinh min dch, v (2) c kh nng kt hp c hiu vi khng th tng ng, tnh cht ny l tnh c hiu. 4.1.1. Tnh sinh min dch Tnh sinh min dch ca mt khng nguyn ph thuc vo cc yu t sau:

(1) Tnh l ca khng nguyn: Khng nguyn cng l bao nhiu th kh nng kch thch to khng th cng mnh by nhiu. Tuy nhin, cn lu rng, trong mt s trng hp bnh l th thnh phn ca chnh bn thn c th cng c th gy ra p ng khng th chng li n, ta gi nhng thnh phn ny l t khng nguyn. (2) Cu trc ha hc ca khng nguyn: Cc khng nguyn thuc loi protein v polysaccharid c tnh sinh min dch cao. Khng nguyn cng phc tp v cu trc ha hc bao nhiu th tnh sinh min dch cng mnh by nhiu. Trn cu trc c nhng cu to chu trch nhim chnh trong vic kch thch to khng th, l cc quyt nh khng nguyn hay epitop. (3) Cch gy min dch v liu khng nguyn: Hu ht cc khng nguyn hu hnh (vi khun, hng cu, cc polymer ln,) khi a vo c th bng ng tnh mch u d dng gy p ng to khng th. Trong khi , c mt s phn t cn phi km thm mt cht h tr khc mi gy c p ng tt, ta gi cht h tr l t cht adjuvant. Loi t cht thng dng l t cht Freund, l mt hn dch vi khun lao cht trn trong nc v du. (4) S di truyn kh nng p ng ca c th: cng mt khng nguyn nhng cc c th khc nhau th to ra cc p ng min dch mc khc nhau. V th m Landsteiner phn bit hai khi nim: Tnh khng nguyn v tnh min dch, trong : Tnh sinh min dch = tnh khng nguyn + kh nng p ng ca c th. 4.1.2. Tnh c hiu Tnh c hiu ca mi p ng min dch c c l do mi khng nguyn c mt cu trc ring. Tnh c hiu ca khng nguyn khng phi do ton b phn t khng nguyn quyt nh, m do mt hoc nhiu on nh nm trn phn t khng nguyn quyt nh. Nhng on nh ny cc l quyt nh khng nguyn hay epitop. Epitop c hai chc nng, mt l kch thch c th to ra p ng min dch c hiu vi khng nguyn , v hai l lm v tr khng th hoc t bo lympho mn cm c th gn vo mt cch c hiu. Mt khng nguyn protein phc tp c th nhiu quyt nh khng

nguyn khc nhau, do m n c th kch thch to ra nhiu loi khng th khc nhau cng mt lc. Ty theo khng nguyn c th phn ng cng mt lc vi mt hay nhiu khng huyt thanh cha khng th do n to ra m ngi ta gi l khng nguyn n gi hay khng nguyn a gi. Trong cc phn ng huyt thanh hc ch c nhng khng nguyn a gi mi c th to ra mng li kt ta hoc ngng kt. 4.1.3. Phn ng cho Phn t khng th c tnh c hiu rt cao, nhng cng c trng hp khng th ca khng nguyn A li tc dng vi khng nguyn B, ta gi l phn ng cho. Nguyn nhn ca phn ng cho c th l do trn hai khng nguyn ny c hai epitop ging nhau hoc t nht l cng tng t nhau Trong thc nghim chng ta c th loi tr c phn ng cho bng phng php cho hp th. V d, ta bit khng huyt thanh khng A thng cho phn ng cho vi khng nguyn B cho nn khi lm phn ng tm khng nguyn A th kt ta d sai lc do tm nhm c B. Nh vy, trc khi tm A ta cho khng nguyn huyt thanh khng A vi khng nguyn B, nhng phn t no cho phn ng cho s to phc hp vi B. Sau khi ly tm loi phc hp ta s cn khng huyt thanh A khng cn phn ng cho vi B. 4.1.4. Hapten Hapten hay bn khng nguyn l mt khng nguyn khng ton nng, c trng lng phn t thp, khng c tnh sinh min dch nhng c tnh c hiu khng nguyn. Khi hapten c gn vi mt cht protein ti thnh mt phc hp th phc hp ny c tnh sinh min dch. Ni r hn, trong thc nghim, nu ta ch a hapten vo c th th khng c p ng min dch c hiu xy ra, nhng nu ta a phc hp protein-hapten vo th c th s p ng bng cch sn xut khng th chng li c hapten ln protein (Hnh 4.1). Khng th chng hapten do phc hp kch thch to ra c th phn ng c vi hapten t do. Trong trng hp ny, ta c th xem hapten nh l mt quyt nh khng nguyn c thm vo bn cnh nhng quyt nh khng nguyn khc c mt trn phn t protein. Trong s cc hapten th nhm dinitrophenyl v nhm azobenzenarsenat l hay c dng trong thc nghim. Nhm dinitrophenyl c th gn vo nhm NH2 ca lysine v nhm azobenzenarsenat c th gn vo gc tyrosin. Mt trng hp khc ta cn lu , c khi ch cn a hapten vo c th l c th gy p ng min dch (loi hapten thng dng nht cho th nghim kiu ny l DNCB,

dinitrochlorobenzen). L do l v hapten ny khi vo c th th gn vi protein ca c th tr thnh phc hp protein hapten c tnh sinh min dch.

Hnh 4.1. S minh ha p ng vi hapten Bn thn hapten khng to ra p ng, nhng khi c lin kt in vitro v/hoc in vivo vi cng hp protein th s to ra khng th phn ng c vi hapten v vi cng hp protein .

4.2. Mt s khng nguyn quan trng 4.2.1. H khng nguyn nhm mu ABO H ny bao gm 4 nhm mu khc nhau: A, B, AB v O. K hiu nhm mu biu th khng nguyn c mt trn b mt hng cu. C th nhm mu A th c khng nguyn A, nhm B th c khng nguyn B, nhm AB c khng nguyn A v B v nhm O th khng c c A v B trn hng cu. Mt c im khc ca c th l ngi mu A c mang khng th chng B trong huyt thanh, ngi mu B th c huyt thanh chng A, ngi AB th huyt thanh khng c khng th chng hai khng nguyn ny cn nhm O th c c hai loi khng th. Cc khng nguyn thuc h ABO do mt locus gen kim sot vi ba allel A, B, v O, trong A v B tri hn O. Tnh c hiu khng nguyn nhm mu trong h ABO c quyt nh bi s c mt ca mt s gc ose trong phn polysaccharid. Cc khng nguyn ny u c chung mt li sphingolipid- polysaccharid. Nu li ny c gn thm gc fucose th xut hin cht H. Cht ny c trn b mt hng cu ca hu ht cc c th v l nn sut hin khng nguyn A v khng nguyn B. Nu ti v tr galactose cui cng ca cht H c gn thm N-acetyl galactosamin th xut hin khng nguyn A. Cn nu gn thm mt galactose na th xut hin khng nguyn B (Hnh 4.2).

Hnh 4.2. S cu to khng nguyn ABO

Cc gen A hoc B m ha cho enzym transferase gn N-acetylgalactosamin hoc galactose vo cht H to nn nhm mu A hoc B. Nu khng c gen A hoc B th mu thuc nhm O. V mt di truyn, tham gia vo s hnh thnh khng nguyn nhm mu c hai h gen, l h Hh i vi cht H v h ABO. Hai h ny hot ng c lp vi nhau. i a s chng ta c gen H, nhng cng c ngi khng c (c th ng hp t hh). Nhng ngi ny d c gen ca h ABO nhng trn hng cu vn khng c khng nguyn A hoc B nn c ghi nhn l nhm O nhng khi truyn mu O thc s vo ngi ny (tc a cht H vo cho ngi khng c H) th c th gy tai bin truyn mu. Nhm c bit ny c gi l nhm O Bombay. 4.2.2. H khng nguyn nhm mu Rh Nm 1930, Landsteinner v Wiener pht hin ra nhm mu Rh. H gi nhng ngi c hng cu ngng kt vi huyt thanh th khng hng cu ca kh Rhessus l ngi Rh+, s ngi cn li l Rh-. Nhng ri sau ny, ngi ta pht hin ra rng, khng nguyn trong h Rh khng n gin nh vy. H Rh c nhiu khng nguyn, phn ln c tnh sinh min dch yu v hay gy phn ng cho. Ch c khng nguyn D l c tnh sinh min dch mnh. Khi hng cu c khng nguyn D th c gi l Rh+ m khng cn n cc khng nguyn khc trong h ny. Khng th khng D khng xut hin t nhim trong mu nh cc khng th ca h ABO. V khng nguyn Rh phn b tha tht trn hng cu nn thng kh gy ngng kt hng cu khi lm phn ng xc nh nhm mu Rh, v th ngi ta phi dng n th nghim Coombs gim tip (Hnh 4.3)

Hnh 4.3. Phn ng Coombs gin tip (a). Hnh nh phn ng m tnh; (b) Hnh nh phn ng dng tnh; (c) C ch phn ng trong trng hp bt ng nhm mu Rh. 4.2.3. Khng nguyn vi sinh vt Khng nguyn vi sinh vt l loi khng nguyn rt phc tp: khng nguyn v, khng nguyn thn, khng nguyn lng, khng nguyn ngoi t bo, v.v V khng nguyn v th khng nguyn v ca ph cu thng hay c nghin cu nhiu nht. Khng nguyn ny thuc loi polysaccaride, c ti 80 typ huyt thanh khc nhau. V khng nguyn thn th cc vi khun rut non, lp ngoi ca vch vi khun c mt lipopolisaccharide: phn lipid c tnh c, cn phn polysaccharid th c tnh khng nguyn v y chnh l khng nguyn thn (cn gi l khng nguyn O). Salmonella c n hn 60 khng nguyn O m cu trc c hai phn: phn nhn c bn v phn chui ngang. Phn nhn ging nhau tt c cc Salmonella. Phn chui ngang gm nhng tiu n v oligosaccharide sp xp lp i lp li. Chnh cc chui ngang quyt nh tnh c hiu ca mi nhm Salmonella. Cc khng nguyn lng ca Salmonella c bn cht l protein, cn c gi l khng th H, quyt nh tnh c hiu ca mi typ Salmonella. Ngi ta pht hin Salmonella c hn 1000 typ huyt thanh khc nhau.

Cc khng nguyn ngoi t bo nh c t v cc enzym cng c bn cht protein. Mt loi khng nguyn ngoi t bo ca lin cu l Streptolysin O thng c dng trong chn on huyt thanh. Cc vi khun trong bch hu, un vn c ngoi c t gy bnh v cc vaccin phng cc bnh ny y l c t c gii c. Khng th virus c th trn b mt ht virus (capsid) hoc bn trong. Ty theo tnh c hiu, c th phn bit cc khng nguyn nhm, cc khng nguyn typ v khng nguyn typ ph. Trong cc khng nguyn nhm, c th k lm v d khng nguyn nucleoprotein (NPA), l khng nguyn typ, chng hn trong bnh bi lit, cho php phn bit ba typ virus bi lit khc nhau. Trong trng hp virus cm, ngoi vic phn bit ba typ A, B, C, ngi ta cn phn bit typ ph na. Cc typ ph ca A v B l kt qu ca nhng bin i ca khng nguyn b mt. 4.2.4. Khng nguyn ha hp m T lu, ngi ta bit rng, vic truyn mu s d thnh cng l nh, s ph hp gia mu ca ngi cho v mu ca ngi nhn. Trong bi pht biu khi nhn gii Nobel vo nm 1931, Ladsteiner cho rng c l c nhng nhm ging nhm mu lin quan n vic chp nhn hoc thi b nhng m ghp khc. tng ny dn dt Gorer i n vic xc nh mt nhm khng nguyn chut m khi nhm khng nguyn ny ging nhau gia con cho v con nhn th mnh ghp c thi gian sng lu hn. Tn gi khng nguyn ha hp m c dng ch khng nguyn tham gia vo vic thi ghp ny. Ngi ta cng nhn thy rng ph trch m ha cc khng nguyn ny l mt vng c bit ca genom v ta gi vng ny l Phc h ha hp m ch yu (Major Histocompatibility Complex, MHC); chut nht n mang tn l vng H-2, v nm trn nhim sc th 17. Nhng h thng tng ng vi phc h ha hp m ch yu chut cng pht hin c trn tt c cc ng vt c v khc. ngi, phc h ha hp m ch yu l cm gen HLA trn nhim sc th s 6. S ti t hp gia cc cc ca phc h gen xy ra khong 1% cc gia nh, nh c th tnh c rng HLA chim khong 1/3.000 trong ton b genom. iu ny c ngha rng c th c hng trm gen nm trong cm HLA ny. Mc d MHC

ln u tin c pht hin nh vai tr ca n trong thi ghp, nhng ngy nay ngi ta bit rng, cc protein sn phm ca on gen ny tham gia vo nhiu cng on trong nhn din min dch, bao gm tng tc gia cc t bo lympho khc nhau cng nh cc lympho bo vi t bo trnh din khng nguyn. 4.2.4.1. S sp xp cc gen MHC Ngi ta xc nh c phc hp gen MHC mang nhiu gen ring l; v mc d phc hp c chc nng chung, tng i ging nhau gia cc loi, nhng chi tit v phn b th mi loi mi khc. Gn y, ngi ta thit lp c bn gen hon chnh cho MHC chut nht. Nh m chng ta bit c rng locus no th chu trch nhim m ha cho on polypeptid no. Ch cn iu vng mc l cch thc cc polypeptid v protein thc hin chc nng ca mnh nh th no cho ph hp vi quy nh ca MHC m ha tm ra c l nh k thut min dch hc (dng khng th n cln), do m ngi ta thng gi cc protein ny l khng nguyn MHC. Cc protein ca MHC gm c 3 lp khc nhau v c cu trc ln chc nng: -Protein lp I (tc khng nguyn MHC lp I) gm c hai polypeptid. Peptid ln c m ha bi MHC, peptid ny lin kt vi mt polypeptid th hai l b2- microglobulin c m ha bi mt gen ngoi on MHC. -Cc protein lp II (tc khng nguyn MHC lp II) gm c hai peptid khng ng ha tr vi nhau c tn l chui a v chui b, c hai u l sn phm ca MHC. - Cc protein lp III (tc khng nguyn MHC lp II) l cc thnh phn b th c m ha bi MHC. Ngoi ra cn c nhng locus ph nm ngoi phc hp H-2 (phc hp TLA) tham gia m ha cho protein lp I v bi v nhng protein ny cng c chc nng min dch nn cng c a vo bn gen Hnh 4.4.

Hnh 4.4. S v tr cc gen MHC C 17 gen Qa trong vng Qa v 12 gen trong vng Tla mc d a s chng dng ngh. ngi, nhng vng chnh l D, B, C, v A. Cc vng A v B ngi l vng c chc nng tng ng vi vng K v D chut, iu c ngha rng nhng sn phm ca chng tc ng vi t cch l nhng phn t nhn din trn b mt t bo, v t bo T gy c s nhn din nhng phn t ny khi thc hin chc nng ca n. Vng D ca ngi tng ng vi vng I ca chut v sn phm ca chng (hai chui protein a v b) tham gia vo qu trnh hp tc ca t bo gia t bo ca h min dch. Cc sn phm vng I ca chut c gi l khng nguyn Ia. Tng ng vi khng nguyn DR, DP, v DQ ca ngi. Ngi ta nhn thy rng, cng ca p ng min dch trn chut c xc nh mt phn bi cc gen p ng min dch. 4.2.4.2. Phn b ca khng nguyn MHC ngi, tt c cc t bo c nhn u nht thit phi mang cc khng nguyn ca vng A, B, C, nhng cn khng nguyn c m ha bi vng D th ch phn b hn ch nhng t bo tng ng vi t bo chut c mang khng nguyn I. Khng nguyn lp I ch c trn t bo B, i thc bo, t bo mono v c l c t bo biu m. Ngoi ra, mt s khng nguyn lp I xut hin c trn t bo T c ch v khng nguyn lp II th c trn t bo T c hot ha (Bng 4.1). Bng 4.1. Phn b ca khng nguyn MHC cc m

Tiu MHC H-2 K, D, L I-A I-E I-J

vng Phn b ca khng nguyn ti cc m HLA A, B, Tt c t bo c nhn v tiu cu C Hng cu (chut) D Lymph B, i thc bo, T bo mn, T bo thng b (?), T bo u sc t, T bo T hot ha Lymph T c ch

4.2.4.3. Cu trc ca khng nguyn MHC Nhng cng trnh gn y nghin cu cc khng nguyn MHC ring bit gip lm sng t cu trc ca chng. Vi t cch l phn t tham gia vo tng tc t bo, khng nguyn MHC thng c tm thy trn mng t bo. Chng l nhng phn t glycoprtein cm vo mng t bo, do nghin cu c chng ta thng phi tch ri chng khi mng bng hai cch: - Hoc l dng cc cht ty (detergent) gii phng chng khi mng. - Hoc l dng enzym papain ct phn MHC nm thi ra khi b dy ca mng. Khi phn t ny c ct bng enzym th chng c khc vi khng nguyn MHC nguyn vn bi v chng mt phn cm su vo mng t bo. Ngi ta lm tinh khit khng nguyn ha tan bng cc k thut ha sinh kinh in nh sc k i tnh, dng lectin hoc khng huyt thanh. Ngi ta nhn thy rng tinh luyn khng nguyn MHC bng sc k i tnh trn ct khng th n cln c nhiu u im hn cc k thut ha sinh khc (Hnh 4.5). Mi khng nguyn lp I bao gm mt polypeptid c gn ng c trng lng phn t khong 45.000 lin kt khng ng ha tr vi mt peptid khng c ng (tc b2 -microglobulin, c trng lng phn t khong 12.000). D b2 - microglobulin khng tham gia vo b mt khng nguyn ca phn t HLA, nhng n cn cho qu trnh th hin ca lp I. Nu mt c th no thiu bm sinh b2 - microglobulin th quyt nh khng nguyn ca lp I khng th hin c.

Hnh 4.5. S minh ha cu trc cc phn t MHC lp I v II S cho thy cc phn t MHC lun c cu trc cm su vo mng t bo Cu trc ca lp II t c bit r hn lp I, chng gm hai chui poypeptid khc nhau a v b gn vi nhau bi lc ni khng ng ha tr, c hai chui u cm vo mng t bo. Chui ngn mang cc khng nguyn allotyp, v hai chui u c mang cc n v ng. Ngi ta bit nhiu v cu trc ca vng H-2I ca chut hn vng tng ng vi vng ny ngi l vng HLA-D. Trn chut, ngi ta pht hin thm nhng tiu vng ca H-2I, l tiu vng I-A v I-E. Kho st ring tng vng peptid v ca khng nguyn I-E chut cho thy rng, a s cc bin i cu trc ch xy ra chui b (trng hp khng nguyn HLA-D cng vy). 4.2.4.4. Chc nng ca khng nguyn MHC Cc khng nguyn MHC rt cn thit cho cc qu trnh nhn din min dch. Cc khng nguyn MHC khc nhau c nhn din bi nhng loi t bo T khc nhau. Nhng t bo T gy c tham gia vo vic nhn din v loi b cc t bo nhim virus v m ghp l c kh nng nhn din cc phn t H-2K v H-2D (tng ng HLA-A v HLA-B ngi) trn cc t bo l, v khi hp tc vi t bo T gip th s gy ph hy t bo l (Hnh 4.6)

a s t bo nhim virus th hin khng nguyn virus trn b mt ca chng, v nhng khng nguyn ny c nhn din bi t bo T gy c. ng thi ngi ta cng bit c rng t bo T gy c ch nhn din c khng nguyn virus khi c phi hp vi vic nhn din khng nguyn K-2K v -D c mt trn t bo b nhim. Bng cch ny t bo T gy c c th git cht t bo nhim. Nh vy, phn t H-2 trn b mt t bo nhim virus tc ng nh mt du hiu hng dn a t bo T gy c n tip cn bo ch, v gip n phn bit t bo ch vi cc t bo khc mang khng nguyn virus. Ngi ta vn cha bit r rng t bo gy c nhn din cng mt lc tnh c hiu virus v khng nguyn MHC t bo ch nh th no. C hai gi thuyt (c minh ha Hnh 4.7): - T bo gy c nhn din c lp hai khng nguyn ny. - S kt hp ca khng nguyn virus v khng nguyn MHC trn b mt t bo t bo lm bin i hnh dng cu trc ca phn t MHC, do m n nhn din nh mt thnh phn bn thn b bin i.

Hnh 4.7. Hai gi thuyt v vic t bo Tc nhn din khng nguyn virus v MHC trn b mt t bo ch. T bo Tc c th nhn din c lp cc phn t khng nguyn virus v MHC (gi thuyt 1) hoc nhn din chung phc hp to nn bi khng nguyn virus v MHC (gi thuyt 2)

Nhiu chc nng ca MHC khc s c cp c th hn, chng ta nghin cu cc b phn ca h thng min dch v MHC tham gia vo ht cc qu trnh nhn din min dch. Nhng hiu bit gn y cho thy rng, MHC v phn t khc tham gia v nhn din min dch ging nhau mt phn cu trc, v iu ny c l c lin quan v mt tin ha vi nhng phn t nhn din u tin trong thi k bo thai. C mt iu chng ta cn lu l c rt nhiu thay i allotyp xy ra cho cc khng nguyn MHC. S xut hin ca nhng tnh c hiu mi ca MHC c th thy nhng loi khc nhau v c lin quan vi nhau. Nguyn nhn ca s thay i ln ny cha c r. V tnh cht rt c th ca tng c th sinh vt m trong mt qun th khng c yu t bnh nguyn no c th gy bin i ging nhau cho ton b cc c th mc nhn din khng nguyn. Tuy vy, chng ta cn bit rng trong mt qun th c th c hin tng mt c th mang mt khng nguyn MHC c bit no th c tnh

d mc mt bnh tng ng hoc khng mc mt bnh tng ng so vi nhng ngi khc. l c im di truyn ca MHC. CC T BO CH YU CA H THNG MIN DCH

Hnh 5.1. Tm tt p ng min dch in vivo Khng nguyn c cc t bo c tua bt gi v tp trung vo hch lymph, chng hot ha cc t bo lymph. T bo T hiu qu v T nh c hnh thnh trong hch ri i vo tun hon c th n cc m ngoi bin. Khng th c sn xut trong c quan lymph v a vo mu c th tip cn khng nguyn bt c ni no. T bo nh cng i vo tun hon v c th dng chn trong c quan lymph hoc cc m khc. p ng min dch thu c pht trin qua nhiu bc lin tc nhau m

trong mi bc cn n tnh cht c bit khc nhau ca t bo v m min dch. Cc giai on ch yu ca nhng p ng ny v vai tr ca cc t bo v cc m khc nhau c trnh by Hnh 5.1. T bo tham gia vo p ng min dch thu c bao gm cc lymph bo c hiu khng nguyn, t bo trnh din khng nguyn v cc loi t bo hiu qu c chc nng loi b khng nguyn. Nhng t bo ny c gii thiu Chng 1, y chng ti m t hnh thi hc v c im chc nng ca lymph bo v t bo trnh din khng nguyn v gii thch nhng t bo ny c t chc th no trong cc m lymph. S lng ca mt s t bo c trnh by Bng 5.1. Mc d nhng t bo ny c tm thy trong mu nhng ni chng phn ng vi khng nguyn l ti m lymph hoc cc m khc. iu ny khng gy bin i g v s lng ca bch cu lu ng.

Bng 5.1. S lng bnh thng ca t bo bch cu mu

T bo bch cu - Trung tnh - i toan - i kim - Lymph - Mn

Tr trung bnh/1 microlit 7.400 4.400 200 40 2.500 300

Gii hn bnh thng 4.500 11.000 1.800 7.700 0 450 0 200 1.000 4.800 200 800

5.1. T bo lymph T bo lymph l loi t bo duy nht trong c th c kh nng nhn din mt cch c hiu v phn bit c cc quyt nh khng nguyn. Chng chu trch nhim v hai c im ca p ng min dch thu c, l tnh c hiu v tnh nh min dch. C nhiu bng chng c a ra chng minh cho vai tr ca lymph bo vi t cch l t bo trung gian ca min dch thu c.

5.1.1. Hnh thi hc Cc t bo lymph nguyn vn, tc l cc lymph bo cha tng tip xc vi khng nguyn trc c cc nh hnh thi hc gi l t bo lymph nh. T bo ny c ng knh 8-10mm, c nhn ln, vi cht nhim sc m c v mt vnh bo tng mng cha mt t ti th, ribosom v lysosom, nhng khng c cc tiu c quan chuyn mn ho (Hnh 5.2). Trc khi c kch thch khng nguyn, t bo lymph nh trng thi ngh, hay cn gi l trng thi G0 ca chu k t bo. Khi c kch thch, lymph bo nh chuyn sang giai on G1. Chng tr nn ln hn (ng knh 1012mm), c nhiu bo tng hn, c tiu c quan v gia tng lng RNA bo tng; lc ny n c gi l t bo lymph ln, hay nguyn bo lymph (Hnh 5.2).

Hnh 5.2. Hnh thi hc lymph bo Hnh nh knh hin vi quang hc ca lymph bo trn tiu bn mu ngoi vi 2. Hnh nh knh hin vi in t ca t bo lymph nh 3. Hnh nh knh hin vi in t ca t bo lymph ln (nguyn bo lymph)
1.

5.1.2. Cc loi t bo lymph T bo lymph bao gm nhiu tiu qun th khc nhau khc bit v chc nng, v sn phm protein nhng khng phn bit c v hnh thi (Bng 5.2). Tnh a dng ca t bo lymph c gii thiu Chng 1. T bo B l t bo sn xut khng th. Chng c tn nh vy l v loi chim chng c trng thnh trong mt c quan gi l Bursa Fabricius (ti

Fabricius). loi c v, khng c c quan tng ng vi bursa v giai on u ca s trng thnh t bo B xy ra trong tu xng (bone marrow). Nh vy gi tn t bo B l ch rng t bo ny xut pht t bursa hoc bone marrow. T bo T l t bo trung gian ca min dch t bo, n c t tn nh vy l v cc t bo tin thn ca chng sau khi c sinh ra trong tu xng di c n v trng thnh ti tuyn c (thymus). T bo T c hai tiu qun th chnh, l t bo T gip v t bo T gy c. C t bo B v t bo T u c th th khng nguyn phn b theo cln, c ngha l nhng cln ca nhng t bo ny mang tnh c hiu khng nguyn khc nhau, cc t bo trong mi cln th c th th ging nhau nhng khc vi th th trn t bo ca cln khc. Gen m ho cho th th khng nguyn ca t bo B v t bo T c hnh thnh bi s ti t hp ca cc on DNA trong sut thi k pht trin ca cc t bo ny. S ti t hp thn (somatic) to ra hng triu gen th th khc nhau v iu ny dn n hnh thnh mt kho cha rt a dng ca t bo lymph. T bo git t nhin l qun th th ba ca lymph bo, c th th khc vi t bo B v T v chc nng ch yu l trong min dch bm sinh. Protein mng t bo lymph c th xem nh l cc du n kiu hnh (phenotypic marker) phn bit cc qun th lymph vi chc nng khc nhau (Bng 5.2). V d, a s t bo T gip u mang mt protein b mt gi l CD4, v a s cc t bo T gy c u mang phn t b mt c tn l CD8. Ngi ta dng khng th c hiu cho cc phn t pht hin chng v phn bit cc qun th lymph. Nhiu protein b mt ban u c pht hin vi t cch l du n kiu hnh phn bit cc tiu qun th nhng v sau ngi ta li thy chng c th mang nhng chc nng khc. Ngi ta thng nht vi nhau dng thut ng CD gi tn cc phn t b mt ny. CD l vit tt ca Cluster of Differentiation c nghi l nhm bit ho; y l mt t lch s dng ch mt nhm cc khng th n cln c hiu cho nhng du n ca qu trnh bit ho lymph bo. H thng CD gip chng ta gi tn mt cch ng b cc phn t b mt ca t bo lymph, t bo trnh din khng nguyn, v nhiu loi t bo khc trong h thng min dch. Bng danh mc hin nay ca du n CD c trnh by trang web: http://www.ncbi.nlm.nih.gov/prow/.

Bng 5.2. Cc qun th lymph bo

Phn trm trong Loi TB T gip Chc nng Th th KNguyn Du n CD3+, CD4+, CD8tng s lymph bo Mu Hch Lch 50- 505060 60 60

Kch thch ab s pht heterotrin v dimer bit ho t bo B;

Hot ho i thc bo bng cc cytokin T gy Git t c bo nhim virus, t bo u;

ab heterodimer

CD3+, CD4-, CD8+

2025

1520

1015

Thi ghp d loi T Sn xut Khng bo B khng th th (Ig) b mt T bo NK Git t bo nhim virus, t bo u; Gy c t bo ph thuc khng th Th th t bo git ging Ig

FcR, 10MHC 15 II, CD19, CD21 FcRg ~10 (CD16)

2025

4045

Him ~10

5.1.3. S pht trin ca t bo lymph Cng nh tt c t bo mu khc, t bo lymph xut thn t cc t bo mm tu xng. T bo lymph phi i qua cc bc trng thnh phc tp cui cng c c mt b th th khng nguyn trn b mt v hnh thnh nhng c dim chc nng cng nh hnh thi ring cho mnh (Hnh 5.3). T bo B hon tt thi k trng thnh ca mnh trong tu xng, cn t bo T th trng thnh trong tuyn c. Sau khi trng thnh t bo lymph ri khi tu xng v tuyn c vo h tun hon v tp trung thnh tng m cc c quan lymph ngoi bin. Nhng t bo trng thnh ny c gi l t bo lymph nguyn vn (naive). Qun th t bo lymph nguyn vn c duy tr vi s lng n nh nh s cn bng gia cc t bo mi n t tu xng v t bo cht do khng tip xc khng nguyn. Chc nng ca t bo lymph nguyn vn l nhn din khng nguyn v to ra p ng min dch thu c. T bo no khng tip xc vi khng nguyn th s cht theo phng thc cht lp trnh (apoptosis). Thi gian na i sng ca t bo lymph nguyn vn vo khong 3-6 thng i vi loi chut v 1 nm i vi loi ngi. Ngi ta cho rng s sng cn ca t bo lymph nguyn vn c duy tr nh s nhn din yu i vi khng nguyn bn thn. Nh vy, nhng t bo ny nhn nhng tn hiu duy tr s sng ca chng nhng khng kch thch chng bit ho thnh t bo hiu qu. Bn cht ca nhng t khng nguyn tham gia vo s sng cn ca t bo lymph vn cn cha bit r. Ngi ta ch bit rng th th khng nguyn trn t bo lymph nguyn vn khng ch cn cho vic nhn din khng nguyn l bit ho thnh t bo hiu qu m cn cn cho s tn ti ca t bo trong trng thi nguyn vn. Ngoi ra, mt s protein do t bo tit ra gi l cytokin cng cn cho s sng cn ca t bo lymph nguyn vn.

Hnh 5.3. S trng thnh ca t bo lymph

S trng thnh ca t bo lymph t t bo mm tu xng xy ra trong cc c quan lymph trung ng v p ng min dch i vi khng nguyn l xy ra trong cc c quan lymph ngoi bin 5.1.4. S hot ho t bo lymph Trong p ng min dch thu c, t bo lymph nguyn vn c hot ho bi khng nguyn hoc nhng kch thch khc bit ho thnh t bo hiu qu hoc t bo nh. (Hnh 5.4). S hot ho t bo lymph tri qua mt lot cc bc ni tip nhau. Sinh tng hp protein mi Ngay sau khi c kch thch, t bo lymph bt u sao chp cc gen m trc y vn yn lng v tng hp mt lot cc protein mi. Nhng protein ny gm: cc cytokin (trong t bo T) l cht kch thch s pht trin v bit ho ca chnh t bo lymph v cc t bo hiu qu khc; cc th th cytokin lm cho t bo lymph p ng tt hn vi cytokin; v nhiu protein khc tham gia vo vic sao chp gen v phn chia t bo. Tng sinh t bo Khi p ng vi khng nguyn v cc yu t tng trng, cc t bo lymph c hiu khng nguyn s chuyn sang thi k phn bo v to nn s tng sinh mnh m i vi cln t bo c hiu khng nguyn, hin tng ny c gi l pht trin cln (clonal expansion). Trong mt s trng hp nhim trng virus cp, s lng t bo T c hiu virus c th tng ln 50.000 ln, t s lng c bn (cha kch thch) l 1 phn triu lymph bo n 1/10 vo thi im nhim trng nh cao. y l mt v d in hnh v s pht trin cln trong p ng min dch chng vi sinh vt.

Hnh 5.4. Cc giai on hot ho lymph bo T bo lymph B nguyn vn (hnh trn) v t bo lymph T nguyn vn (hnh di) p ng vi khng nguyn v tn hiu th hai bng cch tng sinh v bit ho thnh t bo hiu qu v t bo nh. Tnh trng cn bng ni mi c duy tr khi nhng t bo c hiu khng nguyn b cht do hin tng cht lp trnh. S bit ho thnh t bo hiu qu Mt s t bo lymph c khng nguyn kch thch s bit ho thnh t bo hiu qu c chc nng loi b khng nguyn. T bo hiu qu bao gm t bo T gip , t bo T gy c, v t bo B tit khng th. Cc t bo T gip sau khi bit ho s mang trn b mt nhng phn t protein dng tng tc vi cc u ni tng ng (ligand) trn cc t bo khc (nh i thc bo, t bo B), ng thi chng cng tit cc cytokin hot ho cc t bo khc. T bo T gy c sau khi bit ho s mang nhng ht cha cc protein c th git virus v t bo ung th. Lymph bo B c bit ho thnh nhng t bo sn xut v bi tit khng th. Mt s cc t bo tit khng th ny c nhn din l tng bo (plasma cell). Chng c nhn c bit, bo tng ln v cha mng li ni bo dy c, mang nhiu ht; y chnh l ni tng hp khng th, protein mng v protein tit. T bo ny cng c phc hp Golgi c bit nm quanh nhn l ni cc phn t khng th c chuyn thnh th dng cui cng trc khi c bi tit ra ngoi (Hnh 5.5). Ngi ta c tnh rng, khong hn mt na s RNA thng tin (mRNA) trong tng bo chu trch nhim m ho cho protein khng th. Tng bo pht trin trong c quan lymph, ni p ng min dch xy ra v thng di chuyn n tu xng v y mt s tng bo sng rt lu k c sau khi khng nguyn c loi

b. Phn ln t bo hiu qu sau khi bit ho c i sng rt hn ch v khng t i mi c.

Hnh 5.5. Hnh thi ca tng bo

1. 2.

Hnh nh knh hin vi quang hc ca tng bo trong m Hnh nh knh hin vi in t ca tng bo S bit ho thnh t bo nh

Mt s t bo lymph B v T c bit ho thnh t bo nh c chc nng to ra p ng min dch nhanh v mnh hn khi tip xc li vi khng nguyn ln th hai tr i. T bo nh c th tn ti mt cch yn lng trong nhiu nm sau khi khng nguyn c loi b. Ngi ta chng minh rng c mt s t bo nh khng cn nhn din khng nguyn m vn c th tn ti lu di in vivo. T bo nh c mang trn b mt nhng protein gip phn bit chng vi t bo nguyn vn v t bo hiu qu mi c hot ho mc d cho n nay ngi ta vn cha r nhng protein b mt no l du n ca ring t bo nh (Bng 5.3).T bo B nh th hin mt s lp (tc isotyp) Ig mng nh IgG, IgE, hoc IgA. y l kt qu ca qu trnh chuyn i (switch) isotyp v t bo B nguyn vn ch c IgM v IgD. So vi t bo T nguyn vn, t bo T nh mang nhiu phn t kt dnh (adhesion molecule) hn, v d integrin, CD44 l nhng phn t thc y s di chuyn ca t bo nh n

ni nhim trng. ngi, a s t bo T nguyn vn mang mt dng ng phn 200 kD ca phn t b mt c tn CD45, phn t ny c cha mt on protein c m ho bi mt exon c tn gi l A. Dng ng phn ny ca CD45 c th nhn din c bng khng th c hiu i vi on m ho A nn c gi l CD45RA (R c ngha l hn ch - restricted). Ngc li, a s cc t bo T nh v T hot ho th mang mt dng ng phn 180 kD ca CD45 trong exon A ca RNA b ct i, do vy dng ng phn ny c tn l CD45RO. Tuy nhin, dng cch ny phn bit t bo T nguyn vn vi t bo T nh khng c n lm v ngi ta thy c s chuyn i qua li gia cc qun th CD45RA+ v CD45RO+. T bo nh hnh nh rt a dng xt v nhiu kha cnh. Mt s c xu hng di chuyn ra ngoi bin n cc hch lymph to nn mt kho cha t bo lymph c hiu khng nguyn c th c hot ho nhanh tng sinh v bit ho thnh t bo hiu qu khi tip xc tr li vi khng nguyn. Cc t bo nh khc c xu hng tn ti trong nim mc hoc lu thng trong mu c th tp trung n bt c v tr nhim trng no trong c th nhanh chng to ra t bo hiu qu gip loi b khng nguyn.

Bng 5.3. Tnh cht ca t bo lymph nguyn vn, hiu qu v nh

Lymph Lymph bo bo hot ho nguyn hoc hiu vn qu Lymph bo T Di c n cc n m vim hch ngoi bin S t bo p ng Rt t Nhiu vi mt khng nguyn Chc nng hiu Khng Tit cytokin,

Lymph bo nh n m vim, nim mc t

Khng

qu Chu trnh t bo Th hin protein b mt :

Khng c t

tiu t bo C

+/-

Nhiu

- Th th IL-2 i lc cao - Th th xut x hch ngoi bin Nhiu t t hoc thay (L-selectin, i CD62L) - Phn t kt dnh : integrin, t Nhiu Nhiu CD44 - Th th Nhiu t Thay i chemokin: CCR7 - Dng ng phn CD45RO, chnh ca CD45 thay i CD45RA CD45RO (ch ngi) Hnh thi Nh, t Ln, nhiu Nh bo bo tng tng Lymph bo B Isotyp Ig mng IgM v Thng gp Thng gp IgD IgG, IgA, IgE IgG, IgA, IgE i lc ca Ig sn Tng Tng trong Tng i xut ra i thp qu trnh p cao ng min dch Chc nng hiu Khng Tit khng Khng c qu c th Hnh thi Nh, t Ln, nhiu Nh bo bo tng, tng tng bo Th th chemokin: Nhiu t ? CXCR5

Cho n nay, vn cn nhiu cu hi ch cht xung quanh t bo nh

cha c gii p. Chng ta khng bit rng nhng kch thch no lm cho mt s t bo lymph bit ho thnh t bo nh. Chng ta cng cha bit rng lm th no m t bo nh c th sng cn in vivo m khng cn s kch thch ca khng nguyn, trong khi c t bo nguyn vn ln hot ho u s cht lp trnh khi khng c s kch thch thng xuyn ca khng nguyn hoc cc yu t pht trin. 5.2. T bo trnh din khng nguyn T bo trnh din khng nguyn l nhng t bo c chuyn mn ho bt gi vi sinh vt v cc khng nguyn khc, trnh din chng cho t bo lymph v cung cp tn hiu kch thch, tng sinh v bit ho t bo lymph. Theo kinh in, thut ng t bo trnh din khng nguyn dng ch mt loi t bo c chc nng trnh din khng nguyn cho t bo lymph T. Th dng chnh ca t bo trnh din khng nguyn tham gia khi ng p ng t bo T l t bo hnh sao (dendritic cell). i thc bo trnh din khng nguyn cho t bo T trong p ng min dch t bo, cn t bo B th lm chc nng trnh din khng nguyn cho t bo T gip trong p ng min dch dch th. Mt loi t bo c chuyn mn ho c tn l t bo hnh sao vng nang trnh din khng nguyn cho t bo B trong nhng giai on c bit ca p ng min dch dch th. 5.2.1. T bo hnh sao T bo hnh sao ng vai tr quan trng trong vic bt gi khng nguyn v to ra p ng t bo T i vi khng nguyn. T bo hnh sao c tm thy di lp biu b v trong a s cc c quan, chng c t t th sn sng bt gi khng nguyn v vn chuyn khng nguyn n cc c quan lymph ngoi bin. a s t bo hnh sao c ngun gc t dng t bo m n v c gi l t bo hnh sao tu (myeloid dendritic cell). 5.2.2. Thc bo n nhn H thng thc bo n nhn bao gm nhng t bo c cng chung ngun gc v c chc nng thc bo. Nhng t bo thuc h thng thc bo n nhn u xut pht t tu xng, lu thng trong mu, sau trng thnh v c bit ho ti nhiu m khc nhau (Hnh 5.6). Loi t bo u tin i vo mu ngoi bin sau khi ri tu xng c gi l t bo m n, y l nhng t bo cha c bit ho hon ton. T bo m n c ng knh 10-15mm, c nhn hnh ht u, bo tng dng ht mn c cha tiu th, nang thc bo v cc si lm khung cho t bo (Hnh 5.7). Khi chng

c nh v ti m, nhng t bo ny trng thnh v tr nn i thc bo. i thc bo c th thay i hnh dng sau khi b kch thch bi cc yu t bn ngoi nh vi sinh vt chng hn. Mt s th tr nn c nhiu bo tng v c gi l t bo dng biu m (epithelioid cell) bi v chng c hnh dng rt ging t bo biu m da. i thc bo c th ho mng vi nhau to thnh t bo khng l nhiu nhn. i thc bo c th tm thy trong tt c mi c quan v m lin kt v c t tn khc nhau tu theo v tr ca chng. V d h thn kinh trung ng th chng c gi l t bo thn kinh m (microglial cell); khi nm thnh xoang mch mu ca gan th c gi l t bo Kupffer, khi nm phi th gi l i thc bo ph nang; v i thc bo khng l a nhn xng th gi l hu ct bo (osteoclast). Thc bo n nhn hot ng nh t bo trnh din khng nguyn trong p ng min dch t bo. i thc bo cha vi sinh vt n vo s trnh din khng nguyn cho nhiu t bo T hiu qu khc nhau. Sau , t bo T hiu qu hot ho i thc bo git vi sinh vt. Qu trnh ny l c ch ch yu ca min dch t bo. i thc bo n vi sinh vt cng c vai tr trong vic hot ho t bo T nguyn vn to ra p ng s cp i vi khng nguyn vi sinh vt, mc d tht ra th t bo hnh sao mi l t bo khi ng min dch s cp hiu qu hn. Thc bo n nhn cng l t bo hiu qu quan trng trong c min dch bm sinh ln min dch thu c. Chc nng hiu qu ca chng trong min dch bm sinh l thc bo vi sinh vt v sn xut cytokin thu ht v hot ho cc t bo vim khc. i thc bo c rt nhiu vai tr trong giai on hiu qu ca p ng min dch thu c. Nh trnh by trn, trong min dch t bo, t bo T c khng nguyn kch thch s hot ho i thc bo tiu dit vi sinh vt b thc bo. Trong min dch dch th, khng th bao bc hoc opsonin ho vi sinh vt v thc y s thc bo thng qua th th khng th trn b mt i thc bo. Hnh 5.6. S trng thnh ca thc bo n nhn

Thc bo n nhn pht trin trong tu xng, i vo mu di tn gi t bo m n, v n nh v ti cc m ca c th di tn gi l i thc bo. Chng c th bit ho thnh nhiu dng khc nhau trong nhng m khc nhau.

Hnh 5.7. Hnh thi thc bo n nhn A. Hnh nh knh hin vi quang hc ca t bo m n trong tiu bn mu ngoi bin. B. Hnh nh knh hin vi in t ca t bo m n trong mu ngoi bin. C. Hnh nh knh hin vi in t ca mt i thc bo hot ho cho thy c nhiu nang thc bo v cc c quan bo tng.

5.2.3. T bo hnh sao vng nang T bo hnh sao vng nang (follicular dendritic cell) l nhng t bo c mng c rt nhiu ch li ra, hin din trong cc trung tm mm ca nang lymph (v th c tn gi t bo hnh sao vng nang) ca hch, lch v m lymph nim mc. a s t bo hnh sao vng nang khng xut thn t tu xng v khng lin quan g n t bo hnh sao trnh din khng nguyn cho t bo T. T bo hnh sao vng nang bt gi nhng khng nguyn gn vi khng th hoc sn phm b th v trnh by nhng khng nguyn ny ln b mt t bo B nhn din. iu ny gip chn la t bo B hot ho tng ng v th th khng nguyn trn t bo B c i lc rt cao vi khng nguyn trnh by trn b mt t bo hnh sao vng nang.

B TH Chng bao lu sau khi pht hin ra khng th, ngi ta nhn thy rng, kh nng ca khng th trong vic bt hot vt l cn ph thuc vo mt yu t phi hp khc, l b th. B th bao gm mt nhm protein m phn ln l cc proteinase. H thng enzym ny h tr mt cch khng c hiu ca khng th trong vic opsonin ha v ly gii cc t bo ch. Tuy nhin, hiu bit ban u ny v sau c b sung vi nhng kin thc hin i v chc nng sinh hc ca b th. Hin nay ngi ta thy b th thc hin ba chc nng sau y: 1. Hot ha t bo. 2. Ly gii t bo. 3. Opsonin ha: chun b t bo ch iu kin thch hp cho vic thc bng cch gip t bo thc hnh bm dnh tt vo t bo ch. Cc protein ca h thng b th to thnh hai chui enzym m ngi ta gi l con ng c in v con ng khng c in to nn hai cch phn cch hai phn t C3 tc phn t trung tm ca h thng b th. Giai on cui ca hai con ng ny ging nhau, l to ra phc hp protein huyt thanh gn c ln t bo ch, gy tn thng mng dn n hy hoi t bo ch. 6.1. Con ng hot ha c in (classical pathway) Qu trnh enzym v tn cng mng dn n git cht t bo. n v nhn din b th hot ng ca con ng ny c th chia lm ba giai on: nhn dng, hot ha l phc hp C1. 6.1.1. C nh C1 bi immunoglobulin C nh C1 xy ra khi tiu n v C1q gn trc tip ln Ig. Hai tiu n v cn li ca C1 l Clr v Cls khng kin kt vi Ig m tham gia vo qu trnh hot ha c in v sau. Phn t khng th sau khi kt hp vi khng nguyn tng ng s b thay i cu trc khng gian lm l cc th th i vi C1q. Tnh cht kt hp ca b th vo phc hp khng nguyn - khng th l c s ca phn ng c nh b th m chng ta thng hay s dng trong cc xt nghim min dch hc.

Khng phi tt c cc Ig c kh nng kt hp vi b th. ngi ch c IgG1, IgG3, v IgM l c kh nng ny; chut nht c IGg2 v IgM, v chut lang c IgG2, .v.v. Cu hnh khng gian ca phc hp khng nguyn khng th cng c nh hng n kh nng c nh b th. Nhng c th th cha c bit r. Mt phn t IgM pentamer kt hp vi khng nguyn l c th c nh b th nhng i vi IgG th phi c phn t IgG c gn vi khng nguyn v tr gn nhau mi c th c nh c b th (Hnh 6.1). t c iu ny trong thc nghim i vi hng cu cu, ngi ta tnh ra phi cn n 600-800 phn t IgG gn ln hng cu. Do m ngi ta thng dng IgM hn. V tr gn ca b th vo Ig l lnh vc CH2 ca IgG v CH4 ca IgM. Sau khi C1q kt hp vi khng th, s hot ha s c truyn sang C1r v Cls. C ch C1q hot ha C1r vn cn cha c bit. C1s sau khi c hot ha C4 v C2 l hai thnh phn tip theo ca chui phn ng.

Hnh 6.1. C nh C1qrs Mt cp phn t IgG lin kt vi cc phn t protein khng nguyn (protein gn mng). Mnh C1 c nh cc lnh vc CH2 ca IgG. S hot ha C1r v C1s l do phn ct ni b v do s bin i ca thnh phn C1q to nn.

6.1.2. C nh v hot ha C4 v C2 bi phc hp C1qrs

Hnh 6.2. S hnh thnh C4b2b C1s ct C4 to ra C4a v C4b. C4b gn vo mng t bo. C2 huyt thanh n gn vo C4b v b C1s ct gii phng C2a. C4b2b chnh l enzym ct C3 ca con ng hot ha c in. Phn t C1s sau khi c hot ha n tr thnh mt enzym v ct phn t C4 thnh hai mnh: mnh nh l C4a v mnh ln C4b. Mnh C4b c mt v tr hot ng gip n gn ln th th dnh cho n trn b mt mt s t bo. Chng ta cn lu rng mnh C4b khng nht thit ch nm chung quanh ni n c hnh thnh m n th vo mu tun hon v c lu ng, tuy nhin khi n vo tun hon th tr nn b bt hot. Phn C4b cn li ti ch ( khong 10%) s gn ln t bo. C1s c tc dng rt yu ln C2 t do, nhng khi C2 to phc hp vi C4b th tc dng ny mnh hn nhiu. S hp th C2 ln C4b ch xy ra trong iu kin c mt ion Mg++. C2 s b ct lm hai mnh, mnh nh C2a s b mt vo mi trng chung quanh cn mnh ln C2b th vn cn bm trn C4b to thnh phc hp C4b2b c tnh enzym khng bn vng, c thi gian na i sng ngn (5 pht) v mnh C2b d b hy hoi hoc tch ri khi C4b (Hnh 6.2).

6.1.3. Tc ng ca C4b2b ln C3 Phc hp C4b2b hot ha phn t C3 bng cch ct phn t ny thnh hai mnh C3a v C3b. Mnh C3a c trng lng phn t thp, c gii phng vo trong dch c th v c hot tnh ca mt ha cht trung gian ca phn vim. Mnh ln ca C3b c trng lng phn t khong 175.000 kD v c kh nng dnh ln b mt t bo. Tuy nhin, ch c t l nh C3b dnh c vo mng t bo v tr st vi phc hp enzym C4b2b to phc hp C4b2b3b c din tc dng nm trn mnh C3b. Cc phn t C3b bm vo mng t bo cc v tr xa C4b2b th ch c vai tr gip cho vic kt dnh min dch v lm d hin tng thc bo nh vo u kia gn ln th th dnh cho C3 cc thc bo (Hnh 6.3).

Hnh 6.3. C nh C5 C4b2b3b tch mnh C5a t chui a ca C5 ra. Mnh cn li l C5b sau gn vo mng t vo.

6.1.4. Tc ng ca C3b ln C5 Phc hp C4b2b3b m din tc dng l C3b ct phn t C5 thnh ra hai mnh. Mnh C5a l mnh nh cng c gii phng vo dch c th v c tc dng nh mt cht trung gian ha hc ca phn ng vim. Mnh C5b s c c nh ln mng t bo v bt u to phc hp tn cng mng.

6.2. Con ng hot ha khng c in (alternative pathway) Nm 1950, Pillemer nhn thy h thng b th c th c hot ha lm ly gii t bo m khng cn phi khi u bng phn ng khng nguyn khng th, l con ng hot ha khng c in. Con ng ny c cho rt l quan trng bi v: 1. Khng nht thit phi c phn ng khng nguyn khng th nn phn ng c th xy ra tc th, v c th c bo v theo c ch khng c hiu. 2. C con ng khuych i thng qua C3b nn cho php tng hiu qu ca h b th c trong p ng c hiu ln khng c hiu. Cc yu t tham gia trong con ng khng c in gm: - Yu t C3 trc y gi l yu t A, nhng sau khi s kho st cu trc v chc nng xc nhn chnh l C3. Nh vy, C3 c vai tr rt quan trng v n l ni gp g ca hai con ng hot ha b th. Yu t B l mt b - globulin. Yu t B khi cng vi C3b v s hin din ca ion Mg++ c kh nng hot ha mt phn C3. Tuy nhin, kh nng ny tng ln khi c yu t D phc hp C3bB thnh C3bBb. Phc hp C3bBb l mt enzym tc dng ln c cht l C3, v vy n to ra vng mt khuych i (amplifying loop) hay cn gi l vng phn hi dng. Ngoi ra, so snh vi con ng C3bBb s c gn thm C3b to phc hp C3bBb3b c tc dng ct C5 to phn t C5b c hot tnh enzym cn c cc bc tip theo ca chui phn ng b th. -Yu t D khi c s hin din ca C3b th n tc dng nh mt enzym ln yu t B cho ta phc hp C3bBb v mnh nh Ba b tch ra ngoi. -Yu t P hay properdin khng c cu trc ca globulin min dch. P c hp th cho phc hp C3bBb lm cho phc hp ny n nh, v ngi ta cn gi con ng khng c in l ng properdin. So snh hai con ng hot ha b th c trnh by Hnh 6.4.

6.3. S hnh thnh phc hp tn cng mng C5-9 Sau khi C5b hnh thnh n lp tc bm vo mng t bo. Trn c s cc phn t khc trong h b th l C6, C7 v C8 s n gn vo C5b to thnh phc hp C5-9. Sau , phc hp ny to phn ng trng hp (polymerize) cc phn t C9 to mt cu trc ng, l phc hp tn cng mng cm xuyn qua lp mng t bo (Hnh 6.5). Phc hp ny c th thy di knh hin vi in t.

Hnh 6.4. Hot ng ging nhau ca con ng c in v khng c in

Hnh 6.5. S hnh thnh phc hp tn cng mng C5-9 Sau khi C5b gn mng, C6 v C7 n gn vo C5b to C5b67. C5b67 tc ng vi C8 to C5b678. n v ny to phn ng trng hp phn t C9 to mt ng xuyn thng qua mng t bo. ng ny tn ti cng vi C5b678 v ngi ta gi l phc hp tn cng mng

CYTOKIN 7.1. i cng 7.1.1. c tnh chung ca cc cytokin Cytokin l cc polypeptid c sn xut khi c kch thch ca vi sinh vt hay cc khng nguyn khc nhm trung gian v iu ha cc phn ng min dch v vim (Hnh 7.1). Mc d cytokin c cu trc khc nhau nhng chng c nhiu tnh cht chung. - Cytokin c bi tit vi lng nh v t hn ch. - Cc phn ng ca cytokin thng a hng v trng lp (Hnh 7.2). - Cytokin ny thng nh hng n sinh tng hp v tc ng ca cytokin khc.

Hnh 7.1. Cc chc nng ca cytokin trong sc khng ca c th ch (A) Trong min dch bm sinh, cc cytokin c sn xut bi i thc bo v t bo NK v lm trung gian cho p ng vim chng li vi sinh vt. (B) Trong min dch thu c, cytokin kch thch s tng sinh v bit ha lymph bo tip xc khng nguyn v hot ha cc t bo hiu qu c bit, v d nh i thc bo. - Tc ng ca cytokin c th mang tnh cc b hoc h thng. - Cytokin bt u tc ng ca mnh nh gn vo th th c hiu ca mnh trn mng t bo ch. - Nhng tn hiu bn ngoi c th iu ha s bc l ca th th cytokin v th iu ha lun c p ng ca cytokin. - Tc ng ca a s cytokin trn t bo l to ra bin i biu hin gen, lm xut hin cc chc nng mi v i khi gy tng sinh t bo ch.

Hnh 7.2. Cc tnh cht ca cytokin y l cc v d v cc tnh cht ca cytokin: tnh tc ng a hng: mt cytokin c th cho tc dng ln nhiu t bo khc nhau, tnh tc ng trng lp: nhiu cytokin c th c cng tc dng trn mt loi t bo, tnh hip lc: hai hay nhiu cytokin to tc dng mnh hn mt loi, v tnh i khng: mt cytokin c th c ch tc ng ca mt cytokin khc. 7.1.2. Chc nng ca cytokin Cytokin c 3 chc nng chnh: 1. Lm cht trung gian v iu ha min dch bm sinh: y l cc cytokin c sn xut bi thc bo n nhn. Vic sn xut cc cytokin ny c kch thch bi cc sn phm ca vi khun nh lipopolysaccharid (LPS) hoc ca virus nh RNA chui kp v chng hot ng nh l mt b phn ca h min dch bm sinh. Cng c khi cc cytokin ny c sn xut do kch thch ca t bo T c hiu khng nguyn, lc ny chng hot ng vi t cch l mt b phn ca h min dch thu c. Tc ng ca nhm cytokin ny l trn t bo ni m v cc loi bch cu to ra phn ng vim sm. T bo NK cng sn xut mt s cytokin. 2. Lm cht trung gian v iu ha min dch thu c: y l cc cytokin c sn xut bi ch yu l t bo lymph T nhm chng li khng nguyn l. Mt s cytokin c tc dng ch yu l iu ha s trng thnh v bit ha ca cc qun th lymph bo khc nhau do chng ng vai tr quan trng trong giai on hot ha ca p ng ph thuc t bo T. Mt s cytokin khc c xut x t t bo T li quan trng trong giai on hiu qu v chng c chc nng iu ha cc loi t bo hiu qu nh thc bo, t bo trung tnh, i toan, ... 3. Lm cht kch thch to mu: cc cytokin ny do cc t bo m, bch cu v mt vi t bo khc ca ty xng sn xut. Chng c th kch thch s pht trin v bit ha ca bch cu non. Tm li, cc cytokin ca h min dch bm sinh v thu c thng do nhiu loi t bo khc nhau sn xut v tc ng ln nhiu lai t bo ch khc nhau. Tuy nhin, s phn bit ny khng c tnh tuyt i v mt cytokin c th c sn xut c trong p ng bm sinh ln thu c, v cc cytokin khc nhau c th to ra mt s tc dng ging nhau.

7.1.3. Th th v tn hiu cytokin Tt c cc th th cytokin u c mt hoc nhiu protein xuyn mng v phn nm bn ngoi t bo l phn gn vi phn t cytokin to ra lung tn hiu truyn vo bn trong t bo. Cc th th cytokin c phn loi da trn tnh tng ng v cu trc ca cc domain gn kt cytokin bn ngoi t bo. C 5 h th th cytokin (Hnh 7.3A). 1. Th th cytokin typ I: cn c gi l th th to mu, cha mt hoc nhiu bn sao ca mt domain c 2 cp phn t c nh cystein v mt trnh t cn mng tryptophan-serin-X-tryptophan-serin (WSXWS), trong X l mt acid amin bt k. Loi th th ny tip nhn cc cytokin c cu to cun thnh 4 chui xon a. Nhng th th ny c cc chui lin kt ligand c bit v mt hoc nhiu chui truyn tn hiu c cu trc ging nhau khi tip nhn cc cytokin khc nhau (Hnh 7.3B). 2. Th th cytokin typ II: loi ny cng ging typ I v c 2 domain ngoi bo mang phn t c nh cystein, nhng typ II khng c trnh t cn mng WSXWS. Th th loi ny c mt chui polypeptid lin kt ligand v mt chui truyn tn hiu. 3. Mt s th th cytokin c cc domain Ig ngoi bo v c xp vo siu h Ig. Nhm th th ny lin kt vi nhng cytokin khc nhau v truyn tn hiu theo nhng c ch khc nhau. 4. Th th TNF thuc v mt h th th (trong c nhiu th th khng phi ca cytokin) c mang cc domain ngoi bo cha nhiu phn t c nh cystein. Khi lin kt vi ligand, cc th th ny hot ha mt s protein ni bo to nn hin tng cht lp trnh (apoptosis) hoc kch thch biu hin gen, hoc c hai.

Hnh 7.3A v B. Cu trc ca cc th th cytokin A. Th th ca cytokin c xp thnh nhiu h da trn cu to c nh ngoi bo. B. Cc th th cytokin c cu to bi cc chui lin kt ligand c hiu cytokin (thng l chui a) lin kt khng ng ha tr vi cc tiu n v truyn tn hiu l cc cu to c th ging nhau. 5. Th th by vng xon xuyn mng hay cn gi l th th hnh rn bi v cc domain xuyn mng ca chng c hnh dng ging con rn chy qua chy v hai bn mng. Trong h min dch, th th loi ny lm trung gian cho cc phn ng nhanh v thong qua ca mt h cytokin c tn l chemokin 7.2. Cc cytokin trung gian v iu ha min dch bm sinh 7.2.1. TNF (tumor necrosis factor) TNF l cht trung gian chnh ca phn ng vim cp chng vi khun gram m v mt s vi sinh vt khc. TNF ng thi cng l cht chu trch nhim v nhiu bin chng ton thn ca nhim trng nng. TNF ln u tin c tm thy trong huyt thanh ng vt x l vi ni c t vi khun (LPS) v c tc dng gy ra s hoi t ca cc khi u trong c th khi hin din vi

lng ln. 7.2.1.1. Ngun gc, th th Ngun sn xut TNF ch yu l thc bo n nhn, tuy nhin mt s t bo khc nh lymph T, NK, dng bo cng c th tit ra cht ny. Kch thch mnh nht i vi i thc bo dn n sn xut TNF l LPS. Ngoi ra, mt lng ln cytokin ny cn c sn xut bi cc vi khun gram m. Cc interferon g do t bo T v NK sn xut cng c tc dng khuych i sinh tng hp TNF ca i thc bo c LPS kch thch. C 2 loi th th ca TNF, loi c trng lng phn t 55 kD c tn l THF-RI v loi c trng lng phn t 75 kD c tn l TNF-RII. Cc th th ny c mt trn hu ht cc loi t bo trong c th. 7.2.1.2. Hot tnh sinh hc - Chc nng sinh l chnh ca TNF l kch thch tp trung t bo trung tnh v t bo mono n ni nhim trng v hot ha nhng t bo ny tiu dit vi khun (Hnh 7.4). TNF lm bc l cc phn t kt dnh trn t bo ni m lm dnh li t bo bch cu, trung tnh v mn ti y. Hai phn t kt dnh quan trng y l selectin v ligand dnh cho integrin bch cu. TNF kch thch t bo ni m v i thc bo tit ra chemokin nhm tng cng i lc ca integrin bch cu i vi ligand ca chng v to nn s tp trung bch cu. TNF cn kch thch thc bo n nhn tit IL-1 l cht c tc dng rt ging TNF. Ngoi vai tr trong vim, TNF cn khi ng ci cht lp trnh i vi mt s t bo. - Trong nhim trng trm trng, TNF c sn xut vi lng ln v gy nn nhng triu chng lm sng ton thn cng vi cc tn thng gii phu bnh. Nu s kch thch sn xut TNF mnh th n c th gy ra sn xut tha TNF v lng ny s trn vo mu n gy ra cc tc ng xa v tr nhim trng nh mt hooc-mn vy. Cc tc ng ton thn ca TNF bao gm: + TNF tc ng ln vng di i gy ra st, do ngi ta gi n l cht gy st ni sinh ( phn bit vi LPS l cht gy st ngoi sinh). St

xy ra do TNF (v c IL-1) c thc hin qua trung gian ca sinh tng hp prostaglandin. Do vy, cc cht khng prostaglandin c th gim st do TNF v IL-1. + TNF tc ng ln t bo gan lm tng tng hp protein huyt thanh. Nhng protein huyt tng do gan sn xut di tc ng ca TNF, IL-1 v IL-6 to nn p ng pha cp ca phn ng vim. + S sn xut TNF ko di gy ra tiu hao t bo c v m v cui cng dn n suy kit. + Khi mt lng ln TNF c sn xut th kh nng co c tim v c trn thnh mch b c ch gy ra tt huyt p v i khi c sc.

Hnh 7-4. Cc hot tnh sinh hc ca TNF Vi nng thp, TNF tc ng ln bch cu v ni m khi ng phn ng vim. nng trung bnh, TNF lm trung gian cc tc ng ton thn ca phn ng vim. V vi nng cao, TNF gy ra cc bt thng bnh l ca sc nhim trng.

+ TNF gy ra huyt khi ni mch do t bo ni m mt tnh cht chng ng bnh thng. TNF kch thch t bo ni m bc l yu t m l mt cht hot ha ng mu mnh. Kh nng ca cht ny trong vic hoi t u nh tn gi ca n l kt qu ca huyt khi trong cc mch mu ca u. + Lng TNF ln lu thng trong mu cn c th gy ra ri lon chuyn ha, c th l h ng huyt do tng tiu th ng nhng gan khng b li c. C mt bin chng nng ca nhim trng gram m l sc nhim trng (cn gi l sc ni c t). Bnh cnh sc bao gm try tim mch, ng mu ni mch ri rc v ri lon chuyn ha. Hi chng ny chnh l do TNF v mt s cytokin khc nh IL-12, INF-g v IL-1 c sn xut ra nhiu di tc ng ca LPS vi khun. o nng TNF huyt thanh c th d bo c bnh cnh sc ny. Cc cht i khng TNF c th ngn nga t vong trong m hnh thc nghim nhng trn lm sng th khng, m l do c l ngoi TNF cc cytokin cng c tc ng nh TNF v mnh khng km. 7.2.2. Interleukin-1 (IL-1) Chc nng chnh ca IL-1, cng ging nh TNF, l lm trung gian cho p ng vim ca c th ch chng li nhim trng cng nh cc kch thch vim khc. IL-1 hot ng cng vi TNF trong h min dch bm sinh. 7.2.2.1. Ngun gc, th th Ngun sn xut ch yu ca IL-1, cng ging nh TNF, l thc bo n nhn hot ha. Nhng khc vi TNF, IL-1 cn c sn xut bi mt s t bo khc nh t bo trung tnh, t bo biu m, t bo ni m. C hai dng IL-1 gi l IL-1a v IL-1b, c hai u gn vo mt loi th th t bo v c hot tnh sinh hc nh nhau. C hai u c sn xut di dng mt tin cht 33 kD v mt mnh ct 17 kD. Dng hot ng ca IL-1b l mnh ct trong khi dng hot ng ca IL-1a l c tin cht ln mnh ct. a s IL-1 tm thy trong tun hon l IL-1b. C hai th th mng cho IL-1 c gi l th th typ I v th th typ II. C hai u thuc siu h Ig. Th th typ I c trn hu ht t bo cn th th typ II c thy ch yu trn t bo B, tuy nhin cng c th kch thch to ra trn mt s t bo khc. 7.2.2.2. Hot tnh sinh hc

Hot tnh sinh hc ca IL-1 cng ging nh ca TNF v ph thuc vo s lng c sn xut. Khi c tit vi nng thp, IL-1 tc ng nh mt cht trung gian ca phn ng vim ti ch. N tc ng ln t bo ni m tng bc l cc phn t b mt kt dnh bch cu nh ligand ca integrin. Khi c tit vi lng ln, IL-1 i vo mu v c tc dng nh ni tit t. Tc dng ton thn ca IL-1 ging vi TNF l gy st, kch thch gan sn xut cc protein huyt tng pha cp, v to ra s suy kit. S ging nhau v tc ng ca IL-1 v TNF rt ng ngc nhin. Tuy vy chng cng c nhng khc nhau nh: IL-1 khng trung gian qu trnh cht lp trnh (apoptosis) ca t bo ngay c khi c nng cao v bn thn n khng gy sc nhim trng. Thc bo n nhn c sn xut ra mt cht c ch t nhin i vi IL-1. Cht ny c chung th th vi IL-1 hot ng nh mt cht c ch tng tranh vi IL-1 do n c gi l cht i khng th th IL-1 (IL-1 receptor antagonist, IL-1ra). IL-1ra c th l mt cht iu ha ni sinh ca IL-1. 7.2.3. Chemokin Chemokin l mt h gm nhiu cytokin c kh nng kch thch bch cu di chuyn v iu ha s di chuyn ca chng t mu n cc m. T chemokin l vit tt ca chemotactic cytokin c ngha l cytokin ha hng ng. Mt s chemokin c th c sn xut bi nhiu loi t bo khc nhau i ph vi kch thch vim v thu ht bch cu n ch vim. Mt s chemokin khc c sn xut bi nhiu m khc nhau ngay c khi khng c vim v cng thu ht bch cu (ch yu l lymph) n m. 7.2.3.1. Cu to, ngun gc, th th Tt c cc chemokin u l nhng polypeptid c trng lng phn t 812 kD v cha 2 cu di-sulfua bn trong. Ngi ta xc nh c khong 50 chemokin v tng lai c th pht hin thm. Chemokin c chia thnh nhiu h da trn s lng phn t cystein c u tn cng N. Hai h ch yu l h chemokin CC c cc phn t cystein tn cng nm cnh nhau v h CXC c cc phn t cystein tn cng nm cch nhau bi mt acid amin. Khi c phn ng vim th chemokin CXC tc ng ch yu ln t bo trung tnh, cn CC th tc ng ln t bo mono, lymph v i toan. Chemokin cn c h

C tc ch c mt phn t cystein hoc h CX3C tc c 2 phn t Cystein cch nhau bi 3 acid amin. V ngun gc, cc chemokin lin quan n phn ng vim c sn xut bi t bo bch cu khi c cc kch thch n t bn ngoi. Cn cc chemokin iu ha s lu thng t bo qua cc m th c sn xut bi nhng t bo khc nhau trong cc m ny. Ngi ta xc nh c 11 loi th th dnh cho chemokin CC v c t tn t CCR1 n CCR11, 6 th th dnh cho CXC c t tn t CXC1 n CXC6 v y cha phi l ht. Th th ca chemokin c th hin trn t bo bch cu, c bit trn t bo T ngi ta thy c rt nhiu th th chemokin. Tt c th th chemokin c chung mt cu trc c trng l bao gm nhng domain c cu to 7 vng xon a xuyn mng. C mt s th th chemokin nh CCR5 v CXCR4 c tc ng nh nhng ng th th i vi HIV. Mt s lymph bo T hot ha c th tit ra nhng chemokin lin kt vi CCR5 v cnh tranh cng vi virus qua phong b nhim trng HIV. 7.2.3.2. Hot tnh sinh hc Chemokin c pht hin l nh vo chc nng ha hng ng ca chng nhng tht ra chng cn c nhiu chc nng quan trng khc trong h min dch cng nh cc h thng khc. - Chemokin tp trung cc loi t bo ca c th ch n v tr nhim trng. Chemokin hin din trn t bo ni m tc ng ln cc bch cu i qua lm cho cc integrin bch cu tng i lc kt gn vi ligand ca chng. iu ny rt quan trng gi bch cu li ni m ca mao mch vng tn thng. Ngoi ra, chemokin cn kch thch s di chuyn ca bch cu n ni c tn thng trn c s chnh nng ca chemokin ti ni tn thng v cc ni khc. Cc chemokin khc nhau kch thch cc t bo khc nhau nh th m kim sot c thnh phn ca cc t bo ti vim. V d, chemokin IL-8 huy ng ch yu t bo trung tnh, cn chemokin eotaxin tp trung t bo i toan. - Chemokin iu ha s lu thng ca t bo lymph v cc bch cu khc trong cc m lymph ngoi bin. y l mt pht hin mi trong min dch hc. Cc chemokin c kh nng thc y cc t bo hiu qu c hot ha v t bo T nh di chuyn n cc m khng phi thuc h lymph

bao gm c da v nim mc. S chn la nhng t bo khc nhau a n cc m khc nhau ph thuc vo s lng v th th trn t bo ca tng loi chemokin. 7.2.4. Interferon (IFN) typ I Interferon typ I l nhng cht lm trung gian p ng sm ca min dch bm sinh chng li cc nhim trng virus. 7.2.4.1. Cu to, ngun gc v th th IFN typ I gm c 2 nhm protein c tn l IFN-a v IFN-b. IFN-a l mt h gm c 20 polypeptid c cu trc lin quan vi nhau v mi polypeptid c m ha bi mt gen ring. IFN-a c sn xut ch yu bi cc thc bo n nhn v i khi cn c gi l interferon bch cu. IFN-b l mt protein c sn xut bi nhiu loi t bo nh nguyn bo si v v th m i khi n cn c gi l interferon nguyn bo si. Kch thch hiu qu nht i vi s tng hp interferon l nhim trng virus, nht l cc virus RNA chui kp do virus to ra trong qu trnh nhn ln ca chng trong t bo ch. Trong phng th nghim, vic sn xut IFN typ I c kch thch bi cc RNA chui kp nhn to c tn hiu rt ging vi nhim trng virus. T bo T c khng nguyn hot ha cng kch thch thc bo n nhn tng hp IFN typ I. Mc du IFN-a v IFN-b khc nhau v cu to nhng chng li gn vo cng mt th th v to ra p ng sinh hc ging nhau. 7.2.4.2. Hot tnh sinh hc Hot tnh ca IFN typ I l bo v c th chng li nhim trng virus v thc y p ng min dch t bo chng li cc vi sinh vt ni bo. (Hnh 7.5). - IFN typ I c ch s nhn ln ca virus. IFN kch thch t bo sn xut ra nhiu loi enzym nh 25synthetase oligoadenylate c tc dng ngn cn sao chp ca virus DNA hoc RNA v c ch s nhn ln ca chng. Tc dng chng virus ca IFN typ I va mang tnh t thn (autocrine) tc l c ch c s nhn ln ca virus trong bn thn mnh va c tc ng k cn (paracrine) ngha l c tc dng bo v cc t bo cha nhim bn cnh. - IFN typ I c tc dng gia tng s bc l ca phn t MHC lp I. T bo

T CD8+ c kh nng nhn din khng nguyn l lin kt vi MHC lp I, v IFN typ I thc y s nhn din i vi phc hp gm lp I v khng nguyn virus trn t bo nhim, qua t bo gy c d dng nhn ra t bo cha virus v tiu dit chng. - IFN typ I kch thch s pht trin ca t bo Th1 ngi. Hiu ng ny c c l nh IFN typ I thc y s bc l cc th th chc nng ca t bo T i vi cytokin khi ng Th1 l IL-12. IFN typ I cn c kh nng gia tng hot tnh ly gii t bo ca t bo NK.

Hnh 7.5. Hot tnh sinh hc ca interferon typ I IFN typ I (IFN-a v IFN-b) c sn xut bi cc t bo nhim virus v i thc bo. IFN typ I c ch nhim trng virus v thc y hot tnh CTL chng li t bo nhim virus. - Trong phng th nghim, IFN typ I c ch s tng sinh ca nhiu loi t bo, k c lymph. C ch c ch tng sinh ny ca IFN typ I vn cha c

r. Tm li, chc nng ch yu ca IFN typ I l c ch v loi b nhim trng virus. Trong lm sng ngi ta dng IFN-a nh mt thuc chng virus iu tr mt s th vim gan. Cn IFN-b th c dng iu tr a x ha (multiple sclerosis), nhng c ch tc ng th cha c r lm. Ngoi ra, trong p ng min dch bm sinh cn c mt s cytokin khc tham gia nh IL-10, IL-6, IL-5, IL-15, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL24 nhng c ch tc ng ca chng cha hon ton c sng t nn trong phm vi quyn sch ny chng ti cha c iu kin trnh by. 7.3. Cc cytokin trung gian v iu ha min dch thu c y l nhng cytokin lm trung gian cho s tng sinh v bit ha ca lymph bo sau khi nhn din khng nguyn trong giai on hot ha; ng thi chng cng trung gian cho s hot ha ca nhng t bo hiu qu c chuyn mn ha trong giai on hiu qu ca p ng min dch thu c. Vic sn xut cytokin l mt trong nhng p ng chnh ca t bo lymph T i vi khng nguyn. Nhiu loi vi sinh vt v khng nguyn khi tip xc vi c th th khi ng t bo T gip CD4+ chuyn chng thnh cc tiu qun th t bo hiu qu khc nhau l Th1 v Th2. Cc tiu qun th ny sn xut cc loi cytokin khc nhau v thc hin nhng chc nng khc nhau. Trong phn ny chng ti ch cp n 2 cytokin ch yu l IL-2 v interferon-g (IFN-g).

7.3.1. IL-2 IL-2 l mt yu t pht trin i vi lymph T v chu trch nhim pht trin cln t bo T sau khi nhn din khng nguyn.. V l do ny, IL-2 lc u c tn l yu t pht trin t bo T. IL-2 c sn xut ra ch yu tc ng ln chnh bn thn t bo . 7.3.1.1. Ngun gc, cu trc, th th IL-2 c sn xut phn ln bi t bo T CD4+ v mt t bi t bo T CD8+. S hot ha t bo T bi khng nguyn v cc ng kch thch s to ra s sao chp gen IL-2 cng nh tng hp v tit cytokin ny. IL-2 c sn xut trong thi gian ngn vi s lng t sau 6-8 gi c hot ha.

IL-2 c tit ra l mt glycoprotein c trng lng 14-17 kD, cun thnh mt cu trc c 4 vng xon a. S bc l th th chc nng ca IL-2 c thc y bi kch thch khng nguyn, do t bo T no nhn din khng nguyn th s tng sinh u tin khi p ng vi IL-2 c sn xut trong p ng min dch thu c. Th th IL-2 (IL-2R) cu to bi 3 protein khng ng ha tr c tn l a, b, v g. Cc chui a v b tham gia vo lin kt vi cytokin; cc chui b v g th tham gia vo dn truyn tn hiu; cn bn thn IL-2 gn vi chui a n thun c i lc rt thp v khng dn n hiu qu sinh hc no r rng. 7.3.1.2. Hot tnh sinh hc Mc d lc u ngi ta pht hin ra IL-2 nh l mt yu t pht trin t bo T, nhng tht ra IL-2 c nhiu chc nng trong p ng min dch thu c (Hnh 7.6). - IL-2 do t bo T tit ra khi nhn din khng nguyn chu trch nhim v vic tng sinh t bo c hiu khng nguyn. Khi tip xc vi IL-2, t bo T cho thy c tng vt nng cc cyclin dn n hot ha nhiu loi kinase. Cc kinase ny phosphoryl ha v hot ha nhiu protein ca t bo cc protein ny kch thch t bo chuyn t dng G1 sang dng S ca chu k phn bo. Ngoi ra, IL-2 cn lm gim p27 l cht c ch i vi hot ng ca cc phc hp cyclin-kinase do thc y qu trnh tng hp cyclin. IL-2 lm tng thi gian sng ca t bo bng cch khi ng protein Bcl-2 l cht chng kiu cht t bo t nhin (apoptosis). Tc dng ca IL-2 ch yu l ln chnh t bo tit ra n, nhng cng c phn no tc ng vo cc t bo bn cnh.

Hnh 7.6. Hot tnh sinh hc ca IL-2 IL-2 kch thch s tng sinh v bit ha ca lymph bo T v B v t bo NK. IL-2 cng c chc nng c ch p ng min dch (v d chng li t khng nguyn) bng cch to ra hin tng cht lp trnh ca t bo T qua trung gian ca Fas v kch thch hot tnh ca t bo T iu ha.

- IL-2 tng cng s tng sinh v bit ha t bo. N kch thch s pht trin ca t bo NK v to ra ci gi l git t bo do lymph bo hot ha (Lymphokine-activated killer, LAK). IL-2 tc ng ln t bo B trn c hai kha cnh: kch thch pht trin v tng tng hp khng th. - IL-2 to ra ci cht lp trnh ca t bo T c khng nguyn hot ha. S kch thch lp i lp li ca t bo T CD4+ vi s hin din ca IL-2 lm cho cc t bo ny nhy cm vi ci cht lp trnh qua con ng Fas. iu th v l mt cytokin c th va kch thch t bo T sng v tng sinh nhng ng thi cng gy ra ci cht cho t bo. Hnh nh nu mt p ng min dch c xu hng tn ti lu di v t bo T tip xc vi lng IL-2 ngy cng tng th c kh nng cht theo kiu lp trnh v dn n chm dt p ng ny. IL-2 cn c th kch thch pht trin t bo T iu ha lm dng p ng.

7.3.2. Interferon-g (IFN-g) IFN-g l cytokin chnh hot ha i thc bo v ng vai tr rt quan trng trong min dch bm sinh cng nh min dch thu c. IFN-g cn c gi l IFN min dch hay IFN typ II. N cng c phn no chc nng chng virus nhng ch yu l mt cytokin hiu qu ca p ng min dch. 7.3.2.1. Cu trc, ngun gc, th th IFN-g l mt protein dimer do t bo NK, t bo Th1 CD4+ v CD8+ sn xut. N l cytokin c trng ca Th1. T bo NK sn xut IFN-g khi c kch thch ca mt thnh phn vi sinh vt no hoc IL-2, trong trng hp ny IFN-g tc ng nh mt cht trung gian ca p ng min dch bm sinh. Trong p ng min dch thu c, t bo T sn xut IFN-g trong khi nhn din khng nguyn v iu ny c thc y bi IL-2 v IL-18. Th th ca IFN-g bao gm hai chui polypeptid thuc h th th cytokin typ II. Trong hai chui ny th mt chui c chc nng gn vi cytokin v chui kia th truyn tn hiu. 7.3.2.2. Hot tnh sinh hc Chc nng ca IFN - g rt quan trng trong min dch t bo chng li vi khun ni bo (Hnh 7.7). - IFN-g l cytokin hot ha i thc bo, n gip t bo T v NK hot ha i thc bo git cc vi sinh vt c thc bo. IFN-g thc hin iu ny nh kch thch s tng hp cc cht trung gian oxy phn ng v oxid nitric. - IFN-g kch thch s bc l ca MHC lp I v lp II v cc cht ng kch thch trn t bo trnh din khng nguyn. IFN - g cng kch thch s sn xut ca nhiu protein tham gia vo qu trnh x l khng nguyn nh cht vn chuyn (TAP), v hai thnh phn LMP - 2, LMP - 7 ca proteasom v HLA - DM. Nh vy IFN - g thc y s trnh din khng nguyn phi hp vi MHC v khuych i s nhn din trong p ng min dch. IFN-g cng l cht hot ha t bo ni mc thnh mch v tng cng kh nng tc ng ca TNF trn t bo ni mch, to ra kt dnh t bo lymph vo thnh mch v xuyn mch i n v tr nhim trng.

- IFN-g kch thch s bit ha ca t bo T CD4+ cn nguyn vn thnh tiu nhm Th1 v c ch s tng sinh ca t bo Th2. Tc ng ca IFN-g ln Th1 mt phn c trung gian bi IL-12. Ngoi ra, IFN-g kch thch s sn xut yu t sao chp to ra bit ha Th1. - IFN-g tc ng ln t bo B chuyn mch cc tiu lp IgG, nht l IgG2 chut nht v c ch chuyn mch sang cc isotyp ph thuc IL-4 nh IgE v IgG1 chut. Nh vy, IFN-g cng to ra p ng khng th v tham gia vo qu trnh loi b vi sinh vt qua trung gian qu trnh thc bo. - IFN-g hot ha t bo trung tnh v kch thch hot tnh t bo NK.

Hnh 7.7: Hot tnh sinh hc ca interferon-g IFN-g hot ha i thc bo v t bo trnh din khng nguyn v khi ng s chuyn mch mt s isotyp Ig trn t bo B. Tc ng khi ng Th1 ca IFN-g c th gin tip qua trung gian ca s tng sn xut IL-2 v bc l th th ca n. 7.4. Cytokin kch thch to mu

p ng min dch bm sinh v thu c to ra nhiu cytokin tham gia vo qu trnh to mu tc l tham gia to ngun t bo cho p ng min dch. Tuy nhin, trong phm vi ca quyn sch ny chng ti khng cp chi tit m ch trnh by trn s di y c gi tham kho (Hnh 7.8).

Hnh 7.8. Vai tr ca cytokin trong to mu Cc cytokin khc nhau kch thch s pht trin v trng thnh ca nhiu dng t bo mu khc nhau.

MIN DCH CHNG VI SINH VT Nhim trng l nguyn nhn gy ch yu gy bnh tt v t vong trn khp th gii. Ch ring chu Phi, T chc Y t Th gii c tnh c khong 100 triu ngi mc st rt. Bnh nhim trng cng thu ht s ch ca nhiu ngi bi cc l do: (1) s xut hin nhim trng c th gi l mi nh bnh Legionaires v AIDS; (2) thc t lm sng lm bin i m hnh nhim trng bnh vin; (3) ngy cng gia tng s bnh nhn b suy yu min dch dn n nguy c tng cc loi nhim trng c hi; (4) c quan nim cho rng mt s bnh xy ra l do p ng ca c th i vi vi sinh vt t gy tn thng cho mnh mt cch khng c hiu; v (5) ngy cng gia tng cc loi bnh nhp cng do tng giao lu quc t theo ng hng khng. i vi nhim trng, mt cn bng c duy tr gia sc chng ca c th v kh nng ca vi sinh vt c gng vt qua sc chng . S nghing lch ca cn bng ny to ra trm trng ca bnh cnh (Bng 8.1).

1. CC YU T LIN QUAN N VI SINH VT S lng (tc mc tip xc) ng lc vi sinh vt ng vo 2. CC YU T CA C TH CH Tnh nguyn vn ca min dch khng c hiu Kh nng h thng min dch Kh nng di truyn v p ng bnh thng i vi tng vi sinh vt tng tip xc trc hay cha

Bng 8.1. Cc yu t nh hng n phm vi v trm trng ca nhim trng

Trong phm vi ti liu ny, chng ta khng bn lun k v c lc, cho nn nhim trng xy ra hay khng s ph thuc vo p ng min dch c t ra y hoc thch hp hay khng. 8.1. Min dch chng virus 8.1.1. Virus v p ng min dch Virus c nhng tnh cht c o ring: (1) chng c th xm nhp vo m m khng gy ra mt p ng vim; (2) chng c th nhn ln trong t bo trong sut i sng c th ch m khng gy ra tn thng t bo; (3) i khi chng cn tr mt s chc nng c bit ca t bo m khng gy biu hin ra ngoi; v (4) cng c khi virus gy tn thng m hoc cn tr s pht trin t bo v ri bin mt hon ton khi c th. Gn y, ngi ta pht hin c rng mt s bnh trc y khng r nguyn nhn nh vim no x ha bn cp, bnh no cht trng a tiu im tin trin (progressive multifocal leukoencephalopathy) bnh Creuzfeld - Jacob, bnh Curu li l nhng bnh c lin quan n virus hoc nhng vt th ging virus. Biu hin lm sng ca bnh virus rt a dng v mt s v d c trnh by Bng 8.2. Nhm virus herpes bao gm t nht 60 virus, trong c 5 con rt hay gy bnh cho ngi: Herpes simplex (HSV) typ 1, HSV typ 2, Varicella zoster (VZV), cytomegalovirus (CMV) v Epstein-Barr (EBV). C hnh nh bnh l chung cho tt c cc virus nhm herpes ngi, l: Mt, truyn c ngi ny sang ngi khc phi c s tip xc gn gi trc tip, tr vic truyn mu v ghp c quan l ng truyn hiu qu nht ca CMV. Hai, sau ln nhim u tin virus herpes s tn ti trong c th sut i. hn ch s lan ta ca virus v phng nga ti nhim h thng min dch phi c kh nng chn ng s xm nhp ca cc ht virion v t bo cng nh loi b cc t bo b nhim gim ni c tr ca virus. Nh vy, cc phn ng min dch c hai loi: Mt loi tc ng ln cc ht virus v mt loi tc ng ln t bo nhim. Mt cch tng qut, p ng min dch chng virion c xu hng tri v th dch cn p ng t bo th tc dng ln t bo nhim virus. C ch th dch ch yu l trung ha, nhng phn ng thc bo ph thuc b th v phn ng ly gii ph thuc b th cng c th xy ra.

Trung ha virus ngn cn s tip cn ca chng n cc t bo ch. y l chc nng ca khng th IgG trong dch ngoi bo v ca IgA trn b mt nim mc. Chng ta cn nh rng, ch nhng khng th chng li cc thnh phn chu trch nhim v kh nng tip cn mi c tnh trung ha: S to ra khng th c c hiu chnh xc l nguyn tc c bn sn xut vacxin virus. Nhng khng th chng li nhng khng nguyn khng cn thit khng ch khng c tc dng bo v m cn to iu kin hnh thnh phc hp min dch. Mt d ch cn khng th IgG l trung ha hu ht virus, nhng s hot ha b th t ra cng rt c ch trong vic lm tng cng kh nng loi tr virus. S ly gii virus cng c th thc hin ch nh vo b th m khng cn c khng th. Mt s virus nh EBVc th gn vi C1v hot ha b th theo ng c in cui cng l ht virion b ly gii. Min dch qua trung gian t bo lin quan t bo b nhim virus hn l virus t do. Lymph T nhn din virus trong s phi hp vi cc glycoprotein ca phc h ha hp m ch yu (MHC). T bo T gy c s ly gii t bo b virus t nhp hoc lm thay i khng nguyn b mt. Nh vy, min dch t bo (t bo T) chu trch nhim trong qu trnh hi phc sau nhim virus, ch khng phi trong giai on cp tnh ca bnh. Bng 8.2. Hnh nh lm sng ca nhim virus herpes

Loi virus Herpes simplex typ 1

Biu hin lm Cht ly Ni tim sng truyn n Vim ming -li Cht tit ming Hch dy cp ng h V hp Herpes simplex Tip xc da Vim gic-kt mc Vim no Nhim trng lan ta Tn thng khu tr da

Herpes simplex typ 2

Herpes sinh dc Vim mng no Nhim trng lan ta Tn thng khu tr da

Dng sinh dc Qua bo thai

Hch cng

Varicella zoster

(Ung th c t cung ) Thy u Cht tit ming Hch r ng h ngc Thy u tin trin hp Thy u bm sinh Herpes zoster Herpes zoster lan ta Nhim CMV bm sinh Vim gan Vim phi Vim vng mc n nhn nhim CMV n nhn nhim khun U lympho Burkitt Ung th vm Tip xc da Bm sinh

Cytomegalovirus (CMV)

Bm sinh Qua bo thai Ming h hp

Bch cu T bo biu

m tuyn mang tai, Sinh dc c t cung, ng Khng r, c thn th do truyn mu, ghp Cht tit ming Lympho B ng h T bo hp biu m vm hu

EpsteinBarr (EBV)

a s nhim trng virus u t gii hn. Trn mt s ngi, virus c th to ra triu chng lm sng trong lc trn mt s ngi khc th bnh khng bao gi vt qu giai on tin lm sng. S hi phc sau nhim trng virus cp thng li tnh min dch lu di v t khi c th b tn cng ln hai bi cng loi virus .

8.1.2. Tc ng trc tip ca virus Hng tnh ca virus (viral tropism) l mt yu t c bn xc nh tm quan trng lm sng ca nhim trng virus, l mt nhim trng ph thuc khng nhng vo s lng t bo b ph hy cn ph thuc vo chc nng ca nhng t bo . S ph hy mt s lng nh t bo co chc nng bit ha cao nh dn truyn thn kinh hoc iu ha min dch cng c th gy nguy him cho tnh mng bnh nhn. Ngc li, s ph hy mt lng ln nhng t bo t bit ha nh t bo biu m chng hn nhng hu qu li t trm trng hn nhiu. Cng ngy ngi ta cng hiu bit nhiu hn v cc th th virus v tng tc gia th th ny vi virus. Virus Epsptein-Barr dng th th ca C3b (tc CR2), cn HIV th li dng th th CD4 lm ni xm nhp vao t bo ch trong h thng min dch . Mt khi vao trong t bo, virus c th git t bo bng nhiu cch. Mt s virus nh polyovirus, adenovirus v cc sn phm ca chng c th c ch cc enzym cn thit cho s nhn ln hoc chuyn ha t bo. Mt s virus khc c th ph hy cu trc ni bo nh tiu th chng hn lm gii phng ra cc enzym c hi lm cht t bo. Trong mt s trng hp, protein ca virus gn vi mng t bo lm thay i tnh cht ca n: V d nh virus si c hot tnh gy ha mng lm cho cc t bo kt hp vi nhau thnh nhng hp bo (syncytia) . Mt s virus c th lm thay i chc nng chuyn ha ca t bo m khng git cht chng. Nhng t bo ny thng l t bo ca h min dch, thn kinh trung ng hoc h ni tit. V d cc virus si, cm, CMV thng nhim vo t bo lympho ngi v bin i chc nng ca chng. Trong sut thi k nhim trng, cc virus bin tng c sinh sn mt cch chn lc trong lch v c th c ch s hnh thnh cc t bo T gy c. Hu qu l virus khng b loi b khi c th m sng sut i vi k ch.

8.1.3. Ln trnh ca virus (c ch tn ti ca virus trong c th) Virus thng to ra nhiu c ch khc nhau ln trnh hoc ngn cn tc ng ca h min dch. Thay i tnh khng nguyn l cch thy r nht i vi virus cm A, mt loi virus RNA c b bi mt v lipid c gn vi hai loi protein: hemagglutinin v neuraminidase. a s khng th trung ha tc ng ln hai quyt nh khng nguyn ny. Virus c th ln trnh tc ng ca khng th bng cch thay i cu trc ca hemagglutinin: Thay i dn tnh khng nguyn (antigenic drift) hoc t bin tnh khng nguyn (antigenic shift). Thay i dn tnh khng nguyn l s thay i tng phn nh cu trc khng nguyn khi virus truyn t cc th ny sang c th khc bng cch gy t bin im trn b mt khng nguyn ca hemagglutinin. Thay i ny c l chu trch nhim v cc dch cm nh vo ma ng. Thay i tnh khng nguyn l s thay i t ngt ton b cu trc ca hemagglutinin. Ngi ta quan st thy 3 ln thay i khng nguyn kiu ny vo v i dch cm nm 1918, dch cm chu nm 1957, v dch cm Hng Kng nm 1968. Nu p ng min dch khng loi tr c hon ton virus th s xut hin mt tnh trng nhim trng nh vi s tn ti dai dng ca mt s virus trong c th. V d, vim gan B c th tn ti nhiu thng hoc nhiu nm v gan lin tc mang virus. Ngoi ra, virus cng c th to ra tnh trng tim tng nu genom virus tn ti mi trong t bo ch m khng th hin tnh khng nguyn virus. Tt c cc virus herpes ngi u c th tn ti tim n, thnh thong c nhng t hot ng v nhn ln. Khi s cn bng gia virus v c th ch b ph v do nhim trng, ri lon chuyn ha, tui gi , hoc c ch min dch th virus c hot ha v sau c th gy ra bnh. Thng thng mi virus c ni tim n ring ca n (Bng 8.2): V d virus herpes simplex tim n hch dy V, Varicella zoster tim n hch r thn kinh ngc .

S chuyn dng t bo ch c th xy ra do tc ng ca mt s virus c kh nng gy bnh ung th (Bng 8.3). Hu ht cc virus loi ny tn ti tim n, v d, HTLV-I gy bnh bch cu t bo T ngi ln, virus vim gan B gy bnh ung th t bo gan v EBV c th gy ung th vm hng hoc u lymph Burkitt. Bng 8.3. Virus v cc bnh c tnh lin quan

BNH

VIRUS

TNH Mt s bnh bch cu t Virus bnh bch cu t bo T bo T ngi Ung th c t cung Herpes simplex Papilomavirus ngi U lymph Burkitt Ung th vm Ung th da Ung th t bo gan Virus Epstein-Barr Virus Epstein-Barr Papilomavirus Virus vim gan B

Mt s virus c th ngn cn p ng min dch bng cch c ch hoc nhim vo t bo min dch (Bng 8.4). V d, nhim trng CMV tin pht gy bnh in hnh ngi tr. p ng to khng th xy ra nhanh, c th thy c, nhng p ng min dch t bo th li b c ch: Trong nhiu thng c th khng thy c p ng t bo T c hiu vi CMV. Ngoi ra, trn thc nghim ngi ta cn thy rng min dch t bo i vi cc ln th thch khng nguyn trc khng xut hin, c khi n c nm tri. Trong thi gian ny, bnh nhn c th b nhim trng vi khun lp i lp li nhiu ln. Hiu qu gy c ch min dch ny cng thy ngay c nhng ngi c c ch min dch t trc, v d nh

ngi nhn mnh ghp chng hn. Virus si c kh nng nhn ln trong t bo T dn n kt qu l gy gim min dch t bo. Trc y, khi cha iu tr c bnh lao, bnh nhn mc bnh si cp d dng dn n mc lao k. V d in hnh nht cho hin tng ny l hi chng suy gim min dch mc phi (AIDS) do HIV gy ra. Virus ny chn lc t bo lymph T CD4+ tiu dit. Trnh trng c ch min dch sau dn n s xut hin ca cc nhim trng c hi lan ta v trm trng hoc cc bnh cnh ung th c bit cho bnh ny.

8.1.4. Tn thng do p ng min dch chng virus Mc d phn ng min dch ni chung l c li. Thnh thong chng cng gy ra tn thng m kh phn bit vi tn thng do chnh virus gy ra. Bng 8.4. Mt s hu qu sau nhim virus ca t bo h min dch

T BO VIRUS Lymph B Epstein- Barr Lymph T Si HTLV- I HIV i thc bo Lassa Dengue

HU QU Chuyn dng v hot ha t bo B a cln Nhn ln trong t bo T hot ha U lymph hoc bnh hch cu t bo T AIDS St

MarburgEbola

Rubella (ban o) Bi nhim sut thi k tin triu

Trong thi k hi phc sau nhim trng virus (v d n nhn nhim khun hoc vim gan B), trn mt s bnh nhn ngi ta thy xut hin cc t khng th lu ng do t bo B vn cn kh nng p ng vi khng nguyn bn thn khi chng c trnh din mt cch thch hp cho t bo T. Dung np min dch bnh thng i vi khng nguyn t thn do t bo T c ch m trch l ch yu, nhim trng virus ph v s dung np ny bng hai cch:(1) nhng virus nh EBV l nhng tc nhn hot ha t bo B a cln, v (2) virus c th gn ln khng nguyn bn thn lm cho chng tr thnh khng nguyn mi. Khng th i vi nhng khng nguyn mi ny s tc ng ln c cc m t thn bnh thng ln cc t bo nhim virus. S tn ti lu di ca nhim trng virus c th dn n bnh t min trn mt c th thch hp. Mt s v d hnh thnh bnh gan t min mn tnh trn mt s bnh nhn b vim gan siu vi B. Mt s virus li c kh nng kch thch to nhng khng th khng thch hp lm tng thm tn thng m virus gy cho c th ch. V d, virus Dengue c th nhim vo i thc bo qua ng th th Fc, v kh nng ca n xm nhp vo t bo ch s c tng cng nu n gn vi khng th IgG. Nh vy, nhim trng ln th hai bi mt tp huyt thanh khc s c lm d bi khng th do tp huyt thanh trc to ra. S tn cng ca khng th vo nhng t bo nhim virus c th gy ra hiu qu bt li. Khng th khng virus hoc phc hp min dch to nn do virus v khng th c th ngn cn khng cho t bo lympho nhn din hoc phn ng vi khng nguyn virus, do c ch p ng min dch t bo; l trng hp ca vim no x ha bn cp. Trong trng hp ny hnh nh bnh l cho thy c s mt myelin thay th bng x ha lin tc dn n cc ri lon thn kinh trm trng. Khong mt na trong s bnh nhn ny tng b mc si vo hai nm tui u tin. Trong khi trong nhn dn th t l ngi mc si chim t l cao nht vo la tui t 5 n 9. S tip xc vi virus si vo thi im sm ca i sng c l gip cho virus d dng tn ti trong no di dng virus hon chnh. Bi v c th sn xut mt lng khng th khng si tng i cao, phc hp min dch to bi virus v khng th c ch phn ng min dch t bo. Ngi ta cho rng nhiu bnh vim mn tnh ngi nh vim cu thn mn c lin quan n s lng ng ca phc hp min dch bi v chng rt ging vi cc m hnh virus thc nghim. Tuy vy, trong a s cc trng

hp, virus bnh nguyn tng i kh xc nh. Mt v d kinh in cho cc tn thng gy ra do t bo l vim mng no - mng mch lymph chut. Chut c cho nhim virus trong thi k s sinh, virus nhn ln nhanh chng trong nhiu m, k c thn kinh trung ng. Tuy nhin, iu ny khng gy bnh nng. Ngc li, nu tim virus vo no ca chut trng thnh th c th gy ra vim no-mng no nng dn n t vong; tn thng no y c th hn ch bng cch lm ri lon min dch t bo v ng thi c th duy tr tr li tn thng sau bng cch tim cho con vt t bo T mn cm t con vt khc. Cc lympho T gy c t con vt mn cm nguyn virus trn b mt. Nh vy, chng ta hon ton c l do nghi ng rng c ch min dch t bo c vai tr trong vic gy vim no trong nhiu bnh cnh nhim trng virus ngi. Min dch t bo c l cn chu nhiu trch nhim trong vic gy ra cc loi ban c trng thng gp trong nhim trng virus tr con, nh trong si chng hn. Cc tiu im nh virus da c th kch thch to mt phn ng qu mn mun nhm ngn chn s lan ta v nhn ln ca virus. Tr suy gim min dch t bo rt d b nhim trng virus lan ta nh si, herpes simplex, varicella zoster, nhng khng bao gi b ni ban c trng da.

8.2. Min dch chng vi khun 8.2.1. p ng min dch bnh thng i vi vi khun C hai loi khng nguyn vi khun ch yu c th gy p ng min dch: Cc sn phm ha tan ca t bo (v d c t) v cc khng nguyn cu trc tc l mt b phn ca vch t bo (nh cc lipopolysaccharide). Nhiu khng nguyn vi khun c cha lipid gn vi glycoprotein vch; s hin din ca lipid hnh nh c tc dng tng cng tnh sinh min dch ca khng nguyn. a s khng nguyn vi khun l khng nguyn ph thuc t bo T, tc i hi lymph T gip khi ng min dch, dch th cng nh t bo. Tuy nhin, c mt s khng nguyn vi khun nh polysaccharide ca ph cu khng ph thuc t bo T: nhng khng nguyn ny c c trng bi trng lng phn t cao v c nhng quyt nh khng nguyn ging ht nhau lp i lp li nhiu ln trn chui phn t. Trong phn tip y chng ti dng vi khun lin cu lm v d nhng cn nh rng cc vi khun khc cng cho kch thch min dch tng t.

Tng tc gia vi khun v h min dch c th to ra nhiu hu qu: (1) kch thch tnh min dch bo v; (2) c ch min dch; v (3) p ng min dch bt li c th gy ra cc tn thng m. Mt s yu t c nhn c nh hng n tnh min dch c cp Bng 1 phn trn. Lin cu beta tan mu (nht l nhm A) rt thng hay gy ra nhng nhim trng khu tr da v ng h hp trn, nhng n c th gy nhim trng bt c c quan no ca c th. Ngi ta ghi nhn rng nhng la tui khc nhau thng b triu chng rt khc nhau khi nhim lin cu. tr con, khi bnh thng nh v m h vi cc triu chng nh st nh, chy mi nc. Triu chng hng thng ti thiu nhng nhng cn st bt thng vn c th tn ti trong mt vi thng. Hnh nh ny ngc vi bnh cnh vim amidan cp do lin cu tr ln v ngi ln. Bnh cnh cp tnh v khu tr ny c l do s tip xc trc y vi lin cu lm bin i p ng (trong c th c khng th khng c t v enzym lin cu). Tn thng m l do cc sn phm ca lin cu gy ra. Cc sn phm ny gm c t c hiu (streptolysin O v S v c t hng cu) c kh nng tiu m v cc t bo lu ng (k c bch cu), cc enzyme c hiu (nh hyaluronidase v streptokinase) c kh nng gip cho s lan ta nhim trng, v cc thnh phn b mt ca vch bo lin cu (protein M v acid hyluronic). Tt c cc protein ny u c tnh sinh min dch. Phn ng vim ti ch lm tng s lng t bo bch cu nhn a dng trong mu, ng thi cc t bo ny cng thm nhim vng hng hu gy ra nhng bc m ti ch. Khng th c hiu xut hin chm (4 ngy) v hnh nh khng c vai tr trong vic hn ch phn ng nhim trng lin cu cp ln u tin. Antistreptolysin O (ASO) v anti-deoxyribonuclease B (anti-DNAse B) l hai th nghim lin cu c gi tr nht trn thc t lm sng. Hiu gi ASO thng tng ln sau nhim trng hng, khng tng sau nhim trng da; hiu gi anti-DNAse B l mt xt nghim ng tin cy cho c nhim trng da v hng, do c ch cho chn on vim cu thn sau nhim lin cu. Mt s khng nguyn vi khun nh hng trc tip ln hiu qu ca p ng min dch i vi nhim trng. Lipopolysacharid vi khun c th lm tng hoc lm gim sc khng i vi nhim trng thc nghim ty theo thi gian nhim trng. Nu c gim khng th c th ch s tr nn d nhim

trng i vi vi khun khc. S sut hin cng lc ca lao v nhim nm aspergillus phi, hoc s hot ng ca lao tim n sau khi nhim ph cu l nhng v d v s c ch khng ca vi khun. Mt s sn phm vi khun nh ni c t l cht kch thch rt mnh i vi p ng min dch dn n s hot ha lympho B a cln. S gia tng ca Ig huyt thanh trong mt s trng hp nhim trng ko di c l l do s kch thch a cln ny, cn s gia tng khng th c hiu ch chim mt t l nh Ig huyt thanh m thi. Thng chng ta kh phn bit c hiu qu gy c trc tip do nhim khun vi tn thng gy ra do phn ng min dch chng khng nguyn vi khun. iu ny c minh ha bi cc bin chng ca nhim trng lin cu (Hnh 8.1).

8.2.2. Tn thng do p ng min dch chng vi khun Thp khp cp l mt bnh h thng xy ra sau khi b nhim lin cu beta tan mau ng h hp trn t 1 n 5 tun. Nhim lin cu da cng c th gy thp khp cp. Ngi ta nhn thy rng hnh nh khuynh hng di truyn i vi thp khp cp, bng chng l t l mc bnh ny nhng tr c cha m b bnh tim do thp th cao hn so vi nhng tr khc. ng thi tr sinh i ng hp t th t l mc cng cao gp ba ln so vi tr sinh i d hp t. Bnh sinh ca thp khp cp c nghin cu kh k. Nguyn nhn gy tn thng m c l do cc thnh phn hoc sn phm ca lin cu hn do nhim trng trc tip. Tuy nhin, chng ta cn lu n vai tr quan trng

ca phn ng min dch chng lin cu trong c ch gy bnh. Nhng tr b bnh thp khp cp c mang mt nng cao khng th chng khng nguyn tim. iu ny ni ln rng vim tim do thp c th gy ra do khng th khng lin cu phn ng cho vi khng nguyn tim. Ngi ta xc nh l thp khp cp khng tc dng ln c tim m ln van tim, ln khp, mch mu, da v c h thn kinh trung ng (trong trng hp c biu hi n ma vn). a s cc tn thng gy nn u qua trung gian ca khng th v ngi ta chng minh c phn ng cho c th xy ra gia: (1) khng th chng cacbonhydrat ca lin cu nhm A vi glycoprotein ca van tim; (2) khng th chng protein vch lin cu vi mng si c tim v c vn; (3) khng th chng mt thnh phn khc ca vch t bo lin cu vi no ngi; (4) khng th chng mt glycoprotein ca vch lin cu vi mng y cu thn; v (5) khng th chng hyaluronidase lin cu vi mng khp ngi. Ngoi ra, p ng min dch qua trung gian t bo i vi cc khng nguyn phn ng cho c l cng c vai tr trong vic gy mt s bin chng v trn bnh nhn thp khp cp ngi ta thy p ng min dch t bo cng tng d di. Quan h gia nhim trng lin cu vi vim cu thn cp khc vi nhim lin cu trong thp khp cp hai im quan trng: (1) vim cu thn dng nh ch xy ra sau nhim mt trong vi chng lin cu c bit gi l chng gy vim thn (nephritogenic), trong khi , thp khp cp li lin quan vi rt nhiu chng lin cu nhm A; v (2) nhiu bng chng cho thy rng vim cu thn c gy nn do s lng ng phc hp min dch ch khng phi do phn ng cho ca khng th. Nhiu nhim trng khc do vi khun v mycoplasma cng c th to ra mt p ng min dch t gy hi cho bn thn mnh (Bng 8.5). Bng 8.5. Mt vi bnh gy ra do p ng min dch chng vi khun

Khng nguyn phn ng cho (Qu mn tup II) Tim v lin cu nhm A Vim tim do thp No v lin cu nhm A => =>

Ma vn Sydenham Phi hp ca khng nguyn vi khun vi t khng nguyn (Qu mn tup II) Khng nguyn mycoplasma v hng cu =>Thiu mu huyt tn t min Hnh thnh phc hp min (Qu mu tup II) Vim ni tm mc min khun bn cp Shunt nh- tht nhim khun vim mch Giang mai th pht vim khp Nhim khun huyt lu cu vim cu thn Nhim khun huyt mng no cu Phn ng qu mn mun (Qu mn tup IV) Lao s ha phi Phong kinh ngoi bin => To hang v =>Bnh l thn => => =>

8.2.3. S ln trnh h min dch ca vi khun Vi khun s tn ti trong c th ch yu nu ng min dch ch git c mt lng vi khun t hn lng chng sinh sn c. chng vi sc khng min dch, vi khun to ra nhiu c ch: To yu t gy c, cc yu t ny c kh nng dnh vo b mt nim mc, i vo cc m, c ch khng ca c th ch v gy tn thng m. Nhng yu t gy c ch sc khng gi l aggressin, chng rt quan

trng i vi s tn ti lu di ca vi khun. V d, cc polysaccarid ca ph cu v mng no cu c th c ch s thc bo vi khun. Nhiu aggressin cng c tnh khng nguyn v p ng min dch chng li chng c th lm cho chng mt tc dng. Gy bin i khng nguyn, iu ny c ghi nhn rt r i vi trng hp nhim trypanosome v cm nhng cng xy ra vi c vi khun. V d, i vi trng hp nhim Borrelia recurrentis: sau khong mt tun nhim vi khun, khng th ph hy vi khun v bnh nhn bt st. Tuy nhin, sau 5 n 7 ngy na, s vi khun cn li to ra s bin i khng nguyn v tr li nhn ln cho n khi s lng gy st ln th hai. Sau khng th mi i vi khng nguyn bin i ny li xut hin tiu dit vi khun v bnh nhn li bt st. Nhng bin th khng nguyn khc li xut hin. Chu k ny s lp li khong 5-10 ln trc khi mm bnh hon ton b loi b. Mt s vi khun xm nhp qua ng nim mc c th to ra cc protease ly gii khng th IgA tit. Cc vi khun ny bao gm : neisseria gonorrhea, neisseria meningitis, hemophilus influenzae v streptococcus pneumoniae. Vi khun c th tn ti bng cch chim ng tm thi cc t bo khng thc bo, nh vy chng khng b tiu dit bi khng th, bi cc thc bo chuyn nghip v mt s khng sinh. Mt v d l s xm nhp ca Salmonella typhi vo nhng vng so khng c mao mch ca ti mt v ng tit niu. Cc i thc bo thng c thi gian sng kh di, nhng nu chc nng thc bo ca chng b tn thng th cc vi khun b n vo s khng b tiu dit v c th tn ti lu di cng vi i thc bo mt cch an ton trnh khi s tn cng min dch. Phng n tn ti ni bo ny c mt s vi khun nh lao, phong, brucella, v nocardia s dng gy ra tnh trng nhim trng mn tnh. S bin chng sang dng L khng c vch ca mt s vi khun nh lin cu, brucella, gonococcus v mycobateria gip cho vi khun tn ti ko di gy ra mt s nhim trng mn tnh hoc ngi lnh mang trng. Dng L gip vi khun chng li nhng khng sinh tn cng vi khun c vch, v khi dng khng sinh th dng ny l ngun to ra cc vi khun c vch bnh thng c kh nng gy bnh.

8.3. Min dch chng k sinh trng 8.3.1. Cc c ch min dch chng k sinh trng Nu k sinh trng trnh c h min dch v c c lc th n c th git cht c th ch m chng k sinh, nhng ngc li, nu chung b tiu dit d dng bi p ng min dch th s tn ti ca chng coi nh b e da. Nh vy, s tn ti ca mt loi k sinh trng no l th hin ca s cn bng gia kh nng ln trnh gim st ca k sinh trng va tac ng cua h min dch. K sinh trng cn to ra t bin cho c th ch v s t bin ny nhm gip c th ch khng li chng. Plasmodium, mt loi ng vt nguyn sinh gy bnh st rt, l mt v d. Gen ca hemoglobin hng cu lim gp phn vo s khng chng Plasmodium falciparum v ngn chn s pht trin ca k sinh trng trong hng cu. Trong thc t, ngi ta ghi nhn rng nhng ngi c kiu gen (genotype) hemoglobin bnh thng (Hb AA) th d mc st rt falciparum; nhng ngi c kiu gen hng cu lim ng hp t (Hb SS) th b thiu mu hng cu lim rt nng, thng dn n t vong. Nhng nhng ngi c hng cu lim d hp (Hb AS) th c li th khi sng trong vng dch t st rt. Bnh nhn chng chi vi nhim k sinh trng n bo bng nhng phn ng tng t nh trong nhim vi khun. Tuy nhin, c mt s n bo c c ch tn ti c o trnh c tc ng ca min dch c hiu v khng c hiu ca c th ch. Mc d cc khng th IgM v IgG c sn xut trong mi c th c nguyn sinh trong ng vt xm nhp, nhng cc khng th ny khng nht thit c kh nng bo v. V th m chng ta gp nhiu kh khn trong vic tm kim mt vacxin bo v chng li k sinh trng. Hn na, cn c nhng ng vt nguyn sinh c kh nng xm nhp vo bn trong t bo v tn ti : v d leishmania c th xm nhp vo v sng trong i thc bo. Khng th khng th tip cn v tc ng ln nhng ng vt nguyn sinh sng ni bo nh vy c tr phi khng nguyn k sinh b li trn b mt t bo. Vai tr ca min dch t bo rt kh nh gi trong bnh nhim k sinh trng ny. Tuy nhin, ngi ta cng thy c t bo T mn cm c ngha quan trng i vi nhim leishmania. S hnh thnh qu mn mun c hiu c l chu trch nhim gy ra bnh cnh khu tr i vi nhim leishmania da, nhng cn trong nhim leishmania ni tng th khng tm thy phn ng min dch t bo no quan trng. 8.3.2. C ch tn ti ca ng vt nguyn sinh trong c th

ng vt nguyn sinh c th ln trnh hoc bin i s tn cng ca h min dch bng nhiu cch (Bng 8.6). Bin i khng nguyn l v d r nt nht v kh nng thch nghi ca k sinh trng, iu ny gp i vi bnh bun ng gy ra do Trypanosoma brucei c truyn bng rui x-x (tsts) chu Phi. Sau khi nhim, s lng k sinh trng trong mu dao ng tng t; chu k xut hin ri bin mt k sinh trng trong mu ny l do khng th ph hy Trypanosoma, ri sau k sinh trng li xut hin vi cu to khng nguyn khc. Khng th hnh thnh sau mi t ni ln ca k sinh trng ch c hiu cho mt bin th khng nguyn. C l k sinh trng mang nhiu gen m ha cho nhiu loi khng nguyn b mt v chng c kh nng ng hoc m cc gen ny khi cn thit tn ti. Kiu bin i khng nguyn ny trong mi c th c xem ch l bin i kiu hnh (phenotyp). Kiu ny cn phi phn bit vi bin i kiu gen l bin i m qua mi chu k mi c mt chng mi xut hin v gy nn dch mi nh trng hp virus cm chng hn.

Bng 8.6. Cc c ch tn ti ca k sinh trng

C CH Bin i c th ch

V D V BNH NG VT GIUN TRN NGUYN SINH

Cc yu t di truyn St rt c ch min dch St rt, c th ch leishmaniasis Bin i k sinh trng Bin i khng nguyn Vt b khng Trypanosomiasis, st rt Leishmaniasis

Schistosomiasis

Schistosomiasis Schistosomiasis

nguyn Ngy trang khng nguyn Leishmaniasis Tin (premunition) min Toxoplasmosis

khng vi s Trypanosomiasis ph hy ca i thc bo

Cc ng vt nguyn sinh khc c th thay i nhanh chng lp o b mt trnh s kim sot min dch, qu trnh ny c gi l vt b khng nguyn. Sau khi tip xc vi pht vi khng th, k sinh trng Leishmania c th loi b khng nguyn b mt tr nn tr i vi tc dng ca khng th v b th. c ch p ng min dch l mt trong nhng c ch thch nghi d thy nht duy tr s tn ti ca k sinh trng. Ngi ta tm thy c ch ny c trong tt c cc loi k sinh trng. V d in hnh nht l trng hp st rt v nhim Leishmania ni tng. Khng nguyn ha tan do k sinh trng gii phng ra c th c ch p ng min dch mt cch khng c hiu bng cch tc ng trc tip ln t bo lympho hoc bng cch gy bo ha h li ni m. Nhng khng nguyn ny cng c th loi b khng th c hiu mt cch c hiu qu v nh vy ngn chn c s ph hy k sinh trng ca khng th. C nhiu c ch tc ng trc tip ln th sn mng non (schistosomulum) khi n di chuyn t da vo dng mu trng thnh. Sn mng ln trnh nhng c ch tn cng bng cch: (1) ngy trang khng nguyn, (2) tit ra cc peptidase c kh nng ct cc phn t khng th bm ln chng, hoc (3) tit ra nhng yu t c ch s tng sinh t bo T hoc c ch cc tn hiu ca t bo mast cn cho s hoc ha t bo a acid. i thc bo c th git v phn hy rt nhiu loi vi sinh vt. Tuy nhin, mt s nguyn sinh ng vt c kh nng sng v pht trin bn trong i thc bo nh toxoplasma, leishmania, trypanosoma cruzi. Toxoplasma to c

nhng c ch ngn chn s ha mng ca ti thc bo (cha k sinh trng) vi tiu th, cn trypanosome th li khng vi c ch git ni bo ca cc i thc bo trng thi ngh. 8.3.3. Min dch chng giun sn Giun sn c th gy ra mt p ng da kiu qu mn tc th (qua trung gian IgE) nu khng nguyn k sinh trng c tim vo da ca c th ch mn cm. Cc dn tc sng vng nhit i v nhit i, vng dch t ca bnh k sinh trng, c hm lng IgE trong mu cao, v khng th IgE c hiu k sinh trng c l ng vai tr quan trng trong vic bo v c th ch. Mt v d l trng hp sn xut khng th IgE chng li bilharzias v Schistosoma mansoni. C ch chnh xc ca s bo v cha c bit r, nhng c l khng th IgE tc dng vi k sinh trng hnh thnh phc hp min dch v gn ln i thc bo (qua trung gian th th Fc dnh cho IgE). Sau , i thc bo hot ha ny c th git k sinh trng. Tuy nhin, IgE c hiu k sinh trng ch chim mt phn nh trong tng lng IgE ca c th ca mt s bnh nhn. Giun sn to ra mt kch thch rt mnh hot ha t bo B a cln, nhng sau v sao c th li sn xut u tin IgE hn l IgG, IgA hoc IgM th vn cha r. Tng t bao ai toan trong mu cng l mt c im ca nhim giun sn. S di chuyn ca t bo ai toan n ni c k sinh trng c to ra bi nhiu c ch. T bo T hot ha c kh nng gii phng nhiu lymphokin thu ht t bo ai toan. Cc t bo mast khi v ht do tc ng ca khng nguyn k sinh trng cng gii phng ra cc yu t ha hng ng i vi t bo ai toan. Ngoi ra cn c mt s cht liu ca k sinh trng cng trc tip tham gia thu ht t bo ai toan. Gn y ngi ta cn pht hin rng t bo a acid l t bo hiu qu i vi nhim giun sn. V d, sn mng c gn vi C3 hoc IgG th c th git bi t bo ai toan.

8.3.4. C ch tn ti ca giun sn trong c th C ch ngy trang khng nguyn ng vai tr quan trng trong vic duy tr s sng cn ca giun sn. Sn mng trng thnh ngy trang khng nguyn b mt ca chng bng cch t mnh tng hp ra nhng khng nguyn ging khng nguyn c th ch nh 2 macroglobulin che y tnh

l ca chng. Mt cch khc l chng hp th nhng phn t ca c th ch ln b mt ca chng nh khng nguyn hng cu, immunoglobulin, khng nguyn MHC v b th. Thut ng min dch ng thi (concomitant immunity) hay tin min dch (premunition) c dng m t mt dng min dch thu c trong nhim trng hnh thnh vn tn ti nhng nhim trng mi th s b ngn chn bi c ch min dch. Nhim sn mng cng l mt m hnh cho th dng tin min dch ny: sn mng trng thnh c th sng nhiu nm trong c th ch m khng c hay c rt t bng chng ca p ng min dch chng li chng. Tuy nhin, sn mng trng thnh li kch thch c th ch to ra p ng min dch ngn nga s ti nhim i vi sn khng trng thnh tc u trng vo c th .

8.3.5. Tn thng do p ng min dch chng k sinh trng C nhiu bnh cnh lm sng xut hin do phn ng ca c th ch nhm chng li k sinh trng. Ngi ta ghi nhn cc phn ng qu mn tc th (tup I) nh my ay, ph mch trong giai on cp ca nhim giun trn v trong nhiu trng hp nhim giun sn khc. V nang sn trong qu trnh phu thut ct b nang c th gii phng khng nguyn vi lng ln v gy ra sc phn v. Khng th i vi khng nguyn b mt t bo c th gy ra phn ng qu mn (tup II). Nhng khng nguyn k sinh trng cho phn ng cho vi m c th ch, hoc khng nguyn c th ch hp ph ln b mt k sinh trng c th kch thch sn xut khng th i vi t khng nguyn c th ch. Phn ng t gy min dch nh vy l mt yu t quan trng trong bnh l min dch ca bnh Chagas, trong ngi ta cho rng tn thng tim l do t khng th lu ng gy ra. Phc hp min dch lu ng to bi khng nguyn k sinh trng v khng th c th ch c th gy ra mt s tn thng m trong bnh st rt, bnh nhim trypanosoma v bnh sn mng. Trong mt s trng hp, s lng ng mn tnh ca phc hp min dch c th gy ra vim cu thn. Min dch qua trung gian t bo i vi khng nguyn k sinh trng cng c th gy tn thng m trm trng. V d, trong nhim sn mng, s x ha tnh mch ca v tng p ng mch phi c l l do p ng t bo

i vi trng sn dnh trong m.

8.4. Min dch chng nm 8.4.1. Cc c ch min dch chng nm Nm c th gy nhiu bnh. Ngi ta phn loi cc bnh ny thnh: bnh nhim nm cn, nhim nm di da v nhim nm su (Bng 8.7). Trong nhim nm cn, da hoc nim mc l v tr tn cng chnh, trong khi nhim nm di da tc ng vo cc m k cn nh c hoc xng. Thut ng nhim nm ton thn dng m t s xm nhp ca nm v cc m su nh gan, phi hay no. Nhng nm gy nhim ton thn thng c chia lm hai nhm: nm bnh l v nm c hi. Thut ng bnh l ni ln tnh cht c th gy bnh cho bt c c th no m nm tip xc, cn thut ng c hi tnh cht ch gy bnh trn c th b suy gim min dch. Bng 8.7. Mt s bnh nhim nm ngi

Loi bnh Nm cn

Nm gy bnh Trichophyton rubrum Candida anbicans Sporotrichium Schenkii

Tn bnh Tinea corporis Tinea pedis Candidiasis Sporotrichosis

Lm sng To mng trn Bn chn lc s Vim o, m

Nm di da

Lot, to p-xe Histoplasmosis

Nm ton thn

Histoplasma capsulatum

Coccididioidomycosis Candidadiasis

Nhim phi

trng

- bnh Coccididioides l

Vim phi cp

immitis

Ton thn Cryptococcusis Bnh ph qun-phi, vim thc qun, Aspergilosis Vim mng no, tn thng phi rn U do aspergillus, p-xe no, nhim trng mt

- c Candida hi albicans

Cryptococcus Neoformans Aspergillus fumigatus

Trong ti liu ny chng ti dng bnh nhim Candida lm v d. y l loi nm c th gp khp ni v thng gy bnh ngoi da cho cc c th ch bnh thng. Candida albicans thng tm thy trong m o v ng tiu ha t ming cho n hu mn. Da v nim mc nguyn vn l hng ro bo v tt i vi nm. Mc d pH, nhit v mc thay da l nhng yu t ng gp quan trng, cc khun lc vi khun bnh thng cng ng vai tr quan trong vic ngn cn s pht trin ca nm v s xm nhp sau ca chng. Nh vy, s khng ca h tiu ha i vi nhim Candida c lin quan mt thit vi min dch t bo. Ri lon sinh thi ng rut do dng khng sinh hoc do bin i ni tit hoc chn thng l yu t quan trng gy nhim nm Candida cn mn tnh. Bin i p ng min dch ca c th ch l yu t chnh dn n mc nhim nm ton thn. Pht trin nm trong c th c th ch c th xy ra khi nm tm c ng vo qua lp da hay nim mc b tn thng, qua cc dng c tim truyn (nht l khi chuyn cc dung dch ng v acid amin u trng) hoc qua xng tiu. Trong trng hp nhim Candida nng, c th min dch t bo l c ch quan trng nht trong chng nhim nm ton thn, bi v ngi ta thy nhim nm thng lan ta mnh bnh nhn suy gim min dch t bo ch t thy trong cc trng hp suy gim khng th.

8.4.2. Tn thng do p ng min dch chng nm. Nhim nm c th gy nhiu hu qu. Thng ch p ng min dch c hiu chng nm cng vi thuc chng nm ti ch c th tiu dit c bnh nhim nm cn. Nhng ngc li, nhim nm c hi ton thn gy t l t vong cao cho cc c th ch suy gim min dch; nhng hu qu ny c th phng nga nh dung cc thuc chng nm ton thn. Nhim nm cn c th gy mt hu qu khc. Nu nm khng b loi tr hoc ti nhim nhiu ln th p ng min dch i vi khng nguyn nm c th gy phn ng qu mn. V d, nhim Aspergillus c th xut hin di dng lan ta hoc u aspergillus dai dng, trong nm pht trin mnh cc xoang trng phi c hnh thnh trc (v d hang lao iu tr khi). Sau d ng vi khng nguyn aspergillus c th xy ra. Ph qun c th b tc do cc mng nm v vch ph qun c phn ng vim km thm nhim t bo i toan. V mt lm sng, bnh thng xut hin di dng tng t lp i lp li ca nhng cn th kh kh, ho, st, au ngc ging nh trong hen ph qun. Nu mt ngi no trc y c tip xc vi khng nguyn nm v c khng th kt ta chng nm hnh thnh trong mu, nay li ht phi nm th c th c s hnh thnh phc hp min dch trong ng h hp. Mt v d l bnh phi nng dn, mt bnh qu mn qua trung gian phc hp min dch m khng nguyn l mt loi nm (micropolyspora faeni) c trong c

QU MN Khi mt p ng min dch xy ra qa mc hoc sai quy cch th se gy tn thng m, trng hp nay ta gi l qu mn. Qa mn l mt c im ca c th v n xy ra khi c tip xc vi khng nguyn ln th hai. Coombs v Gel chia qu mn ra lm bn typ: typ I, typ II, tyb III, v tyb IV. Trong thc t mt phn ng qu mn thng xy ra trong s phi hp ca cc typ vi nhau. im lu quan trng nht l nhng phn ng min dch ny khng cn mang tnh cht c li cho c th nh cc phn trc chng ta

 cp m chng thng gy ra vim cng nh cc tn thng khc. Ba typ qu mn du l cc phn ng qua trung gian khng th, con typ th t th ch yu l qua trung gian ca t bo T v i thc bo.

9.1. Qu m n typ I Qu mn typ I c c trng bi phn ng d ng xy ra tc th ngay sau khi tip xc vi khng nguyn (trong trng hp ny gi l d nguyn) t ln th hai tr i. Phn ng qu mn ny ty thuc vo s tn cng cc t bo mast c mn cm vi d nguyn v c gn vi cc lgE c hiu d nguyn, gy ra s gii phng cc ha cht trung gian ca phn ng vim. 9.1.1. Hin tng phn v - Mt biu hin c bit ca d ng Nu chng ta tim mt liu duy nht 1 mg albumin lng trng trng cho mt con chut lang, chng ta s khng thy iu g xy ra c. Th nhng, nu lp li liu tim 2 hay 3 tun sau th con vt mn cm s chu mt phn ng rt nng n m ngi ta gi l phn v ton thn. Con vt cht sau mt vi pht. Khi khm nghim gii phu bnh, ta thy cc ph qun v tiu ph qun b cht hp trm trng, ng thi c hin tng co tht h thng c trn cng nh gin ph nang. Nhng phn ng tng t c th gp ngi, c bit khi b rn cn, ong t, hoc tim penicilin cho mt s c th no . Trong nhiu trng hp ch cn tim adrenalin tc th theo ng tnh mch chng co c trn l c th cu c mng sng cho nn nhn. Huyt thanh ly t cc con vt hoc t ngi c c a d ng c mn cm vi d nguyn c th truyn th ng cho con vt khc v gy c phn v thc nghim trn con vt ny khi cho tim d nguyn ln th hai. iu ny ni ln rng t nht c mt yu t th dch quan trng tham gia vo vic gy phn ng phn v. Sau ny ngi ta chng minh c yu t quan trng l IgE. 9.1.2. IgE Khng th quan trng ca d ng p ng to khng th IgE l mt phn ng ti ch ngha l n xy ra ni d nguyn thm nhp vo c th l da v nim mc cng nh ti cc hc lympho ln cn. IgE c sn xut bi cc t bo B c mn cm d nguyn v di s gip ca t bo T. S sn xut IgE ti ch s gy mn

cm t bo mast ti vng , ng thi n s n gn ln t bo mast, mt phn khc IgE i vo mu v gn ln c t bo nm cc m khc. Lng IgE huyt thanh thng tng cao trong bnh d ng v c trong cc bnh nhim k sinh trng. Cn lu rng lng IgE tng cao s gip chn on bnh d ng nhng lng IgE thp khng c ngha l loi tr c bnh ny. Sn xut IgE khi c d nguyn l mt hot ng mang tnh cht di truyn v c kim sot bi nhng gen chuyn bit.

Vi nhiu tc dng bt li m IgE to ra trn nhng c th c c a d ng, ngi ta t cu hi l liu IgE c tc dng no c li i vi c th khng? Cu tr li l: c. Nu IgE khng ngn chn s xm nhp ca vi sinh vt hay giun sn vo nim mc ng tiu ha th vi sinh vt n tip xc vi cc t bo mast c gn IgE a n gii phng cc cht trung gian c tc dng ha hng ng i vi cc t bo trung tnh v t bo i

toan cn thit cho s khng ti ch. Ngoi ra, t lu ngi ta bit rng vai tr ca IgE ng vai tr quan trng trong s khng vi giun sn m c ch tc dng c m ta Hnh 9.1 Mt iu ng lu l bi v khong mt phn ba dn s th gii b nhim k sinh trng nn chng ta c th ngh rng trong qu trnh tin ha ng vt, IgE c hnh thnh nhm chng k sinh trng, cn d ng c l ch l hu qu khng may ca bc tin ha ny m thi. 9.1.3. T bo mast Trung tm ca phn ng T lu ngi ta nhn thy rng t bo mast khng ging nhau gia cc loi, chng khc nhau v tnh cht bt mu thuc nhum, v cu trc bn ngoi ca cc ht v c v c ch v ht. Tuy nhin trong mt c th t bo mast m lin kt hoc nim mc thng c dng lm in hnh cho t bo mast ca ton c th (Hnh 9.2).

Hnh 9.2. Hnh nh knh hin vi in t ca t bo mast (ca chut) T bo mast thng gp xung quanh cc mch mu ca hu ht cc m. Mc d chng tng i thun nht trong mi c th, ngi ta cng thy c s khc bit v kch thc v s lng gia t bo mast phc mc v t bo mast da. ngi, v tr c nhiu t bo mast nht l nim mc ca on gia rut v nim mc phi. Khi c th b nhim k sinh trng ngi ta cng thy tng s lng t bo mast rut.

Mt c im quan trong ca t bo mast l trn b mt ca chng c nhiu th th dnh cho on Fc ca phn t IgE, vit tt l Fce-R. Th th ny c vai tr quan trng trong phn ng d ng v chng s truyn tn hiu gy v ht ni bo khi c hin tng lin kt cho xy ra gia cc th th ny. Nhng, chng ta cn nh rng, trong c th, ngoi t bo mast, mt s t bo khc cng c mang th th Fce nh t bo kim, mt s t bo T v B, t bo mono, i thc bo, t bo i toan v tiu cu. 9.1.4. Lin kt cho gia cc Fce-R gy ra hot ha t bo mast Mt khi IgE gn th th Fce trn t bo mast v t bo i kim, s mt ht s xy ra khi c lin kt cho gia cc phn t IgE dn n lin kt cho cc th th Fce. Cc tnh hung c th to ra lin kt cho c m t Hnh 9.3.

Hnh 9.3. Hot ha t bo mast qua trung gian ca th th Fce T bo mast c hot ha nu hai th th Fce k cn c ni vi

nhau. iu ny c th xy ra do vai tr kt ni ca: (1) khng nguyn, (2) khng th khng IgE, (3) khng th idiotyp, (4) khng th chng th th Fc, (5) lin kt cho ca bn thn IgE, v (6) cc phn t lectin. Ngi ta tch c th th Fce ca mt dng t bo i kim b ung th ha kho st cu trc ca th th ny. N c mt cu trc bn chui, hai alpha v hai beta. Sau khi to c nhng khng th khng cc thnh phn ny, ngi ta dng chng lin kt cho cc th th v gy c s mt ht m khng cn n IgE. Cc lectin trong c PHA v Con A cng c th lin kt cc IgE li cc v tr cc nhnh carbonhydrat v do c th gy mt ht m khng cn d nguyn. iu ny gii thch cc trng hp mt s c th b m ay do n du ty l loi qu cha rt nhiu lectin. Cng nh cc cch cu to cu ni gia cc th th Fce trnh by hnh 9.3, c nhiu hp cht c kh nng mnh trong vic lm mt ht t bo mast. Cht quan trng nht thng gp trong c th l cc sn phm thoi ha trong qu trnh hot ha b th, m c th l C3a v C5a. Ngi ta thng gi chng l c t phn v (anaphylactoxin). Cc c t phn v cn c tc dng trn nhiu t bo khc nhau nh t bo trung tnh, tiu cu v i thc bo. Ngoi ra, cn nhiu ha cht c tc dng trc tip ln t bo mast gy mt ht nh calcium inophore, ACTH tng hp, codein v mocphin tt c cc hp cht ny hot ha t bo mast bng cch to dng ion calci i vo t bo. Dng ion calci i vo t bo c hai tc dng chnh. Th nht, lm cho cc ht di chuyn n mng t bo, ha mng vi mng t bo v v cc ht ra ngoi gii phng cc cht trung gian c tng hp trong ht. Th hai, to ra s tng hp ngay cc ha cht trung gian mi t acid arachidonic dn n s sn xut cc prostaglandin v leukotrien. Cc ha cht trung gian ny c tc dng ln cc m ti ch v ln phi to ra triu chng co tht ph qun, ph nim mc v tng tit a n d ng. 9.1.5. D ng atopy Thut ng atopy ln u tin c Coca v Cooke (1923) s dng m t bnh cnh lm sng ca qu mn typ I bao gm hen, chm, st c kh v m ay nhng c th c ngi trong gia nh cng hay mc bnh cnh tng t. Ngi ta cho rng m hnh sc phn v ng vt c lin quan n bnh hen v st c kh ngi, nhng trong khi m hnh phn v ny cho

thnh cng trong 90% ln th nghim th ngi khi cho tip xc ln th hai vi d nguyn ch c 5-10% l cho phn ng qu mn. Do ngi ta cho rng phn ng qu mn typ I tc phn ng d ng c lin quan cht ch n yu t di truyn m iu ny t quan trng ng vt. V th m Coca v Cooke ngh rng bnh d ng ngi khc v c bn vi phn ng phn v ng vt v h gi cc bnh d ng ngi l bnh atopy. Hin nay, thut ng atopy c dng nh mt thut ng ch mt s bnh c mt s biu hin ging nhau nh hen, chm v vim mi d ng. Nhng ngi u tin m t c ch ca phn ng d ng tc qu mn typ I l Praunitz v Kustner (1921). H pht hin trong huyt thanh bnh nhn c mt cht m h gi l reagin, cht ny c th gip truyn th ng phn ng d ng sang cho c th khc qua ng da. Khong 45 nm sau, Ishizaka v cng s chng minh cht reagin ny l IgE. 9.1.6. Cc th nghim lm sng i vi d ng Tnh mn cm thng c nh gi da vo p ng i vi khng nguyn a vo ni b. S sn xut histamin v cc ha cht trung gian khc nhanh chng to ra nt ph n v da, t ti a trong vng 30 pht v sau gim dn. Vai tr ca khng th IgE c th chng minh bng phn ng phn v th ng da dng huyt thanh ngi bnh th trn da ngi bnh thng hoc da kh. l phn ng Prausnitz-Kustner. Cng ngy ngi ta cng thy r rng sau phn ng ph v da ti ch l mt phn ng mun khc c th tn ti n 24 gi; phn ng ny c c trng bi s thm nhim dy c ca t bo v ph n nhiu hn so vi giai on sm. Ngi ta cho rng ha cht trung gian quan trng trong phn ng mun l yu t ho hng ng t bo trung tnh c trng lng phn t cao. Chng ta c th thy r biu hin ca giai on mun ny trong nim mc mi, ph qun ca nhng ngi b d ng v c bit l bnh nhn hen. i vi vic nh lng IgE c hiu, th nghim hp th d ng phng x (Radioallergosorbent test, RAST) t ra cng tt nh phn ng ly da (skin prick test) nhng li tin li hn v khng phi tin hnh trn bnh nhn. Trong mt s trng hp, cho nim mc mi th thch vi d nguyn li cho kt qu dng tnh nhy hn hai phn ng trn, iu ny c l l do kh nng tng hp ti ch ca IgE.

9.1.7. i u tr bnh d ng Nu chng ta theo di ton b chui phn ng t khi tip xc vi d nguyn cho n khi xut hin cc biu hin atopy th c th thy rng c nhiu bin php nhm ngn chn s xut hin ca bnh ny (Hnh 9.4)

Hnh 9.4. iu tr bnh d ng: cc v tr ca phn v cc b v kh nng iu tr tng ng

Mt bin php cng thng c dng l gii mn cm bng cch tim vo c th lp li nhiu ln nhng liu nh d nguyn. Ngi ta gii thch mc ch ca phng php ny l nhm, to ra s sn xut khng th phong b IgE c chc nng chuyn hng d nguyn khi tip xc vi IgE gn trn cc m c th. Ngoi ra, nu tng tc t bo tht s quan trng trong vic tng hp IgE th vic tim d nguyn liu nh nhiu ln s c li ch to ra cc t bo dung np v c T c ch ng thi qua khng to c hiu d ng (m bn cht l phn ng min dch) i vi d

nguyn khi c tip xc v sau. i vi cc thuc chng d ng, cc loi nh isoprenaline, sodium cromoglycate c tc dng kh tt v chng gn vo nhng th th t bo mast gip t bo ny khi b tc ng. Cc triu chng d ng khng phi lun lun khng ch c bng cc loi khng histamin, nht l khi bnh nhn ang chu tc ng bi phn ng giai on mun v lc th cc loi cocticoid c th gip ch. 9.1.8. Tnh di truy n ca phn ng d ng Nhng nghin cu u tin vo nhng nm 1920 cho thy rng nhng cp v chng b d ng th c t l sinh con b d ng cao hn. T l con b mc bnh d ng nhng cp v chng ny l 50%. C ba c ch di truyn chnh iu ha phn ng d ng: - Lng IgE ton phn: Nghin cu nhng gia nh vi t nht mt thnh vin c mc IgE cao trong mu xc minh gi thuyt cho rng mc IgE cao c lin quan vi mt gen tri. - S phi hp vi HLA: Ngi ta thy tnh p ng vi mt d nguyn no c lin quan n mt HLA nht nh. V d, a s bnh nhn d ng vi d nguyn Ra3 ly t c phn hng (ragweed) c mang HLA-A2, vi d nguyn Ra5 ca c ny l HLA-A3, B7. - C a tng p ng min dch: C nhng ngi c c a tng p ng vi kh nhiu loi khng nguyn. y l c s phn ng d ng d dng xy ra. Nhng ngi c c a ny v mt di truyn c thy l a s mang HLA-B8, HLA-Dw3. Trong HLA-B8 rt thng gp trong nhng dng tng tnh phn ng khc nh trong cc bnh t min chng hn. Do , ngi ta cho rng nhng bnh nhn c phn ng d ng c l c gim chc nng t bo Ts (n cln hoc a cln) di truyn tng t nh trong bnh t min.

9.2. Qu m n typ II Trong th dng qu mn ny, khng th chng khng nguyn b mt t

bo ch hoc khng nguyn m ch tc dng ln cc phn t thnh phn b th ng thi phi hp vi nhiu t bo hiu qu khc gy thng tn cc t bo ch v cc m xung quanh. 9.2.1. C ch tn thng H thng b th c hai chc nng. Khi tc dng mt mnh n c th gy tiu mng t bo mn cm vi khng th. S hot ho b th xy ra theo con ng c in to ra phc hp tn cng mng C5b56789. Ngoi ra, s lin kt ca C3 hot ha vi t bo ch v khng nguyn opsonin ho t bo ch lm cho n d gn vo cc t bo hiu qu c th th C3 (Hnh 9.5). Mt s tiu lp khng th c th th trn mt s t bo hiu qu, nh th n to c s opsonin ha nh trng hp b th t bo hiu qu c th tiu dit t bo ch. Cc loi t bo khc nhau c mt c cu th th khc nhau.

Hnh 9.5. Hot ha b th trong phn ng qu m n typ II

Khng th gn vi khng nguyn trn t bo ch v hot ha b th theo con ng c in dn n hnh thnh C4b2b3b. Sau enzym chuyn C5 c th hot ha con ng ly gii v gy tn thng t bo bng phc hp tn cng mng C5-9.

Cc kch thch ha hng ng thu ht cc t bo hiu qu n ni n phn ng qu mn typ II ging nh chng b thu ht n vim bi cc vi khun. Cht trung gian c bit quan trng l C5a, cht ny c kh nng thu ht c t bo trung tnh ln i thc bo. C ch m cc thc bo gy tn thng cho t bo ch trong qu mn typ II ging ht c ch m h min dch bnh thng gy tn thng cho vi sinh vt. a s cc tc nhn gy bnh b git trong tui thc bo bi cc enzym, cc ion, cc cht oxy ha,... Cc t bo thc bo khng th tiu ha cc t bo ch ln, khi chng buc phi phng thch cc ht tiu th ra ch ch mn cm v cc ht ny v ra, gii phng cc enzym ra ngoi gy tn thng m (Hnh 9.6). Ngi ta gi y l hin tng thc bo ngoi (exocytocis). Trong mt s phn ng, nh phn ng ca t bo trung tnh vi sn mng, hiu qa phn ng l c li nhng nu m ca c th ch cng b mn cm th cng b khng th tc dng theo c ch tng t v gy tn thng cho c th ch.

Hnh 9.6. C ch gy tn thng Phn ng chng vi khun bnh thng: (1) T bo tip cn vi vi khun qua Fc v C3; (2) vi khun b thc bo; (3) v b tiu th ph hy trong tri thc bo. Trong qu mn tp II: t bo ch c gn vi khng th v thc bo theo kiu tng t, nhng v th ch tn cng qu ln, nh trng hp mng y (4) nn t bo trung tnh phi n lc ht sc (5) v gii phng cc enzym bn trong t bo ra ngoi ph hy ch (6). 9.2.2. Phn ng typ II gia cc c th cng loi 9.2.2.1. Phn ng truy n mu Hin nay c t nht l 15 h thng nhm mu c tm thy ngi, mi h thng bao gm mt b khng nguyn c mt trn hng cu c m bi mt locus gen. Mt c th c mt nhm mu no c th nhn dng hng cu mang nhng khng nguyn ca h nhm mu khc v sn xut khng th chng li. Khng th ny c th c sn xut t nhin, l trng hp ca h ABO. Ngi ta cho rng c th sn xut c khng th t nhin ny m khng cn gy mn cm l nh n nhn dng c cc quyt nh khng nguyn nhm mu c mt trn rt nhiu vi sinh vt. Tuy nhin, trong a s cc trng hp, th c th ch sn xut khng th chng cc nhm mu khc sau khi tip xc vi khng nguyn.

Truyn mu cho mt ngi c khng th chng khng nguyn ca hng cu chuyn vo s dn n phn ng truyn mu. trm trng ca phn ng ph thuc vo lp v s lng ca khng th lin quan. Khng th chng khng nguyn h ABO thng l IgM, chng s gy ngng kt, hot ho b th, v tan mu trong lng mch. Cc nhm mu khc thng gy sn xut khng th IgG, v mc d khng th ny t gy ngng kt hn IgM nhng n li hot ho c ch qu mn typ II lm v hng cu. V hng cu c th gy sc, ng thi cc sn phm v ra t hng cu c th gy hoi t ng thn cp. Phn ng truyn mu do khng cng nhm mu cng c th xy ra sau nhiu ngy hoc nhiu tun trn ngi trc y cha h c mn cm v gy ra triu chng thiu mu, vng da. Phn ng truyn mu i vi cc thnh phn khc ca mu nh bch cu, tiu cu cng c th xy ra nhng hu qu ca n khng nng n nh phn ng i vi hng cu. 9.2.2.2. Bnh huyt tn tr s sinh do khng ph hp Rhesus Bnh thng xy ra trong trng hp m mang nhm mu Rh- c bo thai Rh+. S mn cm ca m i vi hng cu Rh+ ca con i ngc vo mu m gy nn sn xut khng th khng hng cu Rh+ trong mu m v ri chuyn sang con qua nhau thai (Hnh 9.7).

Hnh 9.7. Bnh huyt tn tr s sinh Hng cu phi c Rh+ vo tun hon m kch thch sn xut khng th anti-Rh. Khng th ny theo mu vo bo thai thai v gy ph hy hng cu bo thai.

i vi a con u tin, do khng th khng hng cu Rh+ thng t nn tr thng khng b nh hng g nhiu. Nhng nhng a con cng v sau th cng c nguy c tan mu cao hn. Ngoi nhm mu Rh ra, khng nguyn K ca h Kell cng c th gy bnh huyt tn tr s sinh. 9.2.2.3. Ghp c quan Mt mnh ghp c quan cng loi, mt khi tn ti lu di nh chng li c s tn cng d di ban u ca min dch qua trung gian t bo, vn c th kch thch c th nhn to khng th chng li cc mt trn b mt mnh ghp. Cc khng th ny c kh nng gy c trc tip hoc gip cho cc thc bo cng nh t bo K gn vo t bo ch v to nhng tn cng khng c hiu. Chng c th gy kt dnh tiu cu khi gn ln trn b mt ca ni m mch mu. V Phn ng thi ti cp thng xy ra nu trong c th c sn cc khng th ny (do ghp ln trc). 9.2.3. Phn ng qu mn typ II t min C mt s c th t mnh sn xut khng th chng vi hng cu bn thn mnh, do gy ra bnh thiu mu huyt tn t min. Chn on bnh ny da vo th nghim Coombs dng tnh (Hnh 9.8). Th nghim ny gip xc nh khng th hin din trn hng cu bnh nhn. Thiu mu huyt tn t min c chia lm ba loi ty theo loi t khng th c mt trong mu bnh nhn: T khng th nng, ch phn ng vi khng nguyn nhit 37oC T khng th lnh, ch phn ng nhit di 37oC Khng th to ra do d ng thuc.

Hnh 9.8. Phn ng Coomb gin tip Phn ng ny dng pht hin khng th trn hng cu bnh nhn. Nu c khng th th nhng hng cu ny s b ngng kt khi ta cho khng th anti-Ig ngi vo hn dch. Huyt thanh ca bnh nhn mc bnh vim tuyn gip Hashimoto cng c cha mt s t khng th m trong phng th nghim, khi c s hin din ca b th, chng s gy c trc tip t bo tuyn gip c nui cy. Trong hi chng Goodpasture, t khng th chng mng y cu thn c chng minh l c hin din. Khng th ny cng vi cc thnh phn b th gn ln mng y ri phn ng b th s dn n s tn thng trm trng ca mng. Nhiu tc gi cng cho rng phn ng gy ra do khng th chng th th acetylcholine trn cc bn thn kinh vn ng ca t bo c vn (Hnh 9.9) gy bnh nhc c nng nn xp vo phn ng qu mn typ II.

Hnh 9.9. Bnh nhc c nng Bnh thng xung ng thn kinh c truyn vo t bo c vn qua mt ha cht trung gian l acetylcholin. Cht ny gn vo th th ca n trn bn thn kinh vn ng gy tc dng. Trong bnh nhc c nng, khng th chng th th acetylcholin phong b th th lm cho acetylcholin b gim tc dng. y l mt trong nhng c ch gy bnh.

9.2.4. Phn ng do thuc typ II iu ny rt phc tp. Thuc c th gn vo cc thnh phn c th qua cc hapten trong thnh phn thuc tr thnh khng nguyn thc s v kch thch mt s c th no (m chng ta cha bit l c th no) to ra phn ng min dch chng li. Nu khng th IgE c sn xut, phn ng phn v c th xy ra. Trong mt s trung hp, nht l i vi cc thuc m bi ngoi da, qu mn mun qua trung gian t bo c th s xut hin. Ring y chng ta ang cp n qu mn typ II, th chng ta c th ghi nhn rng thuc c th gy ra cc phn ng d ng v phn ng t min chng cc t bo mu bao gm hng cu v tiu cu. Thng th phn ng xy ra nhm chng li thuc hoc cc cht chuyn ha ca thuc v phn ng i hi s hin din ca c thuc ln khng th. Khi ngng thuc th phn ng gim i. Bnh cnh u tin c gp l xut huyt gim tiu cu do dng

Sedormid. Ngi ta thng k c cc thuc gy thiu mu gim tiu cu bao gm rt nhiu loi trong thng gp nht l penicillin, quinin v sulfonamid.

9.3. Qu m n typ III y l typ qu mn xy ra do s tn cng ca cc phc hp min dch (PHMD) ln cc t bo v m c th.

9.3.1. Cc th bnh phc hp min dch PHMD c hnh thnh khi khng th lin kt vi khng nguyn, sau chng s b loi b nh cc t bo ca h li ni m. Tuy nhin, cng c s hnh thnh phc hp li dn n phn ng qu mn. Cc bnh do PHMD c th xp lm ba nhm: Nhm 1, y l nhm ca cc trng hp nhim trng tn ti dai dng bao gm nhim lin cu tan mu, t cu, plasmodium vivax, virus vim gan. Khng th c sn xut mc yu dn n hnh thnh PHMD mn tnh v lng ng vo cc m. Nhm 2, bnh PHMD l bin chng ca bnh t min, trong s sn xut lin tc t khng th i vi mt t khng nguyn no dn n s hnh thnh PHMD ko di v cc t bo ca h li ni m b qu ti khng loi tr c. Cui cng l xut hin lng ng PHMD cc m. Nhm 3, trong nhm ny PHMD c hnh thnh b mt c th nh phi chng hn xy ra sau khi th ht lu di cc cht liu c tnh khng nguyn. Mt v d l bnh phi ca nng dn v bnh ca ngi nui chim.

9.3.2. Cc c ch vim trong qu mn typ III Phc hp min dch c kh nng khi ng nhiu qu trnh vim. Chng c th tng tc vi h thng b th dn n hnh thnh C5a. C5a c tnh cht ha hng ng v cng l cc c t phn v. Chng gy ra s gii phng cc amin hot mch t t bo mast v t bo i kim, do lm tng

tnh thm thnh mch v thu ht bch cu mi, PHMD cng c th tng tc vi tiu cu qua th th Fc, dn n s kt tp tiu cu v hnh thnh cc vi huyt khi, ri lm tng hn na tnh thm thnh mch do gii phng cc amin hot mch. (Hnh 9.10). Cc bch cu mi c thu ht n c gng thc bo PHMD, nhng nu PHMD b gi trong cc m th vic thc bo rt kh khn, v th m cc thc bo phi gii phng cc enzym ra ngoi nhm mc ch lm tiu phc hp nhng cng ng thi lm tn thng m (Hnh 9.10). Tht ra, nu cc enzym ny c gii phng ra trong mu th lp tc n b trung ha ngay bi cc cht c ch nhng ti cc m khng c cc cht c ch ny nn cc enzym ny gy tn thng m d dng.

Hnh 9.10. S lng ng ca phc hp min dch trn thnh mch mu Khng th v khng nguyn to thnh phc hp. Phc hp ny hot ha b th ng thi tc ng gy gii phng cc amin hot mch lm tng tnh thm thnh mch. Phc hp cng to ra kt tp tiu cu to ra cc vi huyt khi v thu ht t bo trung tnh n gy thm nhng tn thng khc cho

thnh mch. 9.3.3. M hnh thc nghim ca bnh phc hp min dch i vi ba nhm bnh ni trn chng ta c ba m hnh: bnh huyt thanh i vi nhm 1, bnh t min chut NZB/NZW nhm 2 v phn ng Arthus nhm 3.

9.3.3.1. Bnh huyt thanh Trong bnh huyt thanh PHMD lu ng s lng ng vo khi tnh thm thu thnh mch tng, sau dn n bnh cnh vim nh vim thn, vim khp. Vo thi k tin khng sinh bnh huyt thanh l mt bin chng nguy him do liu php huyt thanh. Ngy nay, bnh ch yu c nghin cu trn m hnh ng vt. Con vt (th) c tim mt protein ha tan (v d albumin huyt thanh b). Khong sau mt tun khng th hnh thnh i vo tun hon v to ra phc hp vi khng th trong trng thi tha khng nguyn. Cc phc hp min dch nh ny ch b loi tr bi h thc bo n nhn mt cch chm chp. Vi s hin din ca PHMD, lng b th ton phn gim nhiu v cc triu chng ca bnh huyt thanh xut hin do lng ng cc ht phc hp mng y cu thn v trong cc mch mu nh. Khi phc hp b loi b hon ton th con vt hi phc, nhng bnh c th duy tr mn tnh nu hng ngy ta vn lin tc cho thm khng nguyn vo c th con vt.

9.3.3.2. Bnh PHMD Dng th h F1 ca dng chut lai NZB/NZW ta c c m hnh ng vt ca bnh t min ging nh bnh lupus ngi. Trong con vt c rt nhiu t khng th nh khng hng cu, khng nhn, khng DNA v khng Sm. Khi mi sinh ra con vt hon ton bnh thng nhng sau 2-3 thng th c cc triu chng thiu mu huyt tn, th nghim Coombs dng tnh, c khng th khng nhn, c t bo LE, c PHMD nhiu trong tun hon v lng ng c thn cng nh mch mc trong no tht. Bnh gp ch yu con ci, v t vong xy ra khong vi thng sau khi triu chng xut hin.

9.3.3.3. Phn ng Arthus y l mt phn ng xy ra cc b trong v xung quanh nhng mch mu nh v thng thy c ngoi da. Con vt c gy min dch nhiu ln cho n khi c lng khng th (ch yu la IgG). Khi tim khng nguyn vo di da lp tc phn ng xy ra do hnh thnh phn ng khng nguyn khng th v to ra PHMD xung quanh ch tim. Phn ng c cng cao nht sau 4-10 gi. Ty theo lng khng nguyn tim vo m ph v xut huyt c th xy ra ch tim. Sau phn ng yu dn v gim hn sau 48 gi. Cc nghin cu bng hunh quang cho thy ban u khng nguyn, khng th v b th lng ng thnh mch, sau l thm nhim t bo trung tnh v trong lng mch th y tiu cu. S tp trung tiu cu ny c th a n tc mch v hoi t trong nhng trng hp nng. Sau 24-48, gi bch cu mi c thay th bng t bo n nhn v c khi c tng bo. S hot ha b th lun cn cho phn ng Arthus xut hin. T l khng th/ khng nguyn rt quan trng cho phn ng ti a. Nhn chung, PHMD c to ra khi tha khng nguyn hoc tha khng th th t c hi hn phc hp c to ra khi s lng ca chng tng ng nhau.

9.3.4. Ti sao phc hp min dch lng ng m i vi s lng ng PHMD c hai cu hi c t ra: ti sao phc hp lng ng m v ti sao trong mi bnh no th PHMD li c xu hng lng ng mt m nht nh? Chng ta ln lt xem cu tr li qua cc yu t sau y:

9.3.4.1. Tng tnh thm thnh mch Yu t quan trng nht i vi s lng ng c l l s tng tnh thm thnh mch. B th, t bo mast, t bo i kim v tiu cu c th xem l nhng nhn t gp phn tch cc gii phng cc amin hot mch v lm tng tnh thm thnh mch. Nu ta dng cc cht khng histamin c ch trc khi hiu qu tng tnh thm b phong b v s lng ng cng kh xy ra.

9.3.4.2. Qu trnh huyt ng S lng ng ca PHMD cng d xy ra nhng ni c p lc mu cao cng nh c dng chy xoy. Trong cc mao mch cu thn p lc mu cao gp gn 4 ln so vi cc mao mch ni khc. Nu p lc c lm cho gim bng cch tht bt mt phn ng mch thn th s lng ng gim xung. Cn ngc li, nu ta lm tng huyt p thc nghim cho con vt th cc triu chng ca bnh huyt thanh cp xy ra nhanh hn. Ngoi ra, ti nhng ni m thnh mch c hnh dng to ra lung xoy cun nh ni ng mch ch i, ni c hin tng lc mu, .v.v. th s lng ng cng c lm cho d hn. 9.3.4.3. S lin kt vi khng nguyn m Nhng l do k trn khng gii thch c ti sao trong nhng bnh khc nhau th PHMD c xu hng lng ng vo nhng m khc nhau. L do c th l do khng nguyn c mt trong phc hp l khng nguyn c hiu m. Ngi ta chng minh rng DNA c i lc rt mnh vi collagen ca mng y cu thn nn phc hp DNA v anti-DNA trong bnh thn lupus thng hay lng ng mng y cu thn to ra bnh thn lupus. Cng c trng hp c khng nguyn v khng th cng c sn xut ti cng mt ni trong m ch. l trng hp ca bnh vim khp dng thp.

9.3.4.4. Kch thc ca PHMD V tr chnh xc ca PHMD mt phn ph thuc vo kch thc ca phc hp. ta thy r iu ny thn. Phc hp no nh th c th chui lt qua mng y cu thn vo nm gia mng y v t bo c chn (podocyte), cn phc hp no ln th mc li nm gia cc t bo ni m v mng y (Hnh 9.11).

Hnh 9.11. V tr lng ng ca phc hp thn ph thuc vo kch thc phc hp trong tun hon

Phc hp ln d lng ng mng y cu thn, cn phc hp nh th i xuyn qua mng y v tm thy pha t bo biu m ca cu thn.

9.3.4.5. Lp Immunoglobulin Lp Immunoglobulin c th nh hng s lng ng ca PHMD. V d trong bnh lupus, cc lp v tiu lp khng th anti-DNA c lin quan cht ch n tui v gii. Khi chut NZB/NZW gi c s chuyn i lp Ig t ch lp tri l IgM sang lp tri l IgG2. iu ny xy ra chut ci sm hn chut c v ng thi vi s xut hin ca bnh thn tc l trc khi chut cht khong 2-3 thng. iu ny chng t rng lp v tiu lp ca khng th cng quan trng trong qu trnh lng ng ca PHMD.

9.4. Qu m n typ IV Qu m n mun Theo phn loi ca Coombs v Gel, qu mn typ IV hay qu mn mun c dng ch tt c nhng phn ng qu mn xy ra sau 12 gi tnh t khi khng nguyn xm nhp vo ln th 2. Lc c ch ca phn ng vn cha c bit, v cho n nay cng ch bit c c mt phn . C mt iu r l c nhiu phn ng min dch c th gy ra qu mn mun. Khng ging ba typ qu mn kia, qu mn mun ch truyn th ng c t con vt ny sang con vt khc bng t bo T ch khng phi bng huyt thanh. T bo T cn thit to ra qu mn mun c gi l T qu mn mun (tc Td). Qu mn mun thng gp trong nhiu phn ng d ng i vi vi khun, virus v nm, trong vim da tip xc do nhy cm vi mt s ha cht

c cng thc cu to n gin v trong phn ng thi b mnh ghp. M hnh c hiu bit r nht l phn ng Mantoux thc hin bng cch tim tuberculin cho mt c th c vi khun mycobacterium t nhp v c th to phn ng min dch t bo chng vi khun ny. Phn ng Mantoux c c trng bi v cng da xut hin nhiu gi sau khi tim, t ti a sau 24 n 48 gi, sau gim dn. Trong giai on sm nht ca phn ng, ta thy c s tp trung t bo n nhn xung quanh cc mch mu v sau l s thot mch ca rt nhiu t bo mono v bch cu mi. Trong giai on tip theo ta c th thy s thm nhim ko di ca t bo lymph v t bo thuc h n nhn/i thc bo. iu ny ngc vi phn ng Arthus trong ch c thm nhim bch cu mi. Chng ta cng c th thy phn ng da tng t th ny i vi cc protein ha tan trong trung hp trc gy mn cm bng cc protein ny trn vi t cht Freud hon ton. Tuy nhin, trong mt s trng hp, nu con vt c mn cm vi ch khng nguyn hoc t cht Freud khng hon ton (tc khng c xc vi khun lao) th phn ng qu mn mun xy ra trong thi gian ngn hn v phn ng da cng ch tn ti thong qua. Ngi ta gi phn ng ny l qu mn Jones-Mote, gn y c i tn l qu mn t bo i kim da (cultaneous basophil hypersensitivity) v c mt t l rt cao t bo i kim thm nhim da.

Hnh 9.12. C s t bo ca qu mn typ IV T bo Th tit ra lymphokin tc dng ln i thc bo gy kt tp t bo ti v tr khng nguyn. Hin tng thc bo mn tnh sau to nn hnh nh u ht. ng thi t bo Tc cng c hot ha gy tn thng t bo nhim khng nguyn (virus). 9.4.1. C s t bo hc ca qu mn typ IV Khc vi typ qu mn khc, qu mn typ IV khng th truyn cho c th khc bng huyt thanh m ch c th truyn qua t bo lymph, c bit l t bo lymph T. Gn y ngi ta pht hin c th truyn bng mt cht c trng lng phn t thp chit xut t bch cu gi l yu t truyn Lawrence. Tuy nhin, bn cht ca cht ny vn cn cha bit r. Cht chit xut ny c cha nhiu yu t hnh nh c kh nng kch thch cc t bo T c chun b tham gia vo phn ng qu mn mun.

Cn lun nh rng tn thng qu mn l hu qu ca phn ng qu mc gia khng nguyn vi c ch min dch t bo vn cn bnh thng. sau tip xc u tin, cc t bo nh nhn din khng nguyn cng vi cc phn t MHC lp II trn i thc bo ri c kch thch v chuyn dng thnh t bo non tng sinh. T bo T c kch thch gii phng nhiu yu t ha tan c chc nng lm trung gian cho p ng qu mn xy ra sau nh thu ht v hot ha i thc bo; chng ng thi cng gip bin cc t bo tin thn ca T gy c tr thnh cc t bo git v gy tn thng m (Hnh 9.12).

9.4.2. Tn thng m do phn ng typ IV Nhim trng trn bnh nhn lao hoc trn tn thng u ht da ca bnh nhn phong, cc tn thng do phn ng d ng vi vi khun nh to, casein ha v nhim c ton thn c l do tnh trng qu mn qua trung gian t bo i vi cc sn phm vi khun m ra. Khi u tranh gia s nhn ln ca vi khun v s khng ca c th xy ra theo chiu hng bt li cho c th th cc khng nguyn vi khun tn ti trong c th s kch ng mt phn ng qu mn mun ti ch v mn tnh. S gii phng lin tc cc lymphokin bi t bo T dn n s tp trung ca nhiu loi i thc bo ni c khng nguyn xm nhp. Mt s i thc bo s to thnh nhng dy t bo dng biu m, v mt s th bin thnh cc t bo khng l sau khi nut vi khun vo. i thc bo no cn li khng nguyn vi sinh vt trn b mt s tr thnh t bo ch cho cc t bo git v s b tiu dit. Ngoi ra, ti nhng ni ny, cc cytokin cn gy c trc tip t bo ng thi hot ha t bo NK tip tc gy cc tn thng khc i vi m. Ton b cc hot ng va k dn n hnh thnh mt hnh thi tn thng gi l u ht mn tnh v y l phn ng c li nhm mc ch to nn mt lp v bc khoanh khu vc tn thng li. Ngoi cc vi khun Mycobacterium, tn thng qu mn typ IV cn c th gp i vi cc nhim trng virus nh virus u mu, si, herpes simplex. Mt s nm v k sinh trng cng c th gy kiu qu mn ny. 9.4.2.1. Vim da tip xc

ng da l con ng thun li i vi vic gy qu mn t bo nh c nhiu t bo Langerhans l nhng t bo trnh din khng nguyn hu hiu c th nhanh chng mang khng nguyn n trnh din vi t bo lympho hch ngoi bin gn . Qu vy, phn ng qu mn mun d dng xy ra vi cc ha cht ngoi lai tip xc vi c th qua ng da v kt hp vi cc thnh phn protein c th trong da tr thnh khng nguyn l v d dng b bt gi bi t bo trnh din khng nguyn Langerhans, hu qu l xy ra phn ng qu mn mun do ha cht ny gy ra. Phn ng vim da tip xc do qu mn c c trng bi s thm nhim t bo n nhn t cng ti a sau 12-15 gi v ph n lp thng b do hnh thnh cc nang nc nh. Qu mn tip xc c th xy ra nhng ngi lm vic vi cc ha cht v tr nn mn cm vi cc ha cht ny, v d picryl chloride, pycryl chromat, p-phenylene diamin, neomycin, mui nikel l nhng ha cht thng gp c th gy qu mn tip xc. 9.4.2.2. Cc trng hp khc Qu mn mun cng ng gp quan trng trong vic gy phn ng mun cho mt s trng hp b cn trng t. Trong trng hp ghp cng loi, hot ng gy thi ghp do t bo T gy c l mt c ch quan trng, y cng l mt th dng ca qu mn typ IV. Trong mt s bnh t min, ngi ta ghi nhn c vai tr ca qu mn mun trong c ch gy tn thng. 9.5. Qu m n typ V Qu m n kch thch C mt s t bo khi thc hin chc nng cn n s kch thch ca mt loi hormone no . S kch thch ny c thc hin thng qua mt phn t b mt t bo gi l th th. Th th lun c cu trc c bit cho ch hormon . Khi c s kt hp ca hormon ln th th, lp tc xy ra hin tng bin i cu trc ha hc ca th th hoc ca mt phn t k cn v s bin i ny pht ra mt tn hiu truyn vo bn trong t bo lm cho t bo bt u thc hin chc nng ca n. V d khi hormon TSH ca tuyn yn gn vo th th ca n trn t bo tuyn gip th lp tc gy ra s hot ha adenyl cyclase trong mng t bo bin ATP thnh AMP v a vo bn trong t bo. AMP sau s kch thch s hot ng ca t bo tuyn gip (Hnh 9.13).

Hnh 9.13. S c ch phn ng qu m n typ V T bo tuyn gip c kch thch theo kiu bnh thng v bi khng th. C hai kch thch u to ra bin i mng v hot ha t bo. Trn mt s bnh nhn nhim c gip, ngi ta thy c khng nguyn kch thch tuyn gip xut hin trong mu. y l mt t khng th chng li mt khng nguyn c mt trn mng t bo tuyn gip. Khi t khng th kt hp vi khng nguyn, phc hp ny cng to ra kch thch ging nh trng hp THS kt hp vi th th ca n, do chng c kh nng lm tng hot tuyn gip qua con ng AMP vng gy ra chng nhim c gip. Mt iu cng ng lu na l trong bnh lot t trng khng cimetidin, ngi ta cng pht hin t khng th khng th th H 2 ca histamin. Trn thc nghim, ngi ta pht hin c thm mt s khng th kch thch hot ng chc nng ca t bo qua cc khng nguyn c trn b mt t bo. V d, kch thch s chuyn dng lympho bo T bng khng th chng khng nguyn CD3, kch thch s phn bo ca t bo tuyn gip bng t khng th pht trin (growth autoantibody), kch thch s thc bo bng

khng huyt thanh khng i thc bo, Chng ta cn lu rng mc d khng th chng enzyme khi gn vi enzyme v tr gn din hot ng ca n c th lm c ch enzym, nhng khi chng gn vi quyt nh din hot ng th i khi li c tc dng tng hot tnh ca enzym nh cc trng hp ca penicillinase v -galactosidase.

9.6. Cc phn ng qu m n khng c hiu S hot ha qu mc h thng b th theo con ng khng c in cng c th dn n phn ng qu mn gy ra cc tn thng t chc nh ng mu ni mch ri rc. Mt v d c th minh ha r rng cho c ch ny l phn ng Schwarzmann c thc hin trn th bng cch a ni t vo tnh mch ca th. Ni c t hot ha b th theo con ng khng c in ri sau n gn vi mnh C3b v nh vo tiu cu nh kt dnh min dch; phc hp C5, 6, 7 c to ra s gy tn thng tiu cu v gii phng ra cc yu t ng mu. Mc d ngi C3b c xu hng kt dnh ln hng cu v bch cu mnh hn tiu cu, nhng trong trng hp nhim trng huyt gram m v st xut huyt c sc c ch ny ng vai tr quan trng trong vic gy tiu th b th mnh. Mt c ch khng c hiu khc tham gia gy qu mn l trng hp thiu cc protein bt hot C3b lm cho phn ng hot ha b th khng dng li. V d trong bnh cnh i huyt cu t m kch pht, trn mng hng cu b thiu ht protein khng ch C3 nn bnh cnh tiu hng cu nng n xy ra. S tiu th b th qa mc hay ko theo vim cu thn v ri lon chuyn ha lipid nhng bnh nhn c mt yu t gi l yu t vim thn C3, yu t ny c l l mt t khng th thuc lp IgG c kh nng hot ho b th theo con ng khng c in.

THIU HT MIN DCH Tt c mi ngi, ai ai cng u b nhim trng. Khi a tr thot ra khi mi trng v trng trong t cung ngi m th lp tc b xm nhp bi v s cc loi vi sinh vt. Nhng v hu ht cc vi sinh vt ny u khng gy bnh nn khng to ra triu chng. tr con, s xm nhp ca mt mm bnh m chng cha tng tip xc s gy ra bnh cnh nhim trng trn lm sng; nhng ng thi n cng to ra cho a tr mt tnh trng nh min dch v duy tr tnh min dch lu di cho a tr. Mt a tr, hay mt ngi ln, s b nghi ng l thiu ht min dch (THMD) khi trn c th xut hin nhng nhim trng lp i lp li, tn ti ko di, trm trng hoc bt thng. Thiu ht min dch c th chia thnh tin pht hoc th pht, v c th xy ra theo c ch c hiu hoc khng c hiu. Tuy nhin, c nhiu thiu ht c th m h, thong qua hoc khng phn loi c. Theo mt bo co thng k th hn mt na s bnh nhn b nhim trng lp i lp li hon ton bnh thng v mt min dch hc. Trong khi khong 45% c biu hin t nht l mt kiu thiu ht chc nng min dch, m chim phn ln l thiu ht min dch khng c hiu (Hnh 10.1).

Hnh 10.1. Phn b nguyn nhn ca nhim trng lp i lp li tr em 10.1. Thiu ht min dch tin pht 10.1.1. Thiu ht khng th (THKT) tin pht 10.1.1.1. Chn on thiu ht khng th tin pht tr em Thiu ht kh nng sinh tng hp khng th c th xy ra kha cnh s lng hoc cht lng: thiu ht v s lng c th xy ra cho tt c cc lp khng th (thiu ht ton phn) hoc ch mt lp hoc tiu lp (thiu ht chn lc) (Bng 10.1). Thiu ht khng th c th gp c tr em ln ngi ln; tuy nhin, cc kiu thiu ht hai la tui ny thng khng ging nhau v do khng c trnh by chung vi nhau. Bng 10.1. Phn loi thiu ht khng th tin pht

Gim gammaglobulin mu ton phn tr em Gim gammaglobulin mu c lin quan gii tnh Gim gammaglobulin mu nhim sc th thng th ln Thiu ht min dch bin i thng gp Thiu ht Ig c tng IgM Thiu ht min dch vi u tuyn c Thiu ht khng th vi mc Ig bnh thng Thiu ht IgA chn lc Thiu ht IgM chn lc Thiu ht tiu lp Ig chn lc Thiu ht chui kappa

Vic khai thc tin s k c th gip chng ta phn bit nhng th thiu ht min dch tin pht him gp vi nhng nguyn nhn thng gp ca nhim trng lp i lp li. V d, x ha nang hoc d vt ng th l nguyn nhn thng gp ca nhim trng h hp tr con. Thng tin do khai thc tin s: nhim trng lp i lp li ng h hp xy ra trn hu ht bnh nhn thiu ht min dch. Nhiu bnh nhn c nhim trng da (nht, p xe, vim m t bo), vim mng no hoc vim khp. Vi sinh vt thng hay gy nhim trng nht trong thiu ht min dch l cc vi khun sinh m nh t cu, hemophilus influenzae v streptococcus pneumoniae (Hnh 10.2). Nhn chung, nhng bnh nhn ny thng khng d b nhim nm hoc virus v min dch t bo vn c bo tn, tuy nhin ngoi l vn c th xy ra. i vi nhng trng hp thiu ht khng th bm sinh, nhim trng ti i ti li bt u xut hin trong khong thi gian t thng th 4 n 2 tui cn thi gian trc nh c khng th t m truyn sang nn tr khng mc bnh. (Hnh 10.3). Vic nghin cu tin s gia nh i lc cng t ra c gi tr chn on i vi mt s bnh c tnh di truyn. Tuy nhin, cn lu rng hin nay s con ci trong mi gia nh b gim i trong mt s quc gia v th m mt tin s gia nh m tnh khng loi tr c kh nng ca mt bnh di truyn. Thng tin thu c qua thm khm: Rt him khi c triu chng thc th mang tnh chn on i vi bnh thiu ht khng th mc d thm khm c th gip tm thy hu qu ca cc nhim trng trm trng trc , v d nh mng nh thng, dn ph qun, v.v... Mt hnh nh thng gp l chm pht trin.

Xt nghim cn lm sng rt cn thit cho chn on. nh lng cc Ig huyt thanh s cho hnh nh bnh l kh r. Rt t khi gp trng hp thiu hon ton Ig, ngay c trong nhng trng hp trm trng th vn cn pht hin c mt lng nh IgG v IgM. So vi nh lng Ig ton phn th nh gi kh nng sn xut khng th ca bnh nhn cho ch dn tt hn v kh nng nhim trng ca bnh nhn. Mt s c th cho thy mt kh nng to khng th c hiu sau khi tim

chng trong khi lng Ig huyt thanh vn bnh thng. Cc xt nghim v chc nng khng th bao gm: (1) pht hin hot tnh t nhin ca khng th; v (2) p ng vi tiu chun th nghim. Ngoi ra ngi ta cn m s lng t bo B lu ng qua pht hin phn t Ig trn b mt t bo ny (sIg). Trong mu bnh thng, s t bo sIg+ chim khong 5-15% tng s lymph. S vng mt ca t bo B trn mt bnh nhn thiu ht khng th gip phn bit bnh gim Ig mu lin quan gii tnh tr con vi cc nguyn nhn khc ca thiu ht khng th tin pht l cc bnh m trong s lng t bo B vn bnh thng hoc c gim nhng khng mt hn. 10.1.1.2. Nguyn nhn chnh ca THKT tin pht tr em - Gim Ig mu thong qua tr em IgG m c truyn ch ng qua nhau thai n tun hon phi bt u t thng th t ca thai k v lng truyn ny t ti a vo 2 thng cui. Khi mi sinh tr c mt lng IgG t nht l bng lng ca m truyn sang. Sau lng IgG m thoi ha s c thay th bng s sinh tng hp IgG ca c th con, nhng v tr khng tng hp ngay c mt lng ln nn gia thng th 3 v thng th 6 xut hin mt thi k gim Ig mu sinh l. Tr bnh thng th khng d b nhim trng trong thi k ny v khng th c chc nng hot ng tt d s lng IgG c gim st; hn na, chc nng t bo T vn cn nguyn vn. Tuy vy, s gim IgG c th nng hn nu lng IgG nhn t m cn t nh trong trng hp non chng hn. Gim Ig mu thong qua cng xy ra khi a tr chm tng hp IgG cho c th, trong khi lng IgG m tip tc gim, lc tr c th b nhim trng sinh m ti i ti li. iu quan trng l cn phn bit bnh cnh ny vi bnh l thiu ht khng th tht s v vic iu tr chng khng ging nhau. Trong a s cc trng hp, tr vn khe v khng cn iu tr c hiu. Nu c nhim trng nng cn b sung Ig phng t vong. iu tr c th ko di 1-2 nm hoc cho n khi c th sinh tng hp IgG. - Gim Ig lin quan gii tnh tr em (bnh Bruton) Tr nam mc bnh ny thng c nhim trng sinh m lp i lp li vo

khong tui 4 thng n 2 nm. Vng v c quan b nhim trng cng ging nh trong nhng trng hp thiu ht khng th khc. Trn a s thng hoc thm ch cn tng. Khng tm thy tng bo trong ty xng, hch bch huyt hay ng tiu ha. Tt c nhng iu ny ni ln tnh trng thiu ht mt vi mi trng cn thit cho s hnh thnh t bo B (Hnh 10.4), mc d c ch chnh xc vn cha c r.

Hnh 10.4. S minh ha cc bc trng thnh ca t bo B v cc v tr m thiu ht khng th c th xy ra Chn on da vo nng rt thp ca tt c cc lp Ig trong huyt thanh, vng mt t bo B lu ng v tin s mc bnh ca nhng tr nam khc trong dng h. Tuy nhin, cng c khi yu t di truyn khng r rng. Gen b tn thng hin nay c xc nhn l nm trn on gn ca cnh di ca nhim sc th X. iu tr bao gm liu php b p Ig cho tr bnh, hoc x l gen cho bo thai v hin nay vic chn on bnh trc khi sinh l vic hon ton c th thc hin c.

- Thiu ht min dch bin i thng gp (common variable immunodeficieny, CVI) Thut ng ny dng ch mt nhm bnh thiu ht min dch kh a dng xut hin tr con hoc ngi ln. Tuy nhin, a s bnh nhn c chn on trc tui trng thnh. - Thiu ht IgA chn lc y l thiu ht tin pht thng gp nht i vi min dch c hiu, chim t l trong nhn dn l 1/700 Anh. Bnh c th xut hin bt c la tui no v c c trng bi nng IgA huyt thanh rt thp trong khi nng IgM v IgG vn bnh thng. Nhiu ngi b thiu ht IgA vn sng khe mnh bnh thng v ta ch tnh c pht hin trong nhng t kim tra mu nh k. Tuy nhin nhn chung th ngi thiu ht IgA vn c mt s biu hin lm sng bt thng v rt a dng (Hnh 10.5).

Hnh 10.5. Nh ng ri lon thng i k m vi thiu ht IgA Trn khong 1/3 s ngi b thiu ht IgA, ngi ta pht hin thy c khng th khng IgA. Mt s trong nhm ny xut hin phn ng khng may

khi c truyn mu hoc plasma do chng ta cn xem vic nh lng IgA nh mt vic thng quy khi theo di phn ng truyn mu. - Thiu ht tiu lp IgG Thiu ht mt hay nhiu tiu lp IgG l iu thng hay b b qua bi v nng tng i cao ca IgG1 (khong 70%) c th che lp s thiu ht cc tiu lp khc v ta vn o c mt nng IgG gn nh bnh thng. Tt c cc trng hp thiu ht tiu lp ca IgG u d gy ra nhim trng h hp. Tuy nhin hot tnh khng th ch yu c th tp trung vo mt tiu lp no . V d, IgG2 chim u th trong p ng khng th chng cc khng nguyn polysaccharid ca Streptococcus pneumoniae v Haemophilus influenzae, do nu thiu ht IgG2 th d gy ra nhim trng ng h hp lp i lp li, nhim trng huyt hoc vim mng no do pneumococcus. Ngoi ra, chng ta cn phi lu thm rng, mt p ng to IgG1 sau khi gy min dch khng loi tr s thiu ht IgG2. Thiu ht IgG2 c th xy ra km vi thiu ht IgA v IgG4. Nhng ngi b thiu ht kt hp ny d dng mc bnh phi hn l ch b thiu ht mt mnh IgA. Thiu ht IgG1 v IgG3 thng hay phi hp vi nhau v gy ra p ng min dch yu i vi khng nguyn c bn cht protein nh khng nguyn trong vi khun bch hu hoc un vn. Cng c khi ngi ta ghi nhn s phi hp bt thng gia thiu ht cc tiu lp IgG vi bnh cnh trng c v nh khng c lin quan nh ng kinh tr con, tuy nhin s lin h ny c tnh nhn qa khng th cha c r. 10.1.1.3. Chn on phn bit Triu chng ch yu ca thiu ht min dch l nhim trng ti pht lun, nhng thiu ht khng th tin pht l bnh him gp do m chn on phn bit khng d dng. Nu nhim trng ti pht mt v tr duy nht th nguyn nhn c l ch khu tr ti ch. V d, vim mng no ti i ti li thng l do s thng thng gia xoang vi dch no ty, trong lc vim phi ti i ti li th c th do x ha nang hoc d vt ng th. Gim gammaglobulin mu th pht c th xy ra sau nhiu ri lon khc nhau v nhiu sch gio khoa lit k ra mt bng danh mc v nguyn nhn kh di. Tuy nhin, ng trn quan im thc hnh, bng lit k ny t

ra chng gip ch g nhiu. V d, mc d hi chng thn h tng i thng gp tr con (so vi thiu ht min dch tin pht) v chc chn gy ra hm lng Ig thp cho bnh nhn, nhng nhim trng ti i ti li khng phi l mt vn trm trng y. 10.1.1.4. Bin chng ca thiu ht khng th Bnh nhn thiu ht min dch d mc kh nhiu kiu bin chng: Nhim trng mn tnh ng h hp dn n vim mn tnh tai gia, vim xoang, dn ph qun, x ha phi v cui cng l tm ph mn. Bnh tiu ha nh xy ra 2/3 s bnh nhn ngi ln b thiu ht khng th. Hi chng ging thiu mu c tnh tng i ph bin v khc vi thiu mu c tnh c in ch khng c khng th khng t bo thnh d dy v khng yu t ni; vim d dy teo t xy ra trn ton b d dy khng ngoi tr vng hang v v lng gastrin huyt thanh thp hn. Triu chng a chy c km hoc khng km km hp thu xy ra l do nhim giardia lamblia, vi khun ny pht trin mnh trong rut non hoc do nhim trng dai dng crytosporidum, campylobacter, rotavirus hoc enterovirus. Trn mt s ngi ln c thiu ht min dch bin i thng gp, c th c tng sinh t chc lympho ng tiu ha. S tng sinh ny lnh tnh mc d i khi ch tng sinh ln n mc c th gy tc rut. Vim ng mt mn tnh c th xy ra do nhim trng ngc dng ng mt: mt s trng hp c th dn n x gan. Bnh l khp c th gp trn khong 12% cc trng hp thiu ht khng th. Vim khp nhim trng m c bit l do Mycoplasma hoc ureaplasma cn phi loi tr. Mt s bnh nhn b vim a khp mn tnh cc khp ln, mt s khc b vim mt khp khng c hiu v mt s thiu s b thp khp c hiu vi vim khp lot v ht thp di da nhng khng c yu t thp. Theo kinh nghim th kh m chn on nhm bnh nhn thiu ht khng th vi bnh Still hoc vim khp dng thp. Nhim trng virus h thn kinh trung ng him gp trong CVI, nhng nhng tr b gim gammaglobulin huyt lin quan gii tnh th d nhim virus ECHO mn tnh. iu ny c th gy ra vim no-mng no nng v dai dng, i khi c hi chng ging vim da c. Bnh ny thng dn n t vong mc d c iu tr bng liu php truyn Ig.

Bnh nhn thiu ht min dch th v hoc t bo c tng kh nng mc bnh c tnh t 10 n 200 ln. a s cc u c ngun gc lympho-li, mc d cng c khi gp u d dy sau khi c vim d dy th teo t. 10.1.1.5. i u tr thiu ht khng th Chn on trc l iu cn thit h thp t l bin chng. Liu php thay th Ig l iu cn thit cho bnh nhn thiu ht khng th. Hin nay trn th trng lun sn c cc ch phm Ig tim bp. Ngi ta thng sn xut cc ch phm ny t huyt thanh ca mu nhiu ngi cho trn li sn phm c kh trng i vi cc virus truyn theo ng mu, nht l HIV. Cht chim a s trong sn phm l IgG v hot tnh khng th l hot tnh ca huyt thanh trn ln. Cc ch phm kiu ny thng khng bao gi ngi ta tim tnh mch. Liu Ig ph thuc vo trng lng ca bnh nhn. Bnh nhn mi c chn on nn cho 50mg/kg trng lng/ngy trong 5 ngy, sau 25mg/kg/tun. C iu cn lu l vic tim bp Ig c nhiu nhc im. Nhc im ln nht l khong 20% ngi dng b phn ng ton thn. Phn ng xy ra trong vng vi pht sau khi tim ging nh mt phn ng phn v c in tc l gy ra do s kt tp IgG lm hot ha b th v tn cng t bo mast gy mt ht. Tc dng ph ti ch bao gm au, tn thng dy thn kinh v hnh thnh cc p xe v trng. Ngoi ra, s hp th Ig theo ng tim bp rt thay i v c lin quan n s lng tim vo. Do trong liu php ny khng nn lng IgG huyt thanh vt qu 2-3g/l. Cc sn phm Ig tim tnh mch hin nay trn th trng c nhiu u im: (1) c th cho liu ln hn do nng IgG huyt thanh c th t mc cao hn; (2) truyn tnh mch t gy au v khng cn phi tim nhiu ln; (3) t gp phn ng ph. Nh vy ta c th thy rng vic iu tr c th tin hnh nh nh trong trng hp iu tr bnh a chy mu bng truyn yu t VIII. Hiu qu ca Ig tnh mch trong vic lm gim tn s v trm trng ca nhim trng ph thuc vo liu s dng. Cho liu 0,4g/kg cn nng mi 3-4 tun c th gip t nng IgG huyt thanh 5g/l sau 3-6 thng. Nhc im chnh ca Ig tnh mch l c th truyn bnh vim gan khng-A

khng-B, v gi thnh tng i t. Cc phng tin iu tr chung bao gm pht hin v chn on sm cc trng hp bnh mi. Cn phi phn bit mt s bnh cnh d nhm vi bin chng ca gim gammaglobulin huyt nh d vt ng th c th b b qua trn tr thiu ht khng th c triu chng ng h hp. Bnh nhn thiu ht khng th cho p ng nhanh vi khng sinh thch hp nhng chng ta khng nn dng khng sinh trc 10-14 ngy. 10.1.2. Thiu ht min dch t bo tin pht 10.1.2.1. Cc kiu thiu ht Thiu ht chc nng t bo T n thun (Hnh 10.6) him gp: thng thng, suy gim tnh min dch ca t bo T thng i km vi cc bt thng ca chc nng t bo B, ni ln s tng tc t bo T-B cn thit cho s sinh tng hp khng th i vi hu ht khng nguyn. Khc vi thiu ht khng th, suy gim min dch t bo xut hin trong vng 6 thng u ca tr. V d, vo thng th ba v th t, hi chng DiGeorge c th xut hin vi cc triu chng nng n nh co git, d tt ng tim mch ch khng phi do nhim trng.

Hnh 10.6. S cc giai on trng thnh t bo T v nh ng v tr m thiu ht min dch t bo c th xy ra Trn mt s tr ngi ta thy c hin tng mt chc nng ca t bo B ln t bo T, l thiu ht min dch kt hp nng (severe combined immunodeficiency, SCID). SCID c nhiu bin th khc nhau c phn bit da trn s thiu ht enzym, cch thc di truyn v mc sai st trong bit ha. Nhng tr mc hi chng ny hu nh u c triu chng i chy mn tnh v khng pht trin trong nhng tun tui u tin. Ngi ta ch lu n bnh khi thy tr c nhiu t vim d dy - rut. Ghp ty t ra c hiu qu trong vic iu chnh khim khuyt min dch trong trng hp ny. Chng ta cn lu rng nhng bt thng v enzym ca con ng chuyn ha purine (v d nh adenosine deaminase, purine nucleoside phosphorilase) cng th hin thnh thiu ht min dch do cc cht chuyn ha c hi tch t trong t bo T v B. Thiu ht adenosine deaminase c th kt hp vi thiu gammaglobulin mu thong qua tr con. 10.1.2.2. X tr thiu ht min dch t bo (Bng 10.2) Pht hin sm l iu cc k thit yu. Phng nga thiu ht thng l tt hn iu tr v ngi ta thng khuyn l nn cho kho st gen ca nhng a tr trong gia nh nghi ng c th b thiu ht min dch di truyn. Trong trng hp pht hin thy trong nh c ngi b thiu ht enzym, chng ta c th tin hnh pht hin ngi mang gen bnh cng nh pht hin bnh trc sinh. V d trong thiu ht adenosine deaminase, chn on trc sinh c th thc hin bng cch do hot tnh adenosine deaminase (ADA) trong t bo x ca nc i.

Bng 10.2. Cc bin php x tr i vi thiu ht min dch t bo.

Cn trnh tim chng vi vc-xin sng hoc truyn mu c in i vi bnh nhn c nghi ng thiu ht min dch t bo: vc-xin sng c th dn n nhim trng lan ta v truyn mu c th gy ra bnh ghp chng ch tr khi mu c chiu x trc khi truyn. Ghp t bo c thm quyn min dch cho ta mt hy vng duy nht l duy tr thng xuyn p ng min dch thay th trong c th. Ghp ty l iu tr chn la i vi SCID v mt s thiu ht khc nhng n cng c th gy ra mt s nguy him nh bnh ghp chng ch chng hn. thay cho vic ghp ty tc l truyn cc t bo mm, ngi ta a ra mt phng php khc l cc m ly t cc phi sng v cc m ny khng gy bin chng nh trn. Ngi ta dng gan phi v tuyn c phi vo mc ch ny, nhng chng may c hai loi u c th gy bnh ghp chng ch nng c th lm cht ngi d rt him khi xy ra. Thay th cc yu t b thiu l bin php hp l nhng thnh cng rt hn ch. Trong nhng nm gn y ngi ta cho ra i nhiu loi tinh cht tuyn c, nhng qua iu tr th i vi thiu ht min dch t bo tin pht cha c ch phm no cho kt qu mong mun. Bin php thay th enzym cho nhng bnh nhn thiu men adenosine deaminase (ADA) hoc purine nucleoside phosphorilase (PNP) cng ch cho mt kt qu hn ch. Ch phm dng hng cu cha ADA v PNP cho ng lnh v chiu x l mt ngun tt cung cp cc enzym ny nhng kt qu iu tr so vi ghp ty cng chng tt hn. Truyn hng cu l mt bin php cm chn ch khng phi l bin php iu tr. Thit lp bn gen i vi cc gen ADA, PNP, v MHC c tin

hnh mt s c s nghin cu, v ngi ta cng nhn c cc gen tng ng lu gi nh mt ngun cung cp. ng thi ngi ta cng thnh cng trong vic cy gen ADA vo cho mt retrovirus cc t bo c cho nhim virus ny c th sn xut c hot tnh ADA ngi. C l thiu ht ADA v PNP s l cc bnh l ngi u tin c iu tr bng bin php truyn gen mc d hu qu lu di (v d nh nguy c mc ung th do a DNA ca retrovirus vo genom ca ngi) th vn cn cha r. 10.1.3. Thiu ht min dch khng c hiu tin pht Hot ng min dch dch th khng ch ph thuc s sinh tng hp khng th m cn ph thuc vo cc c ch loi tr khng nguyn c gn vi khng th trong s loi tr khng nguyn bng b th v bng thc bo l hai c ch rt quan trng. S ly gii vi khun ph thuc b th cn n s hot ha v c nh b th. Cc vi sinh vt c gn IgG (tc l c opsonin ha) s sn sng c tiu ha bi cc t bo thc bo. Nh vy, hot ng min dch c hiu cn n cc c ch hiu qu khng c hiu hon thnh nhim v ca mnh mt cch trn vn: s ph thuc ny phn no gii thch cc bin chng nhim trng m bnh nhn mc phi khi khng b thiu ht sinh tng hp khng th nhng thiu ht chc nng t bo trung tnh (Hnh 10.2 ) 10.1.3.1. Thiu ht chc nng t bo trung tnh Chc nng chnh xc ca t bo trung tnh l n, git v tiu ha cc vi sinh vt xm nhp vo c th, nht l vi khun v nm. Nu chc nng ny khng thc hin c th nhim trng xy ra. Thiu ht chc nng t bo trung tnh c th do thiu ht s lng (chng gim bch cu trung tnh) hoc thiu ht cht lng (chng ri lon chc nng neutrophil). Tuy nhin, v mt lm sng th c hai loi thiu ht c th ging nhau v thng mang tnh cht ton thn. Thc vy, nhim trng y c cc biu hin sau: Lp i lp li v ko di Hnh nh lm sng c th ngho nn mc d nhim trng rt nng p ng kp vi khng sinh Nguyn nhn thng gp nht l t cu Nhim trng bao gi cng c da v nim mc Bnh gy nhim trng sinh m mch bch huyt. Chng gim bch cu trung tnh thng gp hn ri lon chc nng

neutrophil v gim th pht th thng gp hn gim tin pht. Chng ny cng ng thi l hiu ng th pht thng gp ca liu php ha hc chng ung th. Lng neutrophil lu ng bnh thng khong 1.5 triu/ml. Khi c gim nh t bo trung tnh, triu chng thng khng c, nhng khi gim va ri nng th nguy c cng nh trm trng ca triu chng nhim trng tng ln r rt. Nhim trng c th e da tnh mng khi lng neutrophil xung di 500.000/ml. Gim bch cu trung tnh tin pht thng him gp. Cn cc dng bm sinh c th gy ra t bnh cnh nh nht l gim neutrophil mn lnh tnh n nng nht l gy t vong nhanh. Chng ri lon chc nng neutrophil c th chia thnh thiu ht giai on pht trin v thiu ht cht lng t bo ty theo s thiu ht xy ra khu no (Bng 10.3). Hin tng gim di ng neutrophil c th xy ra m khng gy ra sai st trong kh nng thc bo. Chc nng opsonin ha km do thiu ht khng th hoc lng C3 thp do mt nguyn nhn no cng c th lm tng kh nng nhim trng. Khi c ch dit khun ni bo b mt, vi khun c th tn ti v tng sinh bn trong t bo, trnh c tn cng ca khng th v cc loi khng sinh. Bnh cnh c trng cho trng hp ny l bnh u ht mn tnh (chronic granulomatous disease, CGD). CGD l mt nhm bnh xy ra do gim sn xut cc gc oxy dit khun xy ra trong qu trnh tng cng h hp ca hot ng thc bo. Trong nhm ny c nhiu dng di truyn. Dng c in l ri lon di truyn ln lin quan n gii tnh xy ra in hnh vo 2 thng u ca i sng vi nhim trng da nng do t cu vng, vi khun gram (-) hoc nm. Bin chng thng gp gm vim hch bch huyt vng tng ng, gan lch ln, p xe gan v vim xng ty. Trong c quan tn thng thy hnh nh a p xe v u ht t bo khng l khng casein ha. Xt nghim sng lc n gin nht i vi CGD l th nghim dng nitroblue tetrazolium (NBT) nh gi kh nng t bo ht sn xut cc gc superoxide trong qu trnh thc bo. Bng 10.3. Cc kiu thiu ht chc nng neutrophil ch yu gy ra nhim trng ti pht nhiu ln

Bnh/Hi chng

Hnh nh lm sng

Kiu thiu ht

Bnh u mn tnh

1. Nhim trng gram Chuyn ha (+) c catalase qua 2. Hnh thnh u ht phn ng oxy ha

Hot tnh dit khun Hi chng tng 1. Hnh nh gng mt Bt thng IgE v nhim th ha hng trng ti din ng 2. Nhim candida da nim mc 3. Tng thanh IgE huyt

4. p xe phi, thot v phi (pneumatocele) Hi chng 1. Ht tiu th khng l Bt thng Chediak -Higashi trong t bo tit ha hng ng 2. Bch tng mt-da tng phn Dit khun chm Thiu ht th th 1. Cun rn rng chm Thc bo CR3 2. Nhim trng da v Kt dnh vim li 3. p xe su, vim phc mc, vim xng - ty xng

10.1.3.2. Thiu ht b th Bin i chc nng b th thng xy ra th pht sau nhng bnh c tiu th b th qua ng c in hoc khng c in. Mt v d thng c cp l: trong bnh lupus ban h thng, kh nng ha tan phc hp min dch ca b th b bin i nhng mc nng nh khc nhau

ty thuc vo trm trng ca bnh. Ngoi ra, s tiu th b th theo ng c in i vi cc yu t C1, C4 v C2 trong bnh Luput ban h thng cn c th lm gim kh nng trung ha hoc ly gii mt s virus. ngi, thiu ht di truyn cc thnh phn b th thng i km vi nhng hi chng lm sng c trng. Nhng bnh nhn thiu ht C1, C4 hoc C2 thng th hin hi chng ging lupus (vi cc triu chng nh ban hnh cnh bm, au khp, vim cu thn, st) hoc vim mch mn tnh nhng him khi th hin thnh nhim trng sinh m, ti pht nhiu ln. Khng th khng nhn v khng DNA chui kp thng khng c. Thiu ht nhng thnh phn sm ny ca con ng c in c th lm cho c th kh khn trong loi tr khng nguyn virus v d dn n bnh phc hp min dch do s tn ti dai dng ca khng nguyn trong c th. Bnh thiu ht C3 c th l tin pht hoc cng c khi th pht sau thiu ht cc cht c ch C3b nh yu t I (C3b inactivator), yu t H (beta 1 H globulin). Ngi mc chng ny thng biu hin kh nng d b nhim khun ti pht nhiu ln v gy nguy him cho tnh mng nh b vim phi, nhim trng huyt, vim mng no. iu ny ni ln vai tr quan trng ca C3b trong chng nhim trng. Ngi ta ghi nhn c s phi hp gia thiu ht C5, C6, C7 hoc C8 vi nhim trng neisseria lp i lp li. a s bnh nhn b nhim lu cu nhiu ln, nht l nhim trng huyt v vim khp do lu cu. Bnh nhn c th vim mng no do mng no cu. Thiu ht cht c ch C1 l thiu ht bm sinh thng gp nht ca h thng b th v gy ra chng ph mch (angioedema) bm sinh. 10.2. Thiu ht min dch th pht 10.2.1. Nguyn nhn ca thiu ht min dch th pht Nguyn nhn gy thiu ht min dch th pht ph bin hn nhiu so vi thiu ht tin pht. Bi v chc nng hot ng ca cc thnh phn ca h min dch ph thuc vo s cn bng gia s tng hp v s thai ha chng nn s thiu ht th pht s xy ra khi s tng hp km i hoc s thoi ha tng ln. S mt protein ca c th c th dn n gim gammaglobulin mu. l trng hp thng gp ca hi chng thn h (gy mt protein qua

ng thn) v cc bnh l rut gy mt protein. S mt protein trong bnh thn thng c tnh chn lc, do ta c th thy rng lng IgM vn bnh thng cn IgG th gim r. Trong bnh l rut, mt protein c th gp trong mt s bnh nh bnh Crohn, vim i trng lot v bnh celiac. Trong bnh cnh gin bch mch ng rut, ta c th thy mt c t bo lymph ln protein. Hnh nh gim sinh tng hp c th thy r trong suy dinh dng protein nng lng. Thiu ht protein dn n bin i su sc cc c quan trong c th k c h min dch. Trong trng hp ny chng ta c th thy gim kh nng sn xut khng th khi c th c gy min dch, ng thi, min dch t bo, chc nng thc bo v hot tnh b th cng thay i. Thiu ht min dch do nguyn nhn ny c th hi phc trong mt s trng hp khi c th c b y protein v calo. Bnh nhn b bnh tng sinh lymph c xu hng rt d nhim trng. S xut hin thng xuyn ca nhim trng c hi trn nhng ngi b ung th lan ta ni ln tnh trng b suy gim min dch kh nng n do hu qu c ch ca bnh hoc do iu tr. Bnh bch cu lympho mn tnh thng i km vi gim gammaglobulin mu v nhim trng h hp ti pht nhiu ln v iu ny lm cho bnh ngy cng nng dn nhanh chng. C trng hp nu ta cho b immunoglobulin th bnh s ci thin. U lympho nonHodgkin c th i km vi thiu ht min dch c th dch ln t bo; lng Ig vn bnh thng cho n giai on mun ca bnh. Hu ht cc bnh nhn a u ty u c gim Ig a cln, nhng li tng Ig n cln mt cch rt c trng. Cc thuc c ch min dch tc ng ln rt nhiu khu ca chc nng t bo. Chc nng ca lymph bo v bch cu mi thng gim. Rt t khi c gim gammaglobulin nng. Bnh nhn dng thuc c ch min dch trong qu trnh iu tr ung th hoc bo v mnh ghp thng rt d b nhim trng c hi. Chng ta cng nn lu rng mt s khng sinh cng c tc dng c ch min dch. l khng sinh c cu trc ha hc ging cc thuc chng chuyn ha v gy c t bo. V d nh gentamicin, amikacin v tobramycin c th lm gim kh nng ha hng ng i vi t bo trung tnh; cotrimoxazole, rifampicin v tetracycline c th lm bin i min dch t bo; chloramphenicol,

cotrimoxazole v rifampicin lm thay i p ng khng th s cp v th cp. Trong nhiu bnh nhim trng, vi sinh vt c kh nng c ch min dch hn l kch thch min dch. Ngi ta lu thy iu ny xy ra nng n, mc d ch thang qua, trong nhiu bnh nhim trng virus, nht l cytomegalovirus, si, rubella, n nhn nhim khun v vim gan virus v trong mt s nhim trng vi khun nh lao, brucellosis, phong v giang mai: tuy nhin, v d r nt nht l bnh cnh mi c pht hin trong nhng nm gn y, l hi chng thiu ht min dch mc phi (AIDS). 10.2.2. Hi chng thiu ht min dch mc phi (AIDS) Hi chng thiu ht min dch mc phi (Aquired Immunodeficiency syndrome, AIDS) l mt bnh dch tan cu gy nn do mt loi virus mi c pht hin gn y c tn l virus thiu ht min dch ngi tp I (Human Immunodeficiency Virus 1, HIV-1). y l mt virus thuc h retrovirus tc nhng virus RNA c mang mt enzym c o l enzym sao chp ngc (reverse transcriptase) c kh nng tng hp DNA chui kp c trng cho virus t genom RNA ca mnh. DNA mi ny s gn vo genom ca t bo ch v tr thnh khun sn xut nguyn liu RNA cho virus con. Virus con hnh thnh s to chi mng t bo ch v t bo ch cng s cung cp vt liu thnh lp v virus. Retrovirus c chia lm 3 nhm: (1) oncovirus, bao gm tt c cc virus sinh ung th nh virus bnh bch cu t bo T ngi (Human T cell Leukemia Virus I, HTLV-I); (2) spumavirus, l nhng virus m hin nay cha thy gy bnh g, v (3) lentivirus, trong c HIV-1. Lentivirus gy nhng nhim trng chm tc l virus tn ti mt thi gian kh lu trong c th mi to ra cc biu hin lm sng. HIV-1 l lentivirus gy bnh ngi c khm ph u tin v cng l loi u tin tc ng ln cc lympho bo. Kh v cc loi linh trng (primates) nui trong chung l nhng ng vt rt d b mc bnh thiu ht min dch v ngi ta phn lp c mt lentivirus ging HIV t kh maccacus c th gy hi chng ging AIDS trn kh (ngi ta gi l AIDS kh). Ti chu Phi, cc nh nghin cu cng tm thy mt virus c h hng rt gn vi virus AIDS kh ni trn v gi l SIV1agm; SIV-1agm hnh nh khng gy bnh trn con vt sng trong thin nhin nhng c kh nng gy bnh khi ta tim vo kh macacus.

Nm 1985, ngi ta tm thy khng th chng HIV trong huyt thanh nhng c gi im sng vng Ty Phi, huyt thanh ny cho phn ng vI SIV-1agm mnh hn vi HIV. Kt qu l mt lentivirus mi c pht hin v c t tn l HIV-2, v virus ny cng gy hi chng ging AIDS cho ngi.

10.2.2.1. Dch t hc AIDS Trc tin, mt iu thc s khng khip hin nay l virus gy bnh AIDS, tc HIV, ang lan trn khp th gii vi tc kh nhanh m s ngn chn khng phi l mt vic lm n gin. Theo mt ti liu dch t hc cng b trn t Scientific American nm 1988 ti Hoa K, Jonathan M. Mann, James Chin, Peter Piot v Thomas Quinn cho bit rng n nm 1988 c hn 250.00 trng hp mc bnh c thng k trn khp th gii, bn cnh , c khong t 5 n 10 triu ngi nhim HIV. Nm nm sau tnh trng tr nn xu hn nhiu. Lin minh chnh sch AIDS tan cu (Global AIDS Policy Coalition) c tnh rng vo cui nm 1987 s ngi nhim HIV khong 7 triu, nhng n cui nm 1992 th ln n khong 110.5 triu, tc tng khong gp 3 ln. Mc d c mt s thuc chng virus cng nh mt s phng tin khc c th gip phn no i sng, hu ht ngi nhim i n tnh trng bi quan l t vong. Cho n nm 1993 c khong 3 triu ngi mc bnh giai on ton pht, trong a s cht. Cc tnh ton thng bo rng vo nm 2001 s ngi nhim HIV l hn 40 triu. 10.2.2.2. S lan truy n ca HIV-1 HIV-1 c th phn lp t tinh dch, cht tit c t cung, t bo lympho, huyt tng, dch no ty, nc mt, nc bt, nc tiu v sa m. Nhng khng phi tt c cc dch ny u c th truyn bnh bi v nng virus trong chng rt khc nhau, v th ch c tinh dch, mu v c th c dch c t cung c chng minh l c th truyn bnh. Cch truyn ph bin nht ca virus trn th gii (Bng 10.4) l quan h tnh dc d ng gii hay khc gii. Vic ly truyn cng c th xy ra qua ng dng chung kim tim gia nhng ngi tim chch do nghin ngp hoc nhng bnh nhn c iu tr bnh vin khng thc hin ng qui trnh v trng. Vic truyn bnh t m sang con trong qu trnh mang thai hoc lc sinh l ng ly ch yu i vi AIDS tr em. Ngoi ra chng ta cn nghe ni n nhng trng hp b ly bnh do nhn mu, sn phm mu, nhn c quan ghp hoc tinh dch c HIV.

Bng 10.4. c dim ca bnh nhn AIDS ngi ln T l % bnh nhn Nam tnh dc ng gii/lng gii Ngi nghin tim chch tnh mch Bnh nhn mc bnh a chy mu Ngi nhn mu c HIV Ngi tnh dc khc gii Cc loi khc Nam N Hoa k 66 17 1 2 4 3 93 7 Anh 87,5 1.5 4 2 3.5 0.5 96.5 3.5

Ngoi ra, ngi ta ghi nhn c mt s ca nhn vin y t c phn ng huyt thanh dng tnh do kim m hoc dnh mu bnh nhn. Tuy nhin, ng truyn theo mui, rp, truyn qua h bi, qua dng chung dng c n ung, dng c v sinh hoc th chung khng kh vi bnh nhn th cha c chng minh.

10.2.2.3. Hnh nh lm sng ca nhim HIV-1

AIDS khng phi l hu qu c nht ca nhim HIV-1: virus c th gy ra nhiu bnh cnh (Hnh 10.7) m nhn chung th tin lng u xu.

Hnh 10.7. Cc giai on lm sng ca nhim HIV-1 PGL = Bnh l hch ton thn ko di; ARC = Phc hp cn AIDS; KS = U Kaposi Bnh cnh st c ni hch cp tnh c th xy ra thong qua trn 1020% bnh nhn trong nhng tun l u tin sau khi nhim HIV-1. Xt nghim mu ngoi bin cho thy c 50% t bo lymph khng in hnh, ng thi c gia tng s lng t bo T c ch vo thi im ny. Hu ht nhng ngi huyt thanh dng tnh ri s khng c triu chng g, t nht l trong mt thi gian ngn, v sau s xut hin ca AIDS c l s ph thuc vo cc yu t km theo nh c a di truyn, b kch thch lp i, lp li ca khng nguyn ngoi lai hoc mang thai. Sau mt thi gian tim tng ko di khong t vi thng n 7 nm hay hn na, nhng ngi nhim HIV-1 s i vo mt qu trnh bnh l gi l bnh l hch ton thn ko di (persistent generalized lymphadenopathy,

PGL). Cc nghin cu trn nhng bnh nhn ng tnh luyn i nam b PGL cho thy rng c khong 10-25% nhng ngi ny s tin trin qua AIDS trong vng 3 nm. Mt s ngi huyt thanh dng tnh c th c cc biu hin khc nh sng hch, a chy, ra m hi m, nhim candida ming v st cn m khng gii thch c nguyn nhn. Ngi ta gi phc hp cn AIDS i vi nhng trng hp c t nht hai triu chng lm sng v hai hoc nhiu hn cc du hiu cn lm sng lit k Bng 3.5. HIV cng l mt virus hng thn kinh; do ngi ta thng bo gp nhng bnh cnh thn kinh nh vim mng no v trng cp, bnh l no, bnh l ty sng v bnh thn kinh ngoi bin trn ngi b nhim HIV vo giai on sm. Ngoi ra, vo giai on mun cn c th thy vim mng no mn tnh, bnh l no mn tnh v tr tr tinh thn. Cc biu hin lm sng chnh ca AIDS l ung th v nhim trng c hi. Hin nay, chn on AIDS c thit lp i vi nhng ngi c: (1) bnh l th hin r nt thiu ht min dch t bo mc va v nng nh vim phi do pneumocystis carinii hoc u Kaposi; v (2) khng tm thy cc nguyn nhn khc ca s thiu ht min dch t bo cng nh nguyn nhn ca gim sc khng i vi nhim trng.

Bng 10.5. Chn on phc hp cn AIDS

Hai triu chng lm + Hai bt thng v xt sng nghim St v/hoc ra m hi Gim lymph bo m (>3 thng) Gim tiu cu Mt ngi Gim t bo T gip St cn (>10% trng Tng gammaglobulin mu lng c th) Sng hch (>3 thng) Gim kh nng chuyn dng

a chy khng r nguyn lymph bo nhn D ng da vi cc khng nguyn gp li Chn on b loi b nu tt c cc xt nghim cn lm sng ni ln tnh trng thiu ht min dch u m tnh. U kaposi l loi u thng c cp nht, nhng cc loi u khc cng cng ngy cng c m t nhiu hn nh: u lymph non-Hodgkin, u t bo vy ming v trc trng hu mn. Nhim trng c hi trong AIDS c th xy ra bt c c quan no nhng c quan thng b nht l phi, ng tiu ha v h thn kinh trung ng. Ngoi nhim trng c hi, cc c quan ny cn c th b thm nhim bi u hoc b tc ng trc tip ca HIV-1 m h thn kinh trung ng l mt v d in hnh. Tr b AIDS do m truyn sang thng pht bnh vo tui trung bnh khong 6 thng, trong khi tr s sinh nhim bnh do truyn mu th pht bnh sau khong 12-15 thng. C hai nhm u c bnh cnh lm sng ging nhau: tr khng pht trin v hu nh tt c u c nhim candida ming cng nh nhim trng sinh m lp i lp li. Vim phi k mn tnh l bnh cnh rt c trng. Vo giai on mun, nhim trng c hi in hnh c th xut hin nhng u Kaposi v cc ung th khc th him khi gp cc tr ny. Tin lng i vi AIDS tht bun thm: ni chung l s cht, v thi gian sng st ty thuc vo biu hin lm sng. Thi gian sng cn i vi ngi b nhim phi do pneumocystis carinii l 9-12 thng, i vi cc nhim trng c hi khc l 6-12 thng v i vi u Kaposi l 20-30 thng. 10.2.2.4. Min dch hc ca AIDS HIV-1 chui vo cc t bo thch hp nh gn glycoprotein ca mnh vo mt receptor trn b mt t bo, l phn t CD4. Nhng t bo c mang khng nguyn CD4 u c kh nng nhim HIV-1: in hnh l t bo lymph T gip , mt s t bo B, i thc bo, t bo thn kinh m, v ngoi ra mt s t bo biu m ca i - trc trng cng mang CD4 vi mt thp.

Nhng bnh phi hp HIV (HIV-associated diseases) c c trng bi nhng tn thng ca chc nng min dch (Bng 10.6). Nhng tn thng ny xy ra do s suy gim s lng t bo CD4+, nht l t bo T gip . Khi t bo T gip bnh thng c kch thch bi khng nguyn chng p ng bng cch phn bo v gii phng cc lymphokin, bao gm interleukin-2, interferon v yu t pht trin t bo B (B cell growth factor, BCGF): nhng cht ny iu ha s pht trin, trng thnh v hot ha cc t bo lympho khc, cc t bo mono c i thc bo. T bo T gy c sau khi c hot ha s tiu dit cc t bo b nhim virus, trong khi i thc bo hot ha tiu hy cc vi khun ni bo nh Mycobacterium tuberculosis. Cn interferon, mt lymphokin khc th kch thch s tiu ha ca t bo git t nhin (NK cell) v ng thi tham gia kim sot s hnh thnh ung th. Nh vy, tc ng ni bt nht ca HIV l nhm n p ng qua trung gian t bo T. Cc th nghim in vitro c th cho thy p ng tng sinh i vi khng nguyn lp li b bin i do gim sn xut IL-2 ngay c trn bnh nhn nhim HIV-1 cha c triu chng. Trong qu trnh din tin bnh, bn cnh s xut hin cc triu chng mi l s suy gim s lng tuyt i ca t bo CD4+, nht l t bo T gip . Bi v trong cc nhim trng virus khc c th c tng s lng t bo CD8+ (ch yu l t bo c ch v gy c) trong vng hai tun sau khi nhim, nhng y khi bnh nhn cha c triu chng th s lng t bo lymph v cc tiu qun th ca chng vn cn bnh thng. Bng 10.6. Cc bt thng min dch ch yu trong AIDS Cc bt thng c trng Gim s lng tuyt i t bo lymph CD4+ Gim p ng tng sinh i vi khng nguyn ha tan Thay i phn ng qu mn mun da Gim sn xut interferon khi p ng vi khng nguyn Hot ha t bo B a cln cng vi tng sn xut Ig ngu nhin

Gim p ng dch th khi gy min dch Cc bt thng khc Gim lymph bo Gim p ng tng sinh in vitro i vi mitogen t bo T v khng nguyn cng loi Gim p ng tng sinh i vi mitogen t bo B c hiu Gim sn xut interleukin-2 Gim tnh gy c t bo vi t bo nhim virus Tng lng phc hp min dch Gim hot tnh t bo NK Gim ha hng ng monocyte Khi bnh nhn tin trin n giai on phc hp cn AIDS th cc xt nghim v chc nng t bo T in vitro nh p ng vi mitogen v sn xut lymphokin b gim st v bnh nhn mt phn ng vi cc th nghim da qu mn mun. Cc chc nng ca t bo mono/i thc bo ngy cng tr nn bt thng v hot tnh ca t bo NK cng b gim st. Sinh thit hch bch huyt cho thy hnh nh nhng nang ln trong c thm nhim t bo lymph CD8+, gim t bo CD4+ v ph hy cu trc li bnh thng. Gii thch n gin nht v nguyn nhn ca nhng thay i ny l tnh trng thiu ht min dch gy ra do tc dng ph hy ca HIV trn t bo T gip , t bo mono v i thc bo. Tnh trng gim sn xut lymphokin v gim hot ha i thc bo l do nhim trng virus, nm v vi khun ni bo tn ti lu di. Bnh nhn i khi c biu hin gim t bo trung tnh hoc gim tiu cu; m bnh sinh c th lin quan n phc hp min dch. Sau khi nhim HIV mt thi gian ngn, p ng to khng th vn cha

thay i, do m khng th chng protein v v li virus l bng chng chnh chn on nhim virus. V sau, s hot ha a cln i vi t bo B c phn nh qua s gia tng nng Ig 80-90% bnh nhn AIDS. Nguyn nhn ca iu ny cha c hiu r nhng c l l lin quan trc tip n s hot ha t bo B ca HIV-1, v c th trong phi hp vi virus Epstein-Barr. Tuy nhin, p ng i vi nhng khng nguyn mi b gim st, v ngay c trong nhng bnh nhn b nhim trng c hi lan rng c th khng c t khng th no xut hin lm cho vic chun on huyt thanh hc kinh in khng th tin cy c trn bnh nhn AIDS. 10.2.2.5. Pht hin nhim HIV Khng th chng HIV thng xut hin khong 3 tun n 3 thng sau khi b nhim v sau th tn ti mi hu nh sut i. y l khng th chng cc glycoprotein v in hnh (gp120 v gp41). Mc d khng th trung ha c th nh lng c nhng nng thp v khng c ngha g trong thi im hin nay. Cng nh trong cc nhim trng virus khc, khng th chng HIV l bng chng trc tip ca nhim trng mc. Tuy nhin, khng c khng th khng c ngha l khng c s hin din ca virus.Trn mt s bnh nhn ngi ta thy vng mt cc khng th c hiu. Trong s ny k c nhng ngi ch mi nhim virus c c vi tun nn s sn xut khng th cha c th pht hin c; v nhng ngi giai on cui ca AIDS, lc mc khng th gim st nhiu hoc bin mt. Khng nguyn virus, nht l khng nguyn li ca HIV-1 (gp41) cng c mt trong huyt thanh nhng ch pht hin c vo giai on c tha khng th i vi p24, iu ny xy ra vo lc ban u ca nhim trng v trc khi bnh tin trin sang phc hp cn AIDS hoc AIDS.

10.2.2.6. Cc hng i u tr AIDS Nhng kin thc v ng xm nhp ca HIV vo t bo CD4+ v cch thc nhn ln ca chng gip chng ta tm ra cc bin php iu tr c ha hn (Hnh 10.8)

Hnh 10.9. Cc phng php iu tr nhm ngn nga hoc loi tr nhim HIV-1. (RT = enzym sao chp ngc)

S gn ca virus vo phn t CD4 trn b mt t bo c th c ch c nh khng th chng v virus hay chng receptor. Trong vic phng bnh, khng th chng virus phi l khng th trung ha, v mc tiu ca vc-xin thch hp l to ra mt khng th nh vy. Cc vacxin c in dng virus cht hoc gim c lc hnh nh khng c gi tr trong trng hp AIDS. Tnh cht mong manh ca v HIV lm cho n c tnh sinh min dch km. ng thi kh nng bin i khng nguyn ca retrovirus rt nguy him trong trng hp ca HIV, nht l khi cng t bin tr li dng hot ng. Do , vacxin HIV khng c c nhng on RNA c kh nng nhn ln. Vic dng k thut DNA ti t hp to ra c nhiu sn phm c th dng sn xut vc xin, nhng tt c u trong giai on th nghim. c ch nhn ln ca virus c th thc hin c bng cch c ch hot tnh ca enzym sao chp ngc (reverse transcriptase) l enzym retrovirus duy nht khng c th vt. C nhiu thuc c ch c enzym sao chp ngc trong phng th nghim nhng trong c th th tc dng rt km hoc khng tc dng. Azidothymidin (AZT) l thuc ang thng dng trn th

trng c tc dng c ch s nhn ln ca virus. N l cht ng dng ca thymidin ly c t DNA tin virus. Tuy nhin, AZT khng th cha khi AIDS v n khng dit tn gc c genom ca virus. Ngoi ra, tc dng c ca n i vi ty xng lm hn ch vic dng thuc lu di nht l nhng c th cha c triu chng. Mt bin php khc quan trng khng km s phng nga nhn ln ca virus l xy dng li h thng min dch ca c th ch. Ngi ta th dng IL-2, interferon hoc ghp ty nhng cha thy thnh cng no r rt. Trong iu tr nn phi hp vic xy dng li h thng min dch vi liu php chng virus.

10.2.2.7. Nhim trng trn c th suy gim min dch Nhng ngi b suy gim min dch t nhin hoc do dng thuc thng rt d nhim trng. Nhng bnh nhn ny c th b nguy c t hai ngun: cc tc nhn nhim trng thng gp (thng gy bnh cho c ngi lnh v bnh nhn) v cc nhim trng c hi (tc l cc vi sinh vt thng khng c kh nng gy bnh nhng khi c th b suy yu v mt min dch th chng nhn c hi d gy bnh). Chng ta phi lun lu n nhng nhim trng c hi do thuc gy ra. Theo mt kho st trn 75 bnh nhn b mc cc bnh min dch (nh bnh chng mng y cu thn, lupus ban h thng) c iu tr bng cc thuc c ch min dch th t l nhim trng l 3,7 ln/ngi; hoc 0,74 ln/ngi/tun c suy gim min dch. Vo khong 2/3 s bin chng nhim trng gy ra bi cc vi khun thng thng tc l cc mm bnh i vi ngi bnh thng. Cc tc nhn c hi chim 1/3, trong c mt s nhim trng c hi rt nng (chim 11% ton b cc nhim trng bin chng). Trong s 10 bnh nhn cht do nhim trng trong nhm bnh nhn ny, c n 8 ngi cht do nhim trng c hi: mt iu ng lu l s vi sinh vt gy cht ngi ch tm thy khi m t thi. Nhiu nghin cu tng kt a ra cc m hnh nhim trng c th dng trong chn on i vi cc c th ch lc b c ch min dch (Hnh 10.9).

Hnh 10.9. Lch xut hin ca nhim trng trn bnh nhn ghp thn HSV = Virus Herpes Zoster; CMV = Virus Cytomegalovirus; EBV = Virus Epstein-Barr; VZV = Virus Varicella Zoster; UTI = Nhim trng ng tiu

Nhng bnh nhn c nghin cu k nht l bnh nhn ghp thn. Vo thng u sau khi c ch min dch, cc nhim trng c hi hu nh khng c. Thay vo nguyn nhn nhim trng chnh l nhim trng do vt thng phu thut, do cc ng xng hoc nhim trng phi sau phu thut. Gia thng th nht v thng th t sau khi c ch min dch, nhim trng cytomegalovirus chim u th trong bi cnh c th c nhiu nhim trng khc nh nhim nm, virus v n bo: y l giai on nhim trng nguy him nht. Nhim trng t thng th t tr i c th xp thnh 3 nhm: nhm 1 l nhim virus mn tnh, c bit l CMV; nhm 2 l nhim trng c hi

thnh thong, m ng ch nht l nhim Pneumocystis carinii. Cryptococcus neoformans v Listeria monocytogenes; v nhm 3 l cc nhim trng thng gp trong cng ng. Trong c th c hai cng vo chnh i vi cc vi sinh vt c hi: vng mi hng hu v phn di ng tiu ha. Ht cc vi khun ang sng trong vng mi hng hu vo phi l c ch thng gp dn n vim phi, cn s lan ta vi khun t ng tiu ha th thng gy nhim trng huyt. Phi l ni nhim trng ph bin nht. Hnh nh lm sng khng c hiu: st, kh th v ho khan trn mt bnh nhn c thm nhim phi lan ta trn phim Xquang. Cy m v cy mu thng khng gip tm ra vi sinh vt gy bnh. Cn phi dng nhng phng php phc tp hn nh ra ph qun ph nang hay sinh thit ph qun mi mong chn an c nguyn nhn. Sau khi loi tr cc vi khun gy bnh thng gp nht l CMV, aspergillus, candida hoc pneumocystis carinii. Chng ta cn nhn r tm quan trng ca chn an v iu tr sm (nu c) khi thy rng nhng nhim trng phi nh vy thng mang li hu qu rt xu cho bnh nhn suy gim min dch: t l t vong chung l 50-65%.

TNH T MIN V BNH T MIN 11.1. Tnh t min Nhng nm ca thp nin va qua mang li cho chng ta nhiu hiu bit v s iu ha h thng min dch ngi bnh thng. Th nhng nhng hiu bit trong lnh vc t min th t ra rt chm, phn no l do vn ca trung tm iu ha min dch cha c gii p y : s dung np ca h thng min dch i vi khng nguyn bn thn c xc lp v duy tr th no? Trong lc ch i cu tr li chnh xc cho vn ny, chng ta c th t thm nhng cu hi khc. Mt cch tm tt, vn t min hin nay bao gm ba vn sau:

(1) C phi t min nhm vo c ch bnh thng ca iu ha min dch khng? (2) p ng t min c phi xy ra qua trung gian ca cc tiu qun th t bo T hoc t bo B c bit khng? (3) Tnh t min c ph thuc khng nguyn khng? Chng ta hy ln lt xem xt cc vn ny.

11.1.1. C phi phn ng t min nhm vo c ch bnh thng ca i u ha min dch? S hnh thnh mt p ng khng th bnh thng i vi a s khng nguyn protein i hi s tham gia ca 3 loi t bo: B, T, v t bo trnh din khng nguyn (Hnh 1). Vic sn xut t khng th cng vy, n i hi khng ch t bo B m c t bo T. Ta c th thy bng chng v iu ny qua th nghim ca David Wofsy (1985) v Seaman (1987). Chut NZB/NZW l ni th hin ca m hnh luput ban h thng ngi. Bng cch x l chng vi khng th n cln chng t bo T CD4+ th cc chut ny s mt t bo T gip . Nu ta cho x l sm khi chut cn rt non th c th phng c phn ng t min. Cn nu x l sau khi c phn ng t min th cng c th gip ngn chn s pht trin thm ca bnh. Cateron v cng s chng minh rng ch cn tim cho chut NZB/NZW nhng mnh F(ab)2 ca khng th khng CD4 l c th ngn nga c bnh t min cho n. Ngi ta thy chut c tim khng th ny cc t bo T lu ng c bc bi F(ab)2 ca anti-CD4 nhng cc t bo ny khng b loi b. Nh vy, tc dng ca anti-CD4 trong min dch khng ph thuc vo s loi b t bo T CD4+. iu tr kiu ny c chng minh l c th to ra nhng hiu qu c li cho chut mc cc bnh t min khc nhau trong c i ng typ I, vim khp do collagen, vim no ty t min thc nghim v nhc c nng. V vai tr ca t bo T, s hot ha t bo T c i hi nhng iu kin ging nhau trong p ng t min v p ng min dch bnh thng khng? Hnh 2 cho ta thy hnh nh ca s tng tc gia cc phn t vi nhau khi

xy ra s hot ha t bo T CD4+. Trn b mt ca t bo trnh din khng nguyn, khng nguyn l c gn vi khng nguyn ha hp m ch yu (MHC). i vi t bo T CD4+, loi MHC cn cho s tng tc l MHC lp II nh HLA-DP, -DQ, -DR. Phc hp gm khng nguyn l v MHC c nhn din bi th th khng nguyn ca t bo T (T cell receptor, TCR) to ra mt phn ng tng tc. Phn ng tng tc ny pht ra mt tn hiu khi pht s hot ha t bo T. S hot ha t bo T cn cn n mt tng tc b sung khc, l lin kt gia phn t CD4 vi MHC. Nh trnh by trn, F(ab)2 ca khng th anti-CD4 c th c ch s xut hin ca bnh t min, iu ny chng t rng phn t CD4 tham gia vo p ng ca t bo T trong phn ng t min ging nh trong p ng bnh thng. Qua cc nghin cu v sinh hc phn t, s lin quan ca cc bnh t min vi cc allel c hiu ca MHC lp II (v d lin quan ca vim khp dng thp vi HLA-DR4) ni ln rng s hot ha t bo T t min c th phi cn n cc tiu lp ca MHC lp II. Tuy nhin vai tr ca MHC lp II trong phn ng trnh din khng nguyn vn cha hon ton c sng t. 11.1.2. C phi p ng t min xy ra qua trung gian ca cc tiu qun th T hoc B c bit khng? Nu p ng t min xy ra qua trung gian ca cc tiu qun th t bo T hoc B, v nu cc t bo ny khc vi t bo tham gia vo p ng min dch i vi khng nguyn l th c l chng ta c th c ch chn lc phn ng t min m khng lm gim p ng min dch bnh thng. Chng ta bit rng t bo T CD4+ cn cho p ng to khng th i vi khng nguyn l. Cn min dch t bo th c th tn ta m khng cn chc nng h tr ca t bo T CD4+ d c b yu i phn no. Phn ng t min xy ra c qua trung gian ca tiu qun th t bo T CD4+ khng? Cc tiu qun th t bo T CD4+ c xc nh da vo chc nng, phenotyp b mt v nh vo vic s dng c chn lc cc gen ca TCR trn b mt t bo T. V mt chc nng, Mossan v cng s chng minh rng cc dng t bo T CD4+ thng c chia lm 2 nhm: mt nhm sn xut ch yu l interferon gamma (IFN gamma) v interleukin 2 (IL-2), cn nhm kia sn xut ch yu l IL-4, IL-5 v IL-6. Ngi ta vn cha xc nh c rng nhng

khc bit v chc nng in vitro ny c c trng cho t bo T in vivo khng. Ngi ta cn ghi nhn rng nu ta c ch mt chc nng no (tt nhin l in vitro) th chc nng kia khng b bt hot. iu ny c bit quan trng khi ng dng iu tr bnh t min. Tht tin li bit bao nu ta c th bo tn c mt chc nng no ca t bo T trong khi c th tin hnh c ch chc nng kia. Tuy nhin chng ti cng mun lu rng nhng suy ngh c gng c ch phn ng t min thng qua con ng chc nng t bo T cng c th khng ph hp hoc i sai hng. V phenotyp, ngi ta da vo cc du n b mt phn bit cc tiu qun th t bo T. Cc du n ny hnh nh c lin quan n c tnh trng hot ha ca t bo. V d, ta bit rng tt c cc tiu qun th ca t bo T u c mang nhng dng ng phn ca khng nguyn CD45 (tc T200). Trong s , nhng t bo cha chn mang nhng ng phn c trng lng phn t 205 220 kilodalton (kD) gi l CD45R. Nhng t bo CD4+ khi tip xc vi khng nguyn v thc hin chc nng gip t bo B th trn t bo T ny c s chuyn mch (switch) to ra ng phn 180 kD gi l CD45RO, du n ny c nhn din bi khng th n cln UCHL1. Cc t bo T tp trung trong mng khp ca bnh nhn thp mang ch yu khng nguyn CD45RO. Ngi ta tng xem y l ch tn cng ca mt s liu php min dch. Tuy nhin cc liu php min dch ny gy thng tn c phn ng min dch bnh thng ln phn ng t min, ng thi n tc ng ln khng nhng t bo CD4+ m c t bo CD8+ c mang ng phn ca CD45 nn vic ng dng vn ang cn rt hn ch. Bn cnh khng nguyn CD45, s hot ha t bo T cn dn n bc l thnh phn T55 ca th th IL-2 (cn gi l IL-2R hoc khng nguyn Tac). Thnh phn ny cng c xem l mt ch th hai ca liu php c ch min dch. Nhng, ngi ta cng lu rng, t bo trong mng khp bnh nhn thp ch c mt s rt t mang khng nguyn ny. Quay sang t bo B, t bo ny cng vi hot ng ca gen vng bin i to ra vic sn xut khng th chng li nhiu t khng nguyn ging nhau hoc chng li cc quyt nh khng nguyn khc nhau khi khng nguyn c cu trc phc tp. V d, ngi bnh luput ban h thng v chut NZB/NZW khng th DNA bao gm nhiu loi khc nhau. Ngi ta thy rng chut NZB l chut b m ca NZB/NZW s xut hin ca khng th c khi ng trc tin ch mt nhm t bo B mang

du n CD5, l mt du n thng gp t bo T. y l mt iu ang cn nhiu bn ci. Khng th thuc lp IgG tc lp khng th thng gp nht trong tt c cc bnh t min nng khng th do t bo B CD5+ sn xut c v t bo ny ch sn xut IgM. Cng c th t bo B CD5+ l tin thn (precursor) ca nhng t bo sn xut IgG, nhng iu ny cha c xc minh. Mt t l ng k t bo B CD5+ hnh nh cn c vai tr trong vic sn xut yu t thp IgM bi v trong thc t ngi ta thy rng trn bnh nhn mc bnh bch cu dng lymph mn tnh hu nh tt c cc t bo B u c mang CD5 v phn ln chng sn xut yu t thp IgM. Chng ta cn nh rng yu t thp IgM d l do t bo thng hay t bo ung th sn xut u c m ha bi gen Ig dng mm, c ngha l chng khng b t bin thn. iu ny khng phi do khng c kch thch m v t bo B bnh thng ngi ta thy chng vn c th sn xut yu t thp, v s sn xut ny tng ln trong qu trnh nhim trng. Tm li, nhng quan st trn y ni ln tnh cht iu ha t nhin ca c th i vi phn ng t min l lun lun ngn nga t bin khi to ra yu t thp vi lng ln v bt thng. Tuy nhin, trong trng hp vim khp dng thp th hin tng iu ha b mt, yu t thp c sn xut nhiu vi tnh cht a cln ng thi yu t thp IgG xut hin. 11.1.3. p ng t min c ph thuc khng nguyn khng? R rng l p ng t min cng i hi nhiu yu t nh trong p ng min dch bnh thng v n cng b khng ch bi nhiu quy lut nh trong min dch bnh thng. Do , ta c th quan nim rng phn ng t min c th c to ra nhm p ng kch thch ca mt khng nguyn c hiu. Ngai ra, bnh t min cn c th c khi pht bi nhng nhim trng c hiu nh vim hng do lin cu, nhim trng ng rut do Shigella, Salmonella, Yersinia hoc Campylobacter. Cc kch thch khng c hiu cng c th dn n phn ng t min, nh trong trng hp t bo B c hot ha do t bo T cng loi trong phn ng ghp chng ch. i vi chut NZB/NZW, Steinberg v cng s cho rng p ng t min ca t bo T ban u c th l khng c hiu. Tuy nhin, trong c phn ng ghp chng ch trn ngi ln trn chut NZB/NZW phn ng t min cn nhng iu kin rt cht ch. Trn chut NZB/NZW,vo thi im m bnh ang tin trin, Steinberg v cng s nhn

thy rng bnh tr nn cn s hng dn ca khng nguyn v p ng t min xy ra sau khi truyn t bo lymph.

11.2. Bng chng v tnh cht gy bnh ca phn ng t min: Phn ng t min thc nghim Ngi ta cho rng nu phn ng t min c th gy ra nhng tn thng bnh l no cho ngi th trn ng vt th nghim chng ta cng c th to ra m hnh tn thng t min tng ng. Thc vy, ngi ta c th kch thch to ra bnh t min c hiu cho mt c quan no trn ng vt bng cch tim khng nguyn cng vi t cht Freud hon ton. V d, dng thyroglobulin c th gy bnh vim tuyn gip, dng protein c bn ca myelin c th gy vim no ty thc nghim. Tnh cht c hiu c quan ny hon ton khng phi bn ci v ngi ta tm thy khng nguyn ngay ti cc v tr tn thng. Trong trng hp ng vt c tim thyroglobulin, ngi ta khng nhng ch thy khng th khng gip xut hin m cn thy tuyn b thm nhim bi t bo n nhn, thy cu trc nang tuyn b ph hy di nh hng ca t khng nguyn. Mc d khng ging vi bnh Hashimoto, vim tuyn gip y cng c nhng tng ng quan trng so vi bnh ngi. Tnh cm th dng (strain susceptibility) i vi bnh t min Chng ta c th gy c bnh t min hay khng l ty thuc vo dng ng vt c dng. V d, ngi ta thy rng tnh cm th ca chut i vi bnh vim no ty do protein c bn ca myelin ph thuc vo mt s locus gen nht nh, trong quan trng nht l cc gen ca phc h ha hp m ch yu (MHC) lp II. Khi c c dng ng vt cm th thch hp ri, ta cn c th gy bnh th ng bng cch truyn t bo T mn cm (v d mn cm vi protein c bn ca myelin) cho con vt khc. Nhng t bo ny, v mt phenotyp l nhng t bo CD4+, da vo tnh cht ny ngi ta dng khng th khng CD4+ khng ch bnh v thu c kt qu tt trn ng vt thc nghim. Ngi ta cng thu c nhng kt qu tng t vi bnh vim tuyn gip t d ng thc nghim (experimental autoallergic thyroiditis) do thyroglobulin gy ra. Nhng kt qu ni trn chng t rng cc t bo T t phn ng (autoreactive T cell) hot ng vi iu kin

rt cht ch ca MHC, v iu kin ny rt quan trng trong vic to ra cc bnh cnh thc nghim. Bnh qua trung gian khng th (antibody mediated diseases) Trong mt s m hnh thc nghim, khng th l yu t chnh gy bnh ch khng phi l t bo T. V d, khng th khng th th acetylcholin gy ra tnh cht yu c ca bnh nhc c thc nghim; khng th mng y cu thn c tm thy trong bnh Goodpasture thc nghim c th to ra bng cch tim khng nguyn (cht chit xut t mng y cu thn) km vi t cht Freud cho con vt. Bnh t min t nhin (spontaneous autoimmune diseases) Chng ta c th hc c nhiu iu qua nghin cu nhng trng hp bnh t min t nhin ca ng vt. Bnh tuyn gip g Obese: Trn g thuc dng Obese, ngi ta tm thy khng th khng gip xut hin mt cch t nhin, v tuyn gip b thoi ha dn cng vi tn thng vim mn tnh. Huyt thanh ca cc con vt ny cha khng th khng thyroglobulin. Ngoi ra, khong 15% s mu huyt thanh cho phn ng vi proventriculus (d dy) ca g bnh thng. Khng th ny tng t nh khng th khng t bo thnh d dy ngi ca bnh nhn thiu mu c tnh. Nh vy, m hnh ng vt y coi nh tng ng vi bnh tuyn gip t min ngu pht ngi xt v mt tn thng tuyn, sn xut t khng th chng nhng thnh phn khc nhau ca tuyn gip i km vi phn ng t min i vi d dy. Nu ta lm thay i tnh trng min dch ca con vt th biu hin bnh cng thay i theo: khi ta ct b tuyn Fabricius, th phn ng vim tuyn gip gim r, iu ny chng t khng th c vai tr quan trng trong bnh nguyn ca bnh. Ngc li, nu ct b tuyn c t lc mi sinh th hnh nh bnh c biu hin nng hn. Bnh luput ban h thng ca chut: Ngi ta ch n mt m hnh thc nghim khc trn th h lai F1 ca hai loi chut NZB v NZW. Cc chut lai ny cho ta bnh cnh t pht ca luput ban h thng vi vim cu thn do phc hp min dch v trong mu xut hin nhiu loi t khng th m quan trng nht l khng th khng nhn vi nhiu tnh c hiu. Trn cc ng vt ny, nhng cht c ch min dch nh cyclophosphamid, cyclosporin A, v.v. C tc dng c ch s xut hin bnh v ko di thi gian

sng cn ca con vt.

11.3. S sp xp cc bnh t min thng gp ngi Cc bnh c lin quan n hin tng t min thng c b tr thnh mt danh mc gm c hai cc m ngi ta thng gi l ph bnh t min (Hnh 11.1). Cui mt cc l bnh vim tuyn gip Hashimoto v mt s bnh m trong t khng th v tn thng ch xy ra i vi mt c quan ca c th v c gi l bnh t min c hiu c quan (organ-specific autoimmune diseases). Cui cc kia ngi ta xp luput ban h thng l mt bnh t min h thng in hnh. Trong luput v cc bnh cc ny, t khng th cho phn ng vi nhiu loi khng nguyn nm ri rc khp ni trong c th v tn thng c trng cng xy ra nhiu c quan nn c gi l bnh t min khng c hiu c quan (non-organ-specific autoimmune diseases) Nhng c quan ch thng gp trong bnh c hiu c quan l tuyn gip, tuyn thng thn, d dy v tuyn ty; trong khi bnh khng c hiu c quan trong gm c cc bnh thp th tn thng c th gp da, thn, khp v c. C mt iu cn lu l ti mi u ca bng danh mc cc bnh c xp nm k nhau thng c hin tng trng lp (overlap) v c triu chng cn lm sng ln lm sng. V d, khng th tuyn gip xut hin vi tn sut cao trn bnh nhn thiu mu c tnh l ngi c hin tng t min d dy. ng thi, nhng bnh nhn ny c tn sut mc bnh t min gip cao hn ngi bnh thng. Tng t, trong s bnh nhn t min tuyn gip c mt t l cao bt thng nhng ngi mang t khng th t bo thnh d dy, c ngi c c triu chng ca thiu mu c tnh. c bit, nu ta xt ring qun th cc bnh thp nm pha bnh khng c hiu c quan th gia cc bnh trong nhm hin tng trng lp rt ph bin. V d, cc triu chng ca bnh vim khp dng thp thng xy ra km vi cc triu chng ca SLE. Phc hp min dch gia t khng nguyn v t khng th c xu hng lng ng khp ni trong c th m nht l thn, khp v da gy nn cc triu chng cc c quan ny trong nhng bnh c phc hp min dch ny. Tuy nhin, cn nh rng bnh cng nm xa nhau v hai u th xu hng trng lp cng him gp, v d s xy ra ng thi ca vim tuyn gip v SLE l iu cc k bt thng.

C ch min dch bnh l trong bnh t min thay i ty theo v tr sp xp ca bnh trn bng danh mc. Nu bnh nm cc c hiu c quan th c ch quan trng nht l qu mn typ II v p ng min dch qua trung gian t bo. Cn c ch c hiu trong cc bnh khng c hiu c quan th lun lun lin quan n v tr lng ng ca phc hp min dch. Chng ta c th thy cc biu hin ca bnh c hiu c quan v khng c hiu c quan c tm tt Bng 11.1.

c hiu c quan

Hashimoto Ph vim tim pht Nhim c gip Thiu mu c tnh Vim d dy teo t t min Bnh Addison Mn kinh sm (mt s ca) V sinh n ng (mt s ca) Nhc c nng i ng th tr Hi chng Goodpasture Pemphigus vulgaris Pemphigoid Nhn vim ng cm

Vim mng b o do th tinh th x ha

 cn

Thiu mu huyt tn t min Ban gim tiu cu tin pht v Gim bch cu v cn X gan mt tin pht

Vim gan mn hot ng c HBs m tnh Khng c hiu c quan X gan to ha Vim i trng lot Hi chng Sjogen Vim khp dng thp X cng b Vim da c Lupus dng a Lupus ban h thng

Hnh 11.1. Ph bnh t min Bng 11.1. Cc ri lon c hiu c quan v khng c hiu c quan

c hiu c quan Khng nguyn Tn

Khng c hiu c quan Khu tr mt c quan khp ni trong c no th Khng nguyn c Phc hp min dch

thng

Trng lp

quan l ch ca cc lng ng trn ton phn ng min dch thn, nht l thn, khp v da Vi cc khng th v Vi cc khng th v cc bnh c hiu c cc bnh c hiu quan khc c quan khc

11.4. Tnh di truyn ca bnh t min Tnh cht gia nh ca bnh t min l iu hon ton c khng nh. Tnh cht gia nh ny ch yu l do di truyn hn l do mi trng v iu ny c chng minh bng cc nghin cu di truyn hc cc cp sinh i, nghin cu s phi hp gia t khng th v s bt thng nhim sc th. Khi c hin tng xut hin cng mt lc triu chng ca mt s bnh c hiu c quan trn mt c th no th xu hng xut hin tnh t min trong gia nh anh ta cng nghing v pha t min c hiu c quan. ng thi, lc cc yu t kim sot di truyn s nghing v c quan b tc ng mnh nht. Tht th v khi thy rng h hng ca nhng ngi mc bnh Hashimoto c tn sut mang t khng th tuyn gip cao hn v hiu gi ca t khng th ny cng cao hn so vi nhng ngi khc. Trong bnh thiu mu c tnh cng c hin tng nh vy. Cc bng chng khc v hot ng ca yu t di tryn l xu hng phi hp ca bnh t min i vi cc tnh c hiu HLA. Haplotyp B8, DR3 xut hin vi tn sut cao nhng bnh c hiu c quan. i vi bnh vim khp dng thp, trc y khi ch kho st cc locus A v B th thy khng c lin quan g, nhng n nay th bit l c phi hp vi HLA-Dw4 v DR4. Nhng c th mang HLA ny th c xu hng d mc bnh vim khp ny hn. Trong bnh i ng ph thuc insulin, d hp t i vi DR3 v DR4 rt thng gp. iu ny h tr cho quan nim cho rng cc yu t di truyn tham gia vo s xut hin ca bnh t min gm c hai loi, mt loi l cc yu t lm tin cho s xut hin tnh t min v loi kia l cc yu t xc nh t khng nguyn no tham gia vo phn ng t min. 11.5. Bnh nguyn Nu chng ta tm thy t khng th trong mt bnh no th c th c ba cch gii thch v ngun gc ca bnh.

1. Phn ng t min xy ra trc v chu trch nhim v vic to ra nhng tn thng c trng ca bnh. 2. Bnh xy ra trc, sau cc tn thng t chc do bnh gy ra dn n s sn xut t khng th. 3. C th c mt yu t ring bit no ng thi gy ra c tn thng ca bnh ln phn ng t min. (Hnh 11.2) T khng th xut hin sau tn thng c th gp trong nhng trng hp nh t khng th c tim xut hin sau nhi mu c tim. Tuy nhin, trong a s trng hp s sn xut t khng th khng xut pht t s gii phng t khng nguyn sau mt chn thng n gin. Nhn chung ngi ta c cho rng trong s nhng bnh c mang t khng th th a s l cc bnh gy ra do c ch t min.

Hnh 11.2. Gi thuyt v s phi hp gi a bnh t min vi phn ng t min Ba kiu phi hp c th xy ra: (1) Phn ng t min c th to ra bnh; (2) Bnh chu trch nhim to ra phn ng t min; hoc (3) Mt yu t th ba to ra c phn ng t min ln bnh t min.

Bng chng trc tip nht v gi thuyt cho rng phn ng t min gy ra bnh t min l chng ta c th to m hnh ca bnh trn con vt bng cch gy phn ng t min thc nghim cho chng. Thc vy, ngi ta thc hin c nhiu bnh t min trn ng vt thc nghim bng cch tim khng nguyn c trn vi t cht Freund. V d, tim thyroglobulin c th gy bnh vim tuyn gip, v tim protein c bn ca myelin c th gy vim no thc nghim. Trong trng hp tim thyroglobulin khng nhng khng th khng gip c sn xut m tuyn gip cn b thm nhim bi t bo n nhn v cu trc tuyn b bin i. Vim tuyn gip thc nghim ny nhn chung rt ging vi bnh cnh vim tuyn gip nhng ngi mc d khng ging ht Hashimoto. C nhng m hnh bnh t min ngu nhin trn ng vt rt c ch cho chng ta nghin cu. u tin l bnh tuyn gip t min trn g trng Obese (OS). Bnh xut hin t nhin vi tn thng vim tuyn gip mn tnh v xut hin khng th khng gip. Nu chng ta kho st huyt thanh ca nhng con vt ny th ngoi khng th thyroglobulin ra, cn c khng th d dy trn 15% trng hp. Nh vy, trn con vt tn ti ng thi hai qu trnh t min i vi tuyn gip v tuyn tiu ha d dy, ging nh vn thng gp trn ngi. Nu ta lm bin i tnh trng min dch ca con vt th bnh cnh cng thay i theo. V d, nu ct b tuyn Fabricius th trm trng ca vim tuyn gip gim hn chng t vai tr ca t khng th trong bnh ny rt quan trng. Ngc li nu ta ct b tuyn c c vai tr trong vic khng ch bt s pht sinh bnh.

Trn ngi, r rng l khng th lm th nghim trc tip, nhng c kh nhiu bng chng cho thy t khng th l mt yu t gy bnh quan trng. Trong mt s bnh ngi ta pht hin rng cc t khng th chng th th hormon gy phn ng kch thch th th nh tc dng ca hormon (Hnh 11.3) v th m gy ra bnh cnh nh tng hot hormon tht s. Nhim c gip c l l ri lon u tin ca kiu ny c bit n, trong khng th khng th th TSH c cng nhn l nguyn nhn. ng thi, bnh nhim cnh nhim c gip cng c khi xy ra tr s sinh ni ln tnh cht di tryn th ng ca khng th t mu m sang v khng th th ng ny cng c th gy bnh. Mt v d khc ca bnh t min l bnh v sinh n ng, trong t khng th khng tinh trng lm cho tinh trng dnh li vi nhau. V, khi , r rng l chng kh c th bi n tip cn vi trng c nh bnh thng. Trong bnh thiu mu c tnh c xut hin mt t khng th ngn cn s hp th vitamine B12 theo ng n ung. Chng ta bit rng B12 khng th hp thu di dng t do c, m cn phi c gn vo mt protein do d dy tit ra gi l yu t ni, v ch c phc hp B12 - yu t ni mi c th hp th qua nim mc rut. Trong bnh nhn thiu mu c tnh ngi ta tm thy mt khng th c kh nng phong b tc dng ca yu t ni. Khng th ny c tit ra bi cc tng bo c mt trong nim mc d dy v phong b yu t ni dn n ngn cn hp thu B12 v bnh thiu mu c tnh hnh thnh (Hnh 11.4).

Cc v d khc v nguyn nhn gy bnh ca t khng th l trng hp hi chng Goodpasture, khng th khng mng y cu thn. Trong SLE, s lng ng ca phc hp khng nguyn - khng th ti cu thn l nguyn nhn ca tn thng thn; m trong thnh phn ca phc hp c rt nhiu loi t khng th tham gia; khng th khng nhn, khng th khng DNA, khng th khng cardiolipin,.v.v. Tm li, chng ta c th xem phn ng t min ng vai tr ch yu trong nguyn nhn ca hu ht cc bnh t min.

11.6. C ch bnh sinh Cho n nay, ngi ta hon ton cng nhn rng c tn ti trong c th cc t bo lymph t phn ng. Cn cc t khng nguyn phn ng vi cc t bo ny nh thyroglobulin chng hn, trc y c coi nh n np trong tuyn gip khng tip xc vi h min dch th n nay c bit l cng c mt trong h tun hon cng vi cc lymph. Do t khng nguyn

ln t bo lymph t phn ng u c iu kin tip xc vi nhau ngi bnh thng. iu ny c ngha rng, ngi bnh thng c mt c ch ngn cn phn ng t min. V t bo T c ch c xem nh c vai tr quan trng trong vic c ch tnh t phn ny. Hnh 11.5 m t mt c ch m trong s kim sot bnh thng i vi tnh t min b qua, ngi ta gi l c ch ng tt (bypass). Hot ng kim sot bnh thng trong c th c m trch bi nhiu loi t bo c ch to nn mt phc hp c ch do t bo T ph trch. Tuy nhin, khi c sai st xy ra cho t bo T c ch th phn ng t min c th xut hin. iu th v l trn lm sng ngi ta tm thy nhng ngi c quan h h hng vi bnh nhn SLE c sai st cc t bo T c ch. iu ny ni ln rng: mt l, s sai st t bo T c ch khng phi l hu qu ca bnh, v hai l, tnh trng sai st ny khng th t n gy ra bnh SLE. iu ny cng vi nhng iu cp trn y chng t rng c nhiu yu t tham gia gy bnh t min. ng thi,cng t , c th suy thm ra rng, nhng bt thng ca t bo T iu ha c hiu khng nguyn hoc c hiu idioptyp cng tham gia vo c ch gy nn. Trn mt s th nghim ngi ta pht hin rng mt s phn t th th trn b mt t bo bnh thng c tnh cht im lng min dch v mng nhng t bo ny khng c khng nguyn MHC lp II; nhng khi c kch thch mt cch thch hp th c th xut hin sn phm MHC lp II. V d t bo tuyn gip c th to phn t HLA-D khi c kch thch bng cc lectin thc vt v cc phn t ny cng vi cc th th b mt kch thch cc t bo T t phn ng to ra phn ng t min i vi th th t bo tuyn gip. Ngi ta cng a ra nhiu c ch khc v s hnh thnh bnh t min. Cc c ch c minh ha cc hnh 11.6, 11.7, v 11.8.

Hnh 11.5. Bnh t min do mt kim sot phn ng t min T bo B t phn ng, t bo T hiu qu v t khng nguyn bnh thng vn c mt trong c th nhng khng c khi ng nh s c ch ca t bo Ts i vi t bo Th tng ng. Khi c mt nguyn nhn g hot ha t bo Th ny hoc c t bo chng Ts (Tcs) xut hin th phn ng t min khng cn b kim sot na v bnh t min xy ra.

c bit, Hnh 11.7 minh ha mt v d th v l mng idioptyp c th tham gia gy bnh t min bng cch tc ng vo t bo T hoc t bo B t phn ng c mang idioptyp chung phn ng cho vi idioptyp trn mt khng th c to thnh do kch thch ca vi sinh vt hoc phn ng cho vi cu trc khng nguyn trn vi sinh vt. Nhng, ngay c trong trng hp ny, phn ng t min cng vn khng xy ra nu khng c sai st mc t bo T c ch v iu ny li mt ln na nhn mnh vai tr a yu t trong vic thit lp mt phn ng t min ko di. 11.7. Chn on v tin lng D cho quan h gia khng th v qu trnh bnh c th no i na, th s hin din ca khng th r rng l cung cp nhng du hiu c gi tr chn on bnh. Mt v d in hnh l ngi ta tm khng th khng ty lp th chn on xc nh x gan mt tin pht. iu ny gip cho cc

nh lm sng khi phi m bng thm d nh thi k trc y c th gy nhiu nguy him cho bnh nhn.

Hnh 11.6. Khi ng phn ng t min qua ng tt 1 i vi t bo T (1) Bnh thng phn ng t min khng xy ra v t bo T t phn ng v t khng nguyn b c ch hoc loi b. (2) Khi c khng nguyn phn ng cho xut hin, mt qun th Th mi s to ra phn ng gip . (3) Cng c khi mt phn t mng li c tc dng nh t khng nguyn to hiu ng gip to ra bnh t min.

Hnh 11.7. Khi ng phn ng t min bng ng tt 2 i vi t bo T Cc t bo t phn ng c th c kch thch bi cc cht hot ha a cln nh virus Epstein-Barr hoc lipopolysaccharid vi khun.

T khng th cn c gi tr tin lng. V d trng hp mt a tr c anh ch em mc bnh i ng ph thuc insulin, n c chung HLA vi anh ch, ng thi trong huyt thanh c c khng th khng t bo o ty. Sau 3 nm nghin cu, th thy a tr cng xut hin bnh i tho ng nng, iu ny chng t gi tr tin lng ca cc t khng th ny, v khng th xut hin kh lu trc khi bnh xut hin. 11.8. iu tr Mt cch kinh in, trong cc bnh t min c hiu c quan, tn thng thng iu chnh c nh kim sot chuyn ha. V d, trong suy gip, thiu hormon tuyn gip c th khng ch c bng cch cho thyronxin cn nhim c gip th thuc khng gip thng c th cho tc dng tt. Trong thiu mu c tnh, iu chnh chuyn ha c th thc hin c bng cch cho tim vitamin B12 b sung, v trong nhc c nng th dng cc cht c ch cholinesterase. Nu chc nng tuyn hon ton mt v khng th b c bng hormon nh trong trng hp vim thn lupus hoc vim khp dng thp mn tnh th cn phi tin hnh ghp m hoc thay c quan gi.

Hnh 11.8. Khi ng phn ng t min bng con ng idiotyp Phn ng t min cng c th xy ra nu t bo T hoc B t phn ng mang mt idiotyp ph bin c phn ng cho vi idiotyp trn khng th hoc

vi cu trc trn vi khun.

Cc liu php c ch min dch kinh in dng thuc chng phn bo c th dng gim phn ng min dch nhng do nhng phn ng ph ca thuc m cc thuc ny ch dng trong trng hp bnh qu nng nh SLE, vim da c. Tt nhin, cc thuc chng vim c th dng cho cc bnh thp. Bi v chng ta bit qu nhiu v c ch bnh sinh nn ty theo tng khu ca c ch bnh m ta c th dng nhng phng tin khc khng ch bnh t min (Hnh 11.9). c bit vic khai thc mng idioptyp c ch cc idioptyp trn t bo T khi ng v T hiu qu ang l mt ha hn kh quan.

Khng lp II Khng T4 Thuc Khng phn bo Thuc Khng vim Kim sot chuyn ha

Hnh 11.9. iu tr bnh t min

Trn s , cc phng tin iu tr kinh in hin nay c in bng ch thng trn nn xm. Cn cc bin php mi c in nghing m.

11.9. Mt s hiu qu thun li ca phn ng t min

Cng c khi vic gy phn ng t min cho mt c th li t ra c li cho c th (Bng 11.2). Mc d y l nhng vic lm c th thc hin c, vn chnh (nhng khng phi l duy nht) i vi bnh nhn l lm th no nhn din chnh xc cc epitop cn gy phn ng t min m khng gy phn ng cho vi cc t khng nguyn khc; v ngoi ra l chng ta phi lm th no tm c nhng cht ti (carrier) hiu qu nht cng nh cc t cht thch hp c th gy phn ng mc mong mun Bng 11.2. Cc hiu qu c li ca phn ng t min

ch tc ng 1. Human gonadotropin 2. LHRH 3. Ung th 4. Idioptyp

Nhm mc ch

chorionic Chng th tinh Gi thin (i vi b tht) iu tr bng min dch iu chnh p ng min dch

CC K THUT MIN DCH THNG DNG Ngy nay, k thut min dch dng trong lm sng rt phong ph v a dng, v th m cc nh lm sng r rng l cng nn c mt s kin thc nht nh v nhng k thut ny, ti thiu l cng phi nm c chnh xc v tin cy ca k thut m mnh yu cu. Mc ch ca chng ti trong chng trnh ny l nhm gii thiu nhng nguyn l ca cc k thut min dch lm sng ang c dng ph bin cc c s chn on v iu tr trn th gii; ng thi nu ln mt s nhn nh ca chng ti v nhng kh khn trong khi phn tch kt qu t c. Cc th nghim la-b cng c phn cp ty theo gi tr ca chng i vi tng trng hp bnh nhn c th. Mt s th nghim c xp vo

loi cn thit (essential) cho chn on hoc theo di, mt s thuc loi ty chn (optional) nhng c ch v s cn li l loi ch nghin cu. Mt s xt nghim s tr nn v ch nu chng ta yu cu khng ng lc, ng ch. Cc phn chia nh trn ca chng ti s gip cc nh lm sng c c ch nh thch hp cho mi th nghim. Trong chng ny, chng ti cng khng m t chi tit phng php tin hnh k thut v l ni dung ca cc sch chuyn v k thut min dch m chng ti d kin cho xut bn trong nay mai. C ba nhm k thut c xy dng nh gi nng lc min dch ca cc b phn ring l trong p ng min dch. Cc yu t dch th nh immunoglobulin, khng th, cc thnh phn b th v cc protein c hiu khc u c th nh lng c chnh xc. Gii hn bnh thng cho cc yu t ny s c trnh by v kt qu s c phn tch theo lm sng mt cch d hiu. Ngc li, cc th nghim v cc thnh phn t bo th kh thc hin hn cng nh kh phn tch hn. Cha c k thut no c gi l chun i vi phng php nh gi t bo, v th m mi la-b ngi ta thng lm mt cch khc nhau. cho vic phn tch kt qu c tt, cn phi c lin h cht ch gia cc nh min dch v nh lm sng. Cc th nghim in vivo nhm nh gi c yu t dch th ln t bo c gi tr khi kho st thiu ht min dch v qu mn nhng rt kh chun ha. 12.1. nh lng immunoglobulin v cc protein c hiu khc nh lng immunoglobulin (Ig) t ra rt cn thit i vi nhng bnh nhn nhim trng nng hoc lp i lp li nhiu ln cng nh i vi nhng bnh nhn ri lon tng sinh lympho. Vic nh lng nhiu ln c th gip chng ta phn bit thiu ht min dch thong qua v thng xuyn cng nh gip chng ta theo di iu tr trong bnh tng sinh lymph. Vic nh lng ny t ra c ch i vi cc bnh cnh c gim gammaglobulin mu nh nhim trng HIV, bnh gan v SLE.

Hnh 12.1. S minh ha cc im cn i ca t l khng nguyn khng th c th to ta. Khi tha khng nguyn hoc khng th th t lin kt cho xy ra nn ta rt t hoc khng c. K thut thng c dng ph bin nht l min dch kt ta (immunoprecipitation). Ta min dch c hnh thnh khi khng nguyn v khng th kt ta tng ng cng hin din vi nng tng ng ti u (cn bng) (Hnh 12.1). Min dch khuych tn n (single radial imminodifusion, RID) l k thut c Mancini s dng v m t u tin. K thut ny s dng mt khng huyt thanh ny c ha tan vo thch un lng, v hn hp thch-khng huyt thanh c ri u ln mt phin knh t trn mt phng ngang. Sau khi thch ng, ngi ta c cc l trn trn thch v cho huyt thanh cn o hoc huyt thanh chng vo. Khng nguyn, m trong trng hp ny l immunoglobulin, s khuych tn theo

hng ly tm t cc l ra vng thch c cha khng huyt thanh chung quanh. Bi v nng khng th (khng huyt thanh trong thch) c nh nn khi khng nguyn trong l khuych tn th nng gim dn cho n khi c t l thch hp vi nng khng th trong thch th mt vng ta s hnh thnh. i vi mi m ngi ta lm ba l cha khng nguyn vi nng bit trc v thnh ng chun (Hnh 12.2).

Hnh 12.2. ng chun dng trong nh lng protein c hiu bng khuych tn n, k thut Mancini. L 1-3 cha nng , chun bit ca loi protein mun o. Trn trc ta l ng chun c v. QC = quality control, kim tra cht lng.

iu khng thun li ca phng php ny l vng ta phi mt 48 gi mi n nh. Phng php ny tng i nhy (gii hn di l 5 mg/lt) v ng tin cy (h s bin ng gia cc k thut vin thnh tho l 3-10% vi iu kin khng huyt thanh tt). Ngi ta xy dng mt phng php ci tin khc c th c kt qu nhanh trong vng 6 gi, nhng phng php ny km chnh xc hn. nng thp, phc hp min dch tn ti di dng nhng ht rt nh

trong nh dch v c th lm tn sc nh sng. S tn sc ny c th o c vi mt ci my gi l my o c (nephelometer), trong phc hp min dch c t nhin nh vy khi o; hoc dng mt my o khc gi l my phn tch ly tm (centrifugal analyzer), trong lc ly tm lm cho phc hp min dch c hnh thnh nhanh hn. C hai phng php i hi khng c c cc cht bn gy tn sc nh nh bt kh hoc ht nh tng lng. Khi nng khng th c nh, cn tia s t l thun vi nng khng nguyn. y l mt phng php thc hin nhanh v d t ng ha; ta c th c c kt qu chnh xc sau khi ly mu 1-2 gi.

Bng 12.1. Mt s protein c th nh lng bng khuych tn n.

1.

Protein huyt thanh

(a) Protein tham gia p ng min dch: Immunoglobulin: IgG, IgA, IgM, tiu lp IgG, (IgD) Thnh phn b th: C1q, C3, C4, yu t B, (C2, C5, C6,C7, C8, C9) Cht c ch b th: C1INH (H,I) b2 microglobulin a (b) Mt s protein pha cp: a1 antitrypsin a2 macroglobulin (c) Protein vn chuyn: Transferin Haptoglobin Ceruloplasmin Protein phn ng C Orosomucoid

(d) Protein ng mu: Fibrinogen fibrinogen (FDP)# (e) Du hiu ch im ca u Khng nguyn ung th CEA Phosphatase kim nhau thai HCG a-FP 2. Nc tiu Chui nh t do tp kappa v lambda 3. Dch no tu (CSF) IgG Albumin C min dch khuych tn n v o c u c th dng nh lng nhiu loi protein trong huyt thanh, nc i, dch no ty, nc bt v dch tiu ha (Bng 12.1). Cc huyt thanh chun dng v ng chun hoc thang chun phi theo ng quy nh ca T chc Y t Th gii. Hin nay trn th gii c huyt thanh chun cho cc php o protein huyt thanh thng quy, vi iu kin lng protein phi ln hn 5mg/lt trong dch o. Mi phng th nghim ca mi bnh vin phi t mnh xc nh gii hn bnh thng cho mi protein v gii hn ny thay i ty theo phng php, khng huyt thanh, huyt thanh chun c dng cng nh ty theo nhm dn tc m ta kho st. Gii hn bnh thng ca a s protein cng thay i ty theo tui, nht l tr em. Chng ta cng c th o nng ca IgG v albumin trong dch no ty; l bi v albumin khng c tng hp trong no nn t l IgG/albumin l mt ch s gin tip ni ln mc IgG dch no ty c t bo lympho tng hp no. Ngy nay y l mt th nghim cn thit kho st nhim trng hoc tnh trng mt myelin ca h thn kinh trung ng. Lysozyme Sn phm thoi ha

K thut khuych tn min dch in di (electroimmunodifusion), m ngi ta thng gi l in di ha tin, c chnh xc v nhy cao hn khuych tn n, gii hn di ca k thut l 1mg/lt. Protein kho st c cho chy trong mt in trng vo trong gel cha khng th tng ng (Hnh 12.3). Gi s chng ta t n im n nh cui cng, chng ta thy c s tng quan tuyn tnh gia chiu cao ca ct ta vi nng ca khng nguyn. Trong khi thi gian cho chy in di khng ngn hn bao nhiu so vi khuych tn n t nhin, phng php ny khng thch hp cho vic nh lng Ig v y l cc protein km tch in nn di chuyn chm khi in di. C nhiu khng th n cln khng cho ta vi khng nguyn tng ng, iu ny c gii thch l do c qu t epitope c th cho phn ng vi khng huyt thanh. Tuy nhin, cng c cc hn hp khng th n cln c th to ta min dch; v cc tiu lp ca Ig c o theo cch ny, v d nh trong trng hp nh lng IgG2 chn on thiu ht IgG2.

Hnh 12.3. S minh ha hnh nh in di min dch ha tin. cao ca cung ta t l thun vi nng khng nguyn. Ta c th nhn thy r sau khi nhum. Cc nng chun c dng v ng chun, t

 tnh c cc nng cha bit da vo chiu cao x o c

12.2. Kho st nh tnh immunoglobulin 12.2.1. Huyt thanh Tt c cc mu huyt thanh ngi ln c ngh nh lng Ig nn c sng lc trc bng in di protein huyt thanh tm s hin din ca paraprotein (cc di n cln). Nn thng dng nht l mt mng cellulose acetate. Tm mng t c cho vo hp in di v nhng dung giy thm gip cho vic cung cp lin tc dung dch m. Cc mu huyt thanh c cho ln mng pha cc m v mt dng in c cho qua mng trong 45 pht. Sau ly mng ra, v cc di protein c th thy c nu chng ta cho nhum vi thuc nhum thch hp (Hnh 12.4). Chng ta lun nh phi cho chy mt mu huyt thanh bnh thng song song vi huyt thanh th d so snh. Nhng di n cln (di M) l c th xut hin mt v tr no trn mng in di v chng ta cn tch chng ra kho st su hn. Trn mng in di c th xut hin nhng di gi (false band), c th l sn phm ca hemoglobin (thy r khi mu nghim c mu hng) hoc ca fibrinogen (khi mu l huyt tng hoc l huyt thanh nhng mu ng khng c hon ton). Do c nhc im l cc IgG b ta trong nhng mu ng lnh c th ng li ti gn v tr l cha mu. Do , iu quan trng khi lm xt nghim ny cn phi gi mu nghim i sm v mu phi ng hon ton.

Hnh 12.4. Nguyn l ca in di protein huyt thanh

Cc di M c th nh lng bng mt dng c gi l mt k (densitometer); dng c ny c c m c ca thuc nhum bt mu vo cc di v cho ta mt biu tng ng vi cc di in di (Hnh 12.5). T l ca mi loi protein ring c tnh thnh phn trm so vi tng lng protein c c trong mu nghim; t l bch phn ny c th chuyn ra s lng tuyt i (g/lt) bng cch tnh n gin khi ta bit c nng ca protein ton th trong huyt thanh. o mt l mt phng php quan trng nh lng protein trong cc di n cln, nht l khi chng ta kho st cc mu kp c ln nhiu immunoglobulin a cln.

Hnh 12.5. Phn tch in di protein bng mt k nh lng di M (A= albumin) Khi mt gii M c pht hin trn in di protein, mu huyt thanh cn phi chy in di min dch hoc lm phn ng c nh b th xc nh bn cht ca di. Nguyn tc ca in di min dch cng ging nh in di protein huyt thanh nhng ngi ta dng gel thch lm cht nn. Sau khi tch cc thnh phn protein huyt thanh bng in di, mt ng rnh s c ct gia cc l cha huyt thanh v khng huyt thanh c hiu c cho vo rnh ny (Hnh 12.6); nhng protein no c phn ng vi khng huyt thanh c hiu s cho ta mt cung kt ta. Sau 12-24 gi, cc protein khng ta s c ra sch khi gel v cc cung ta c em nhum d thy v c kt qa. Trong cc la-b min dch ca cc bnh vin hin nay, ngi ta thng dng cc huyt thanh c hiu cho IgG, IgM, IgA hoc cc

tiu lp ca chng, cho cc chui nh kappa v lambda t do cng nh c nh trong cng tc chn on. Cc immunoglobulin a cln bnh thng cho ra nhng ta di, trn lng khi phn ng vi khng huyt thanh c hiu trong phng php xt nghim ny. Mt protein n cln th cho mt cung ta dt khot v gy gn hn.

Hnh 12.6. Nguyn l ca in di min dch. (b l hnh phng i ca a) nh tnh mt gii M ngi ta c th cng phng php c nh min dch (immunofixation). Nhiu mu ca huyt thanh th trc ht c cho in di trn celluose acetate hoc gel thch (Hnh 12.7). Sau , khng huyt thanh c hiu i vi IgG, IgA, IgM hoc cc tiu lp ca chng cng nh i vi cc chui kappa v lambda c nh c cho tc dng vi cc mu nghim in di bng cch nhng mng cellulose acetate vo tng loi khng huyt thanh (i vi trng hp in di trn mng cellulose aceteat) hoc cho tng loi khng huyt thanh ph ln mt gel thch in di (i vi trng hp in di trn gel thch). S kt ta (tc c nh min dch) ca protein M s thu c sau khong 2 gi . Cn cc protein khng c c nh (tc khng to ta) s ra sch khi gel v cc gii ta c em nhum c. Phng php c nh min dch nhy hn v thc hin nhanh

hn in di min dch.

Hnh 12.7. nh tnh mt di M bng phng php c nh min dch. Trong v d ny, di M c tm thy trn giy cellulose acetate l mt Ig thuc tp k Trong trng hp khng c bt thng chui nng, khng huyt thanh chui nh t do (tc khng phn ng vi chui nh c nh vo chui nng) s cho chng ta bit gii M c phi l ca chui nh n cln t do hay khng. Rt him khi c mt gii M phn ng vi khng huyt thanh c hiu chui nh c nh m khng phn ng vi chui nh t do cng tp; v nu iu xy ra th di M l mt paraprotein IgD hoc IgE, bi v IgG, IgA v IgM c loi tr trn gel u tin. Mt bt thng xy ra vi ch khng huyt thanh chui nng ni ln mt bnh chui nng him gp. S tng cao hm lng immunoglobulin huyt thanh buc chng ta phi o qunh huyt thanh tng i; k thut ny i hi nhiu thi gian cho mt th tch huyt thanh cho i qua mt ng mao qun, v so snh vi thi gian cho nc i qua. qunh huyt thanh tng i bnh thng c tr s t 1,4 - 1,8. Triu chng lm sng ca tng qunh xut hin khi tr s ny vt qu 4,0. Nu nh huyt thanh cn mi, s lng ng nhiu protein phn gc in di ni ln kh nng hin din ca cryoglobulin. Cryoglobulin l nhng immunoglobulin c th chuyn thnh dng ta, dng gel hoc kt tinh khi gp

nhit lnh. trm trng ca triu chng, m ch yu l da, ph thuc vo nng cryoglobulin v nhit khi ta lnh xut hin. Nu trn lm sng c du hiu nghi ng v cryoglobulin, khi ly mu xt nghim cn ly mu ti trc tip vo ng tim lm m v chuyn cho phng xt nghim trong nhit m, mu mu ny khi cho ng cng nh khi tch huyt thanh u phi c tin hnh 37oC. Mu huyt thanh sau c 4oC. Ta sau c ha tan bng cch cho lm nng tr li 37oC v em xt nghim tm cc thnh phn protein cu to bng in di min dch hay c nh min dch. 12.2.2. Nc tiu Xt nghim nc tiu l iu cn thit trong trng hp bnh a u ty, trong mt s bnh khc c thy di M trong huyt thanh khi in di, trong thiu mu gim gammaglobulin khng r nguyn nhn v trong nhim tinh bt. S tng hp immunoglobulin bnh thng i km vi s sn xut mt lng tha chui nh a cln t do. Cc chui nh ny c bi tit ra nc tiu v chng ta c th pht hin chng di dng vt tt c mi ngi. Bnh nhn b tn thng thn th s tit mt lng ln chui nh t do a cln trong nc tiu. Chui nh n cln t do (tc protein Bence Jones) c t tn ca ngi u tin m t tnh cht nhit hc c bit ca n l kt ta khi cho hm nng dung dch ln n 56oC, nhng nu cho nng hn th ta li tan ra. Tuy nhin, phng php pht hin c in ny ch pht hin c khong 40% chui nh t do trong nc tiu. C phng php thng qui nh lng protein nc tiu ton phn ln th nghim Clinistix u khng th pht hin chui nh t do. Hin nay, xt nghim thng qui i vi trng hp nghi ng c protein Bence Jones nc tiu gm 3 giai on: (1) c c nc tiu; (2) in di cellulose acetate tm s hin din ca di M; v (3) c nh min dch hoc in di min dch xc nhn di M c cu to bi chui nh kappa n cln hoc chui nh lambda n cln. S bi tit ton b paraprotein ca thn tn thng c th cho mt kt qu dng tnh gi, do chng ta phi tm bn cht ca chui nh t do ca di M xc nhn kt qu. 12.2.3. Dch no ty in di dch no ty l mt xt nghim c ch i vi chn an bnh x ha nhiu ch v cc bnh mt myelin khc. Cng nh trong huyt thanh, immunoglobulin ca dch no ty cng nm vng gamma. Nhng ngc

vi huyt thanh, IgG thng to nn nhng di thiu cln; c ngha l mt vi di ri rc ch khng phi l mt m lan to. Cc di thiu cln khng th pht hin c bng in di thng qui dch no ty cha c c, do cn c c dch no ty (80 ln) c th cho nhng di thy c. nhy ca phng php c th c tng cng bng cch nhum c bit nh nhum bng khng huyt thanh nh du enzyme hoc bng dung dch c tng cng bc. Tuy nhin, phng php nhy v ng tin cy nht l in di dch no ty khng pha long trn gel acrylamide. Mi trng gel ny s tch cc protein theo trng lng phn t cng nh theo in tch. Sau gel c c nh v nhum nh thng thng. Xt nghim ny hin cha c dng rng ri. 12.3. Khng th i vi khng nguyn ngoi sinh Trong nhim trng, p ng min dch i vi sinh vt c tnh cht bo v, lm cho c th hi phc sau khi b nhim trng, ng thi tnh min dch cn gip c th chng li s ti nhim vi sinh vt . Tuy nhin, bn cnh tc dng c li , mt s khng nguyn vi sinh vt li c phn ng cho vi khng nguyn ca c th ngi, do khng th chng cc khng nguyn ny c th phn ng vi t khng nguyn v gy ra bnh t min. p ng qu mn i vi khng nguyn ngoi sinh cng c th gy ra tn thng m. 12.3.1. Khng th chng vi khun T nhiu nm nay, ngi ta dng phng php pht hin khng th chng vi sinh vt chn on nhim trng do vi sinh vt gy ra. S hin din ca khng th trong tun hon ch chng t rng c th gp khng nguyn trc . chn on mt nhim trng cp, chng ta phi thy c c s gia tng hiu gi ca khng th hai ln ly mu xt nghim cch nhau hai tun. Nu cn c kt qu tr li ngay, s hin din vi hiu gi cao ca khng th IgM c hiu chng t ang c p ng s cp vi vi sinh vt. Pht hin khng th chng vi khun cng l mt iu cn thit kho st thiu ht min dch. Kh nng to khng th ca ngi bnh l mt hng dn tt cho tnh cm nhim ca ngi i vi nhim trng l mc immunoglobulin ton phn trong huyt thanh. Khng th chng cc vi khun ch ng tiu ha nh E.coli c th o c vi hiu gi cao (<1/32) trn hu ht ngi bnh thng, cn nhng ngi b thiu ht min dch tin pht th khng. Nu bnh nhn c chng nga, vic tm khng th chng c t un vn, c t bch hu v virus bi lit cng t ra c ch. Vic pht hin khng th i vi khng nguyn lin cu t ra quan trng khi kho st cc bnh nhn mc bnh

do phn ng min dch sau nhim lin cu. 12.3.2 Khng th chng khng nguyn khng sinh sn Mt s khng th i vi khng nguyn khng sinh sn c th gy ra tn thng min dch (qu mn). Loi xt nghim dng trong trng hp ny ph thuc vo c ch tn thng l tup I qua trung gian IgE, tup III qua trung gian IgM hay tup III qua trung gian IgG. Trong hen ngoi sinh hay vim mi d ng, th nghim b rt c ch v: (1) n ni ln rng y l mt phn ng tup I qua trung gian ca IgE; v (2) n gip pht hin khng nguyn lin quan. Cc xt nghim la-b thng c ch i vi nhng bnh nhn c chng ch nh i vi th nghim b, v c rt nhiu bnh nhn dng tnh vi c th nghim b v xt nghim la-b. Th nghim ly da (prick test) l kiu th nghim trong cht em th c a vo da nh mt u kim a xuyn qua mt git cht trn mt da v ly da ln (Hnh 12.8); th nghim ny d lm . Th nghim ni b (intradermal test) gy au nhiu hn. Mt iu cn lu hn khi lm cc th nghim ny cng nh cc th nghim khc l cht em th phi l cht tinh khit v ang c hot tnh tt, khi th nghim mi cho kt qu tt. iu ny gy rc ri khng t cho th nghim ly da trc y mc d hin nay c sn nhiu ch phm tng i tinh khit ca nc ong, phn hoa, b bi, lng th v mt s khng nguyn thc phm nh trng, c, cc loi ht v cng c nhn. Tuy nhin, s phn tch kt qu trong lm sng cn phi xem xt i chiu vi cc triu chng. Mt bnh nhn atopy thng cho th nghim ly da dng tnh vi nhiu khng nguyn, mc d ch c mt loi khng nguyn c th gy ra triu chng lm sng. Th nghim kch thch (provocation test), tc th nghim kch thch nim mc mi hoc nim mc ph qun bng khng nguyn, l mt th nghim kh ph bin. Tuy nhin, th nghim ny kh nguy him nn cn phi c tin hnh trong bnh vin bi nhng thy thuc c kinh nghim. Th nghim ly da mc d an ton hn nhng cng khng phi l hon ton khng gy phn v; v th m cng nn c tin hnh di s gim st ca thy thuc. cc nc pht trin vic nh lng IgE ton phn trn bnh nhn nghi nhim k sinh trng t ra c li. nh lng IgE ton phn cn gip phn bit c ch bnh l c hay khng vai tr trung gian ca IgE. nh lng IgE thng c thc hin bng phng php min dch phng x v lng IgE bnh thng trong huyt thanh cc k thp (120-480 ng/ml). Lng IgE thng c tnh bng IU (n v quc t, 1 IU = 2,4 ng IgE). K thut o thng dng nht i vi IgE l k thut hp th min dch phng x trn giy (paper radioimmunosorbent technique, PRIST). Th nghim ny, mc d gi thnh hi t, nhng l mt xt nghim nhy, chnh xc v r rng.

Hnh 12.8. Cc th nghim b. (a) Th nghim ly; (b) Th nghim ni b. K thut hp th d ng phng x (radioallergosorbent technique, RAST) (Hnh 12.9) cho php chng ta nh lng c khng th IgE c hiu khng nguyn. Trong nhng k thut ny, khng nguyn c gn ln nhng tm a nh bng giy hoc ln cc ht khng ho tan; sau cho huyt thanh th vo v ch nhng khng th IgE no phn ng vi khng nguyn ny mi cn gi li sau khi ra. Khng th IgE c hiu ny s c pht hin bng khng th th cp c nh du phng x. Kt qu ca th nghim RAST hon ton ph hp vi kt qu ca th nghim b nhng t nn t c dng trong trng hp th nghim b b chng ch nh hoc khng c li. Nhng bnh nhn thch hp cho th nghim ny gm c tr nh b vim da nng, tr nh ang dng cc thuc gy bin i phn ng da nh khng histamine, ngi c kh nng b phn ng nng nu lm phn ng b v mt s bnh nhn d ng thc n. Khng th kt ta i vi khng nguyn c hiu thng l IgM hoc IgG. chn on cc bnh vim ph nang d ng ngoi sinh ngi ta thng dng xt nghim tm nhng khng th ny. K thut kt ta c lm theo phng php Ouchterlony; y l mt phng php km nhy nhng r hn nhiu so vi k thut min dch phng x. Chit xut ca cc khng nguyn nghi ng c t trong cc l ngoi (Hnh 12.10) cn huyt thanh bnh nhn c cho vo l gia. Sau nhiu ngy, tm xem c ta xut hin khng. Hin nay, trn th trng ngi ta c bn mt s khng nguyn thng dng, nhng vn cha c cc sn phm tiu chun. Khi c mt cht nghi ng l th phm gy ra triu chng phi cho bnh nhn, chng ta c th

dng cht nh mt khng nguyn th bng th nghim kt ta vi huyt thanh bnh nhn.

Hnh 12.9. Nguyn l ca php o khng th IgE c hiu d nguyn

Hnh 12.10. Pht hin khng th kt ta trong vim ph nang d ng ngoi sinh. Bnh nhn c khng th kt ta chng albumin chim chng t ang b bnh phi ca ngi nui chim.

12.4. Pht hin t khng th 12.4.1. Trong huyt thanh cc la-b xt nghim thng quy, ngi ta thng dng 4 phng php sau y pht hin t khng th lu ng: min dch hunh quang (immunoflurescence), ngng kt hng cu (hemagglutination), min dch phng x (hay min dch enzym), v in di ngc dng (countercurrent electrophoresis). Mi phng php u c u nhc im ring. Min dch hunh quang l k thut km nhy nht trong s ny, v kt qu ph thuc vo kh nng ch quan ca ngi c. K thut ngng kt hng cu c nhy cao hn nhng li mt nhiu thi gian. K thut min dch phng x (radioimmunoassay, RIA) th i hi sinh vt phm t tin; cn c my o tia gamma hoc beta v trang b x l cht thi cng l nhng th rt tn km. K thut min dch enzym (enzym-linked immunosorbent assay, ELISA) trnh c vn tip xc vi tia phng x nhng li i hi nhng dng c rt chuyn bit. in di min dch ngc dng th r v d lm nhng tng i km nhy. 12.4.1.1. Min dch hunh quang gin tip

y l k thut thng c dng pht hin nhiu loi t khng th trong huyt thanh. Ngi ta thng dng m ng vt lm c cht nu khng nguyn hin din chung trn c m ngi ln m ng vt. Cn nhng t khng th ch gii hn m ngi hoc thm ch ch mt dng t bo ngi th chng ta s khng dng m ng vt c. Vt phm m dng cho xt nghim ny c cho ng lnh ngay sau khi ly khi c th con vt v khi dng th a my ct lnh v ct -200 C. Huyt thanh bnh nhn c vi c cht (m) trong 30 pht. Sau , nhng khng th khng gn vo m s c ra sch trc khi cho khng th cp 2, c gn cht nh du (thng l hunh quang). Khng th nh du s lin kt vi immunoglobutin ca huyt thanh bnh nhn gn vo khng nguyn trn c cht. Nhng v tr c c nh khng th s nhn thy c di knh hin vi hunh quang (Hnh 12.11). Mi t khng th s c xc nh bng mt kiu bt mu hunh quang c bit trn mt c cht c bit. Sau khi huyt thanh c xc nh l dng tnh th n s c nh hiu gi xem khng th mnh n mc no. Kt qu nh lng c tnh bng t l hiu gi (v d 1/4, 1/8, 1/32,...) hoc bng IU (n v quc t). a s cc phng th nghim u dng khng th cp 2 c hiu IgG, do m ch pht hin c cc t khng th lp IgG (tc khng th c ngha lm sng); t khng th lp IgM khng quan trng lm. Tuy nhin, khng th khng nhn l mt trng hp ngoi l. Kiu pht quang ca khng th khng nhn cng c ch cho nghin cu lm sng, nhng khng c tnh chn on. Hin nay ngi ta vn khng khuyn khch vic lm xt nghim sng lc i vi t khng th. Ch nhng xt nghim mang li li ch lm sng mi c yu cu.

Hnh 12.11. Min dch hunh quang gin tip

Vic phn tch kt qu ca xt nghim min dch hunh quang gin tip ph thuc vo lp khng th, hiu gi ca chng, tui cng nh gii ca bnh nhn. Ngi gi, nht l ph n thng c sn xut t khng th m khng c triu chng lm sng no ca bnh t min. Ngc li, hiu gi t khng th cao ngi tr cho bit rng mt bnh tim n s xut hin sau ny. 12.4.1.2. Ngng kt hng cu Hng cu c dng nh mt t bo ch th (indicator) v chng c th cm li hoc ngng kt khi c khng th phn ng cho vi khng nguyn trn b mt ca chng. Khng nguyn y c th l khng nguyn ca chnh hng cu (nh khng nguyn ABO hoc nhm mu khc) hoc khng nguyn tinh khit khc c gn ln b mt hng cu. Ngi ta c dng th nghim ngng kt hng cu hay khng l ph thuc vo vic c sn khng nguyn tinh khit hay khng. Phng php gn nhn chung khng qu n gin tr trng hp ca xt nghim tm yu t thp. Yu t thp (mt khng th IgM phn ng vi IgG ng vai tr khng nguyn) s cho phn ng vi IgG ngng kt mnh hn l vi IgG ngi cn nguyn bn. Do m ngi ta lm cho IgG ngng kt bng cch cho chng phn ng vi mt khng nguyn bit ca chng (tc hng cu cu) hoc bng nhit. a s cc phng th nghim dung ht latex trong xt nghim tm yu t thp thng quy: IgG ngi c cho ngng kt bng nhit v gn ln ht latex v nhng ht ny s ngng kt khi gp yu t thp. y l mt xt nghim nhanh v r tin, c th dng lm xt nghim sng lc i vi yu t thp, nhng nhc im ca n l hay cho phn ng dng tnh gi. Huyt thanh dng tnh sau s cho lm li vi xt nghim Waaler-Rose. Trong xt nghim ny, khng th IgG th (c nhng quyt nh khng nguyn chung vi IgG ngi) c dng gn ln hng cu cu. Mt liu di ngng kt ca khng th ny c em vi hng cu cu v nhng hng cu ch th mn cm ny s c dng pht hin yu t thp l cht c kh nng lm ngng kt nhng hng cu cu mn cm, ch khng lm ngng kt hng cu nguyn bn. Hng cu khng mn cm c dng pht hin khng th t nhin i vi hng cu cu. Kt qu ca phn ng Waaler-Rose c tnh bng IU/ml hoc tnh thnh t s hiu gi. Mc d c tn l yu t thp nhng yu t ny khng c tnh chn on i vi bnh vim khp dng thp m ch c ch theo di tin lng ca bnh.

12.4.1.3. Phng php min dch phng x (RIA) v min dch enzym (ELISA) y l nhng phng php rt nhy dng pht hin t khng th vi nng thp. Nhiu k thut c dng v mi k thut iu c nhc im ring ca n. Cc enzym cng c th c dng nh cc cht nh du thay cho ng v phng x trong RIA, v khi k thut c gi l min dch enzym (ELISA). K thut ny c v nhy hn RIA. Mt khi chng ta nghi ng bnh nhn b mc SLE th cn phi tm khng th chng DNA chui kp. C th pht hin khng th ny bng nhiu cch; nhng cch ph bin nht l dng 14C-DNA, 125I-DNA hoc DNA nh du phng x trc bng cch cho 14C-thymidine vo mi trng cy vi khun tiu th. Phng php ny nhy cho n ni nh n m ta c th pht hin c mc lin kt DNA rt thp trong nhng bnh nhn khc ngoi SLE. Dng 125I-DNA c th thc hin mt th nghim khc t nhy hn, nhng kt qu dng tnh th thng ni ln kh nng ch SLE hoc vim gan mn hot ng. DNA chui kp dn dn tch ra thnh DNA chui n, do iu quan trng l phi quan st tr s lin kt chng cho mi m bit mc tch ra ca khng nguyn l bao nhiu. Ngi ta cn dng mt xt nghim khc l min dch hunh quang trn k sinh trng Crithidia luciliae tm khng th khng DNA chui kp; k thut ny cho c hiu rt cao, nhng li tng i km nhy v khng phi tt c huyt thanh SLE phn ng c trong xt nghim ny. Gn y, T chc Y t Th gii cho cng b tiu chun th gii v khng th khng DNA chui kp. Mt cht ly t nc rn c tn l a-bungarotoxin c kh nng cho lin kt rt mnh vi th th ca Acetylcholine trong dch chit xut ly t c vn ngi. Cht ny c s dng lm xt nghim tm khng th chng th th acetylcholine (AChR). Alpha-bungarotoxin tinh khit c nh du bng iod phng x v cho kt hp vi cht chit xut t c ngi. Khng th AChR s phn ng vi cht ny v c th lm ta bng khng huyt thanh khng Ig ngi. y l mt xt nghim rt nhy; khong 90% bnh nhn nhc c nng cho kt qu dng tnh khi lm xt nghim, ng thi c rt t trng hp dng tnh gi. 12.4.1.4. in di min dch ngc dng (countercurrent electrophoresis) Phng php ny c th c dng pht hin khng th i vi

nhiu loi khng nguyn nhn chit xut c bng nc mui v khng nguyn bo tng m ta gi chung l khng nguyn nhn chit xut (ENA). Tuyn c ca b hoc th c dng lm ngun cung cp phn ln khng nguyn nhn, cn khng nguyn Ro/SSA l khng nguyn bo tng v c tch chit t lch ngi. Huyt thanh ca mi c th thng cha khng th chng li nhiu khng nguyn; nhng mi tnh c hiu khng th thng ch thy trn mt nhm nh bnh nhn mc bnh m lin kt v v th m khng th ny c tnh chn on i vi bnh (Bng 12.2).Tuy nhin, v khng nguyn tinh khit khng phi r c th xt nghim thng xuyn nn ngi ta ang c gng s dng cng ngh DNA ti t hp sn xut. Ring huyt thanh chng c cha khng th bit th hin c bn sn.

Bng 12.2. c kt qu v khng th chng cc thnh phn ENA

KHNG TH Khng nguyn Ngun khng nguyn LIN QUAN LM SNG

K/nguyn Smith (Sm)

RTE

Mt mnh hoc km vi K/th U1-RNP: tiu nhm ca SLE (20%) Hiu gi cao: bnh m lin kt hn hp (100%)

Ribonucleoprotein RTE (U1- RNP)

Ro/SSA

HSE

SLE khng c khng th khng nhn Lupus s sinh v block tim

RTE La/SSB RTE Scl 70 Jo -1 CTE

bm sinh Lupus da bn cp

Hi chng Sjogren tin pht X ha h thng (20%)

Vim c thng km x ha phi RTE = Tinh cht tuyn c th; HSE = Tinh cht lch ngi; CTE =Tinh cht tuyn c b.

in di min dch ngc dng tc l cho in di khng nguyn v khng th chy ngc chiu v pha nhau. Vi pH thch hp, nhng khng nguyn hi c tnh axt s di chuyn nhanh chng v pha anode cn khng th th chy v pha cathode; trong khi , nng ca chng khng thay i. Nu huyt thanh bnh nhn c cha khng th thch hp mt ng ta s hnh thnh gia cc l cha khng nguyn v khng th (Hnh 12.12).

Hnh 12.12. in di min dch ngc dng.

in di min dch ngc dng thng c dng tt nht l sng lc huyt thanh. Sau , tnh c hiu khng nguyn ca huyt thanh dng tnh c xc nh bng k thut Ouchterlony (xem Hnh 12.10). Cht chit xut khng nguyn c t l gia, xung quanh l huyt thanh th thy dng tnh v huyt thanh chng bit tnh c hiu. Huyt thanh chng v huyt thanh th c t cnh nhau: mt ng ta tng t s chng t rng huyt thanh c tnh c hiu khng nguyn tng t. 12.4.2. Trong bnh phm sinh thit Kho st bng phng php ha m min dch (immunohistochemical) trn cc mu sinh thit ly t m bnh thng v bnh l c th cho thy c lng ng immunoglobulin, b th, v i khi c c khng nguyn. Immunoglobulin thy y c th l khng th n phn ng vi khng nguyn c hiu m hay c hiu c quan, hoc c th l trong phc hp min dch hnh thnh t trc n lng ng m, mt s phc hp c cha khng nguyn ngoi sinh.

Cc mu sinh thit dng cho xt nghim bng k thut min dch hunh quang khng c c nh, v phi c chuyn ngay cho phng th nghim trong nhit lnh. Sau , chng s c lm ng lnh t ngt v ct mng; cc lt ct c ra bng nc mui gim nhum bn ca nn trc khi cho vi khng huyt thanh c cng hp (conjugate) thch hp. Mt mu song song c nhum vi hematoxylin v eosin xem hnh nh hnh thi hc. K thut ny thng c dng cho cc mu sinh thit thn, da v ty xng v n t ra rt c ch cho chn on. Ch nh s dng k thut ny c cp cc chng lm sng.

12.5. Kho st b th Cc phng php dng kho st b th huyt thanh c chia lm hai; k thut o hot tnh chc nng nh gy tan mu, v k thut nhn din bn cht khng nguyn ca mi thnh phn b th. 12.5.1. nh gi chc nng K thut gy tan mu l k thut c dng ph bin nht trong cc phng th nghim thng quy. Ch s thng c nh gi l CH50 (b th gy tan mu ton phn). K thut ny tnh lng huyt thanh cn thit (tc lng b th cn thit) gy ly gii 50% s lng hng cu mn cm. Huyt thanh bnh nhn lun c nh hiu gi da theo mt huyt thanh chun. Gi s rng cc mu huyt thanh c a n phng th nghim ngay lp tc, th k thut ny cho kt qu rt nhy v ng tin cy. y l mt xt nghim cn thit nu chng ta nghi ng bnh nhn b thiu ht di truyn mt thnh phn b th no , tc l bnh nhn thng b nhim trng lp i lp li hoc bnh nhn l thnh vin ca mt gia nh b SLE hay hi chng ging SLE (SLE like). 12.5.2. Xt nghim tng thnh phn b th nh lng C3 v C4 bng phng php ha min dch l cc xt nghim c ch nht. Trn th gii hin nay sn c cc huyt thanh chng quc t. nh lng cc thnh phn b th khc c th thc hin c nhng him khi cn n, tr phi c trng hp nghi ng b thiu cc thnh phn do di truyn th hin qua tr s CH50 gim st. Chng ta cn phi nh lng cht c ch C1q (C1qINH) nu nghi ng bnh nhn b ph mch (angioedema). Tuy

nhin, c iu chng ta cn nh l tt c cc tr s o c ni trn ch l nhng con s mang tnh thi im, trong khi cc thnh phn ny li tc ng nh nhng protein pha cp cho nn s tng hp chng gia tng ng k trong vim; hu qu ca s tng tng hp lm cho chng ta khng thy kh nng tiu th b th v c th chng ta li cho rng lng b th vn bnh thng. iu ny gi vi chng ta rng lc cn phi nh lng thm cc protein pha cp khc xc nh phn ng pha cp ang din ra vo thi im nh lng b th. c th hiu c vai tr ca s bin i lng b th trong cc qu trnh bnh l, chng ta c th xem xt cc thnh phn b th theo 3 nhm: (1) cc thnh phn sm ca con ng c in (C1, C4 v C2 ); (2) cc thnh phn sm ca con ng khng c in (Yu t B, D v P); v (3) cc thnh phn mun chung cho c hai con ng (C3 n C9 ). Trong thc hnh (Bng 18.9), khi lng C3 v C4 thp nhng yu t B bnh thng th s hot ha ch xy ra theo con ng c in; cn nu c C3, C4 v yu t B u thp th c l con ng khng c in ang c hot ha theo li vng cung phn hi (feedback loop) (xem li chng 1) hoc do hot ha ng thi. Nu lng C4 bnh thng cn C3 v yu t B thp th c ngha l ang c s hot ha ca ch con ng khng c in. Nh vy, chng ta c th thy rng vic o C3 v C4 nhiu ln c th gip ch cho vic theo di cc bnh nhn b mc mt s dng bnh vim cu thn, SLE v vim mch. Nu chng thp khi mc bnh, th c th tr li bnh thng khi hi phc, do , C3 v C4 cng gip ch cho vic theo di iu tr. Xt nghim b th thng quy rt t gi tr i vi a s cc bnh vim cp v mn tnh (Bng 12.3). Bng 12.3. Phn tch cc bin i b th trong bnh l LNG B TH CH50 C4 C3 Y/t B

CON NG HOT HA

V D

Bt

C in

SLE; vim mch

C hai ng Gim hp cc phn

Mt s ca SLE

tng Nhim khun mu gram m thnh Hoi t gan cp

Bt

Bt

Bt Khng in T khng c C3NeF th

Ph mch di truyn

C in i vi ch C4 v (thiu ht C1IHN) C2 Cryoglobulin mu Vim cp v mn Tng hp cc phn (Bt= Bnh thng) 12.5.3. Pht hin cc sn phm phn ct ca C3 Xt nghim ny rt c ch trong trng hp bnh nhn b sc ni c t, tc l khi trong c th c kh nng hot ha C3 theo ng khng c in. di chuyn trn in di ca C3 v cc sn phm phn ct ca n (v d C3dg) khc nhau. i vi cc mu huyt tng ly t bnh nhn c phn ct C3 in vivo th cc sn phm phn ct c th pht hin c trong huyt tng chng ng bng EDTA, trong khi trong cc mu huyt tng bnh thng ch c th pht hin C3 cn nguyn vn. S hin din ca EDTA ngn chn c s phn ct tng thnh

xy ra in vitro sau khi ly mu tnh mch. 12.5.4. Yu t vim thn C3 (C3NeF) Yu t vim thn C3 l mt t khng th chng C3 hot ha. T khng th ny lm bn vng enzym C3 convertase ca con ng khng c in v cho php s phn ct C3 tip tc xy ra. Ngi ta nghi ng c C3 NeF trn nhng bnh nhn c mc C3 thp khng gii thch c; y thng l nhng ngi mc bnh thn hoc nhim trng ti i ti li. Yu t ny c pht hin bng cch cho huyt thanh bnh nhn vi huyt thanh bnh thng; cch ny lm cho yu t vim thn C3 ca bnh nhn phn ct C3 trong huyt thanh bnh thng. V chng ta em hn hp ny cho nh lng C3c. 12.6. Kho st phc hp min dch Rt nhiu bng chng cho thy rng phc hp min dch tham gia vo c ch bnh sinh ca tn thng m trong nhiu bnh ca ngi. Vic tham gia gy triu chng lm sng ca phc hp min dch thng c nh gi bng hai cch: cch th nht l phn tch cc hnh nh tn thng m tm bng chng ca s lng ng phc hp min dch, v cch kia l tm phc hp min dch trong huyt thanh v cc dch c th. Trong mt s bi cnh lm sng vic pht hin phc hp min dch t ra khng cn thit v s hin din ca phc hp min dch lu ng khng c hiu cho bt c bnh phc hp min dch no. Cc tn thng do phc hp min dch gy ra c th xut hin m khng thy c phc hp min dch lu ng; v ngc li chng ta li thng c th tm thy phc hp trong huyt thanh ngi bnh thng. Pht hin phc hp lu ng c th c ch cho vic nh gi hiu qu ca thay huyt tng. i vi tt c nhng trng hp nghi ng c vai tr bnh sinh ca phc hp min dch, chng ta nn tin hnh kho st trc tip sinh thit m nu c, v nh rng kho st ny khng th thay th bng th nghim tm phc hp lu ng c. Vic xt nghim phc hp min dch huyt thanh khng phi bnh vin no cng thc hin. Hn na, gia cc bnh vin lun c s khc nhau rt ln v kt qu t c v th m vic chun ha l mt iu kin quan trng trc khi a xt nghim vo thng quy xt nghim. Hin nay, trn th gii ta c bn nhng sn phm chun cho nhng phng th nghim min dch c bit chuyn khoa. Nhng d sao, khi lm xt nghim ny, cc kt qa phi c nh gi trong phi hp gia la-b v bc s lm sng.

C nhiu phng php pht hin phc hp min dch lu ng, mi phng php iu c u im ring. Nguyn l ca nhng phng php ny l pht hin immunoglobulin c trong phc hp m khng cn ch bn cht ca khng nguyn l g. C s ca k thut kt ta lnh (cryo-precipitation) cha c hiu hon ton v phng php ny ch pht hin c mt s phc hp no . Nhng xt nghim ph thuc vo th th b th khng pht hin c phc hp c mang khng th thuc loi khng c nh v hot ha b th. Nhng th nghim i vi th th Fc khng pht hin c nhng phc hp cha nhng immunoglobulin khng phi l IgG. Ngoi ra, tt c cc phng php u d b gy tr ngi bi nhng cht khng phi l phc hp min dch. V, hin nay, cha c cch no phn bit nhng immunoglobulin kt ta khng c hiu vi phc hp min dch tht s. Vic bo qun huyt thanh khng ng cch, vic lm tan ri lm ng huyt thanh nhiu ln c th lm cho immunoglonulin kt ta. Tuy vy, qua nhiu bo co ca cc cng trnh hp tc ca T chc Y t th gii, ngi ta thy r rng c mt s xt nghim (c bit l xt nghim lin kt C1q, th nghim conglutinin, th nghim c ch yu t thp n cln, xt nghim dng t bo Raji) gip phn bit c huyt thanh bnh thng. Kt qu dng tnh ca nhng xt nghim ny chng t c s hin din ca phc hp min dch lu ng trong mu bnh nhn. 12.7. Kho st lymph bo C ba kiu xt nghim dng nh gi t bo: (1) m s lng cc loi t bo; (2) th nghim in vivo; v (3) nh gi chc nng ca tng loi t bo. 12.7.1. m s lng t bo lymph Chng ta bt u kho st c cc tiu qun th t bo lympho t khi bit rng chng c mang cc du n b mt khc nhau. m s lng t bo lympho trong cc tiu qun th T v B rt c ngha i vi cc bnh thiu ht min dch v tng sinh lymph. Xt nghim ny ngy cng c p dng cho bnh nhn nhim HIV nh gi mc suy gim min dch v tin lng cng nh theo di cc liu php chng virus thc nghim. Ngi ta a ra mt s m bo cht lng chun ha dn xt nghim ny. Tt c mi nh gi i vi t bo lympho u phi tin hnh vi mu chng ng mi ly v ch sau khi c kin tham vn ca la-b min dch. Trong xt nghim ny, chng ta c th dng mu ton phn hoc t bo lympho tch. Vic tch t bo lympho t mu ton phn c thc hin bng cch t mu chng ng bng heparin ln cht Ficoll c t trng thch hp. Sau khi ly tm, hng cu v bch cu mi v chm vo lp Ficoll

li ton b t bo lympho v mt vi monocyte trn b mt ca lp Ficoll. Lp t bo ny c th ht ra d dng bng ng ht v em ra sch dng (Hnh 12.13). Tt c sn xut khng th n cln nhn din cc tiu qun th t bo lympho T trong mu ngoi bin. Mu ton phn hay t bo lympho thun khit c vi khng huyt thanh chut c hiu tng ng v sau em nhum vi khng th cp 2 chng Ig chut c nh du. Cc t bo dng tnh c th m c di knh hin vi. Mt cch khc l ngi ta cho lympho bo nhum i qua mt chm tia laser v cc tia sng pht ra t cc cht nh du trn t bo s c mt cm bin tip nhn. Cc tn hiu in t thu c s gip phn tch cc tiu qun th t bo. l nguyn l ca phng php gi l php m t bo bng my (cytometry). Hin nay trn th gii c sn nhiu khng huyt thanh n cln dng nhn din v m cc loi khng nguyn CD xut hin c trng trn cc loi t bo khc nhau nh T gip /khi ng (CD4), T c ch/gy c (CD8). C iu chng ta cn lu l khi kt qu c th hin bng t l CD4:CD8 th kt qu ny khng c ngha lm; v t l CD4:CD8 thp c th gp trong hai trng hp bnh l khc nhau xa, l suy gim t bo gip v gia tng t bo c ch. Do , kt qu nn c trnh by di dng cc con s tuyt i da vo s lng lymph ton phn.

Hnh 12.13. Quy trnh tch t bo lymph ra khi mu ton phn

Lymph bo B hu nh ch yu c nhn din qua s hin din ca immunoglobulin b mt l cc phn t c tng hp trong cc t bo ny. Phng php pht hin l k thut min dch hunh quang trc tip dng khng huyt thanh chng immunoglobulin ngi cng hp (conjugate) vi cht hunh quang (fluorescein). T bo lympho c vi cht cng hp

ny, sau em ra v c vo knh hin vi hunh quang hoc my m t bo. Immunoglobulin b mt c nhn thy nh mt vng nhn pht quang xung quanh t bo. Vi phng php ny, s t bo lympho B m c chim 4 12% tng s t bo lympho trong mu ngoi bin. Ngoi ra, ngi ta cng bn sn cc khng th n cln khc c hiu t bo B chng ta dng khi cn. 12.7.2. Phn ng da qu mn mun ( in vivo) C hai loi phn ng da in vivo c dng pht hin lympho bo T mn cm c hiu, l: th nghim ni b, dng khng nguyn tim vo lp ni b (xem Hnh 12.8), v th nghim p: p khng nguyn ln da cho hp th qua da. Th nghim ni b c nhiu ngi bit l phn ng tuberculin (Mantoux). Dn xut protein tinh khit (PPD) ca tuberculin l mt cht chit xut t Mycobacterium hominis. Phn ng dng tnh ca th nghim da qu mn mun xut hin sau 48 gi: ch tim v cng nhng khng nga hay au. Phn ng c cng ti a sau 72 gi v nht dn sau nhiu ngy. Hnh nh ny c th phn bit d dng vi phn ng Arthus, l phn ng xut hin sau khi tim 12 24 gi, c ph v i khi nga. Trn 75% qun th ngi ln cho kt qu dng tnh i vi phn ng tuberculin. Nu phn ng xy ra mnh th c ngha l ang c nhim trng mycobacterium hot ng trong c th v kt qu ny rt c ch cho chn on nhng trng hp ang nghi ng mc lao; cn phn ng m tnh th ni ln rng c th trc y cha tip xc vi vi khun lao hoc h min dch t bo b suy gim, v d nh trong trng hp sarcoidosis hoc thiu ht min dch. Phn ng b cho bit rng, trc y bnh nhn c mn cm vi khng nguyn c th hay cha (do , khng nguyn th cn c gi l khng nguyn gi li). trnh kh nng phn ng m tnh do cha tip xc, khi xt nghim tnh trng suy gim min dch ngi ta dng mt panel khng nguyn thng gp th. Panel ny thng bao gm PPD, Candida albicans, streptokinase-streptodornase, quai b v trichophyton; hn 95% ngi ln bnh thng p ng vi t nht l mt trong nhng khng nguyn ny. Ring i vi tr em th c th chng cha tip xc vi cc khng nguyn ni trn trong mi trng. Bi v chng thiu ht t bo T tin pht thng th hin vo tui tr em nn chng ta c th dng thm th nghim DNCB (dinitro-choloro-benzene) nh gi. Bnh nhn c cho mn cm vi DNCB bng cch bi ln da v 10 ngy sau th cho th thch li vi DNCB c ha long nhiu ln. Vi ngi bnh thng th phn ng dng tnh s xut hin trong vng 48 gi vi v cng da.

Th nghim p l th nghim nht thit phi dng n khi cn xc nh khng nguyn no l nguyn nhn gy vim da tip xc. Mt s khng nguyn d dng hp th khi bi ln da. Mt s khc hp th rt km nn c cho ln giy cellulose v dn vo da. S la chn khng nguyn ph thuc vo tin s tip xc, v nhiu bnh nhn c th nhy cm cng lc vi nhiu khng nguyn. Nng khng nguyn dng ch yu da vo kinh nghim v khng c sn phm chun. Thi gian phn ng dng tnh xut hin ph thuc vo mc hp th v c th thay i t 2 7 ngy. cho tin, ngi ta thng c th nghim p sau 2 4 ngy. Kt qu c gi l dng tnh khi thy c da, ph, nga, v cng ch tip xc khng nguyn. 12.7.3. Cc th nghim chc nng Cc th nghim chc nng in vitro i vi min dch t bo ch nn tin hnh khi cc triu chng lm sng c gi nhng bt thng ca min dch t bo. Nh vy, c ngha rng, nhng th nghim ny ch cn thit i vi nhng trng hp b thiu ht min dch; tuy nhin chng cng c ch trong vic theo di iu tr bng liu php min dch. Khi t bo lymph c cho tip xc vi mt cht kch thch no , mt s t t bo lymph nh s p ng bng cch chuyn dng thnh cc nguyn bo trong thi gian vi ngy. Qu trnh ny c gi l chuyn dng lymph bo (lymphocyte transformation). Cc cht kch thch gm c ba loi (Bng 12.4). p ng tng sinh sau kch thch c th o c bng k thut cho thm nhp thymidine c nh du phng x vo DNA ca t bo lympho. c ch di tn bch cu (leukocyte migration inhibition, LMI) l mt th nghim d thc hin hn nhng khng c dng lm xt nghim thng quy. Lymph T sn xut lymphokin khi c tip xc vi khng nguyn m chng c mn cm trc y. Mt trong nhng lymphokin ny gy c ch s di chuyn ca mt s t bo trung tnh, cht ny c gi l yu t c ch di tn bch cu v c th nh lng in vitro. Cc th nghim chc nng ny lun i hi phng tin tn km cng nh mt nhiu thi gian (Bng 12.4). Ngoi ra, khi cn xt nghim trn t bo sng th mu mu i xt nghim phi c chng ng v a ngay n la-b. V c s khc nhau gia cc l th nghim cng nh v cha c sn phm chun m vic phn tch kt qu tr nn ht sc kh khn. Tt nht nn cng phn tch vi chuyn gia phng th nghim min dch. Bng 12.4. Cc tc nhn gy chuyn dng lymph bo T

Tnh c Tc nhn hiu kch V d ca thch p ng Khng PPD ca Mycobacterium C nguyn hominis Khng Mitogen Phytohaemagglutinin C (PHA) Lymph bo ng Phn ng lymph hn loi hp

Yu cu c tip xc trc C Khng Khng

12.8. nh gi t bo trung tnh v t bo mono 12.8.1. m s lng t bo trung tnh v t bo mono S lng tuyt i ca cc t bo ny trong mu c th tnh d dng t cng thc mu. 12.8.2. To ca s da Kh nng tp trung t bo trung tnh v t bo mono ti vim ph thuc vo s sn xut cc cht thu ht c tnh ha hng ng i vi cc t bo ny cng nh kh nng cc t bo ny c th di chuyn v ni c cc yu t thu ht . C hai thnh phn ny u c th nh gi c in vivo bng cch to ra mt ch try da ti thiu (thng l cng tay). Tc cc t bo n xut hin ti ni try da ny c th nh gi c bng cch thu thp t bo bng mt tm lam knh nh t ln trn ch try da. cho vic thu thp t bo vim c chc chn hn ngi ta thng bi ln ch try mt cht ha hng ng (vi s lng nh sn). 12.8.3. Th nghim cc chc nng in vitro T bo trung tnh c th tch c t mu ton phn dng phng php li tm gradient t trng nh m t trong tch lymph, sau c lm cho thun khit bng cch cho ly gii ton b hng cu b ln vo. T bo mono c th thu hoch c trong lp giao din (interface) cng vi lymph bo

(xem Hnh 12.13) v tch ring bng cch cho bm dnh ln b mt thy tinh hoc cht do v ri ra t bo lymph i. (T bo mono l nhng t bo bm dnh, khc vi t bo lymph.) Ha hng ng l s di chuyn c mc ch ca t bo v pha cc cht thu ht m thng l casein hoc mt peptid tng hp f-Met-Leu-Phe. Kh nng to ra tnh ha hng ng ca huyt thanh bnh nhn c th kho st c bng cch huyt thanh ti vi ni c t. Cc t bo cn th nghim s c tch t kch thch ha hng ng bng mt mng siu lc (c l rt nh). Sau khi , mng lc c ly ra, c nh v nhum. Khong cch t bo di chuyn c qua mng lc hng n kch thch c th o c di knh hin vi quang hc thng dng. Thc bo l chc nng n vt l ca mt t bo no . Kh nng n ny c th xc nh c bng cch t bo thc bo vi cc ht tr nh ht latex, hoc vi khun. Cc ht hay vi khun bn trong t bo thc bo c th thy c di knh hin vi. Chng ta c th khuch i kh nng thc bo d quan st bng cch cho opsonin ha cc ht trc vi huyt thanh bnh thng ri mi cho vo mi trng c t bo thc bo. ng thi qua phng php thc bo ny chng ta cng c th nh gi c kh nng opsonin ha ca huyt thanh bnh nhn bng cch lm ngc li tc l sau khi cho ht latex tip xc vi huyt thanh bnh nhn, ta a chng vo cho t bo trung tnh bnh thng n. Hot tnh enzym ni bo (intracellular enzyme activity) c th nh gi c bng th nghim git vi khun (bacterial killing) hoc bng kh nng kh thuc nhum (dye reduction). Mt th nghim kh nng dit khun ni bo chun bao gm bch cu vi vi khun sng nh t cu vng chng hn. Sau khi , t bo c ly tm v loi b vi sinh vt ngoi bo. Vi khun c n vo, nhng cha b git cht, c nh gi bng cch cho ly gii t bo bng nc ct v gii phng vi khun bn trong ra; nhng vi khun ny s c nui cy trn thch dinh dng xem t l vi khun cn sng l bao nhiu. Nu kh nng thc bo vn bnh thng th s lng vi khun sng phn nh mc git ni bo. Th nghim nitroblue tetrazolium (NBT) gip chng ta nh gi kh nng n ca thc bo v kh thuc nhum NBT t mu vng sang chuyn sang mu xanh. Cc t bo phn lp c cho vo dung dch cha NBT. Sau khi , t bo c em ra ri chit xut NBT c n vo bn trong t bo v o mc kh bng quang ph k. Mt cch khc l t bo c quan st di knh hin vi v m s lng bch cu mi c cha cc tinh th xanh. Cc t bo thc bo ch c th kh NBT nu chng c hot ha.

S lng t bo hot ha trong mu ngoi bin bnh thng rt thay i; c ngi cho rng s lng t bo hot ha ny s tng cao khi c nhim trng vi khun, nhng iu ny vn cn ang tranh ci. Trong xt nghim ci tin t th nghim trn c tn l th nghim NBT hot ha, ngi ta cho mi t bo trc bng cch cho chng tip xc vi mt lng nht nh ni c t trc khi cho tip xc NBT. Th nghim ny c u im l khng ph thuc vo s hot ha t bo trung tnh in vivo v c th xem nh mt xt nghim sng lc d lm c th dng rng ri. Khi lm th nghim pht ln quang (chemiluminescence): t bo trung tnh (ca ngi bnh thng) s pht ra mt chm tia sng c di sng ln khi c kch thch bi nhng ht c opsonin ha. Th nghim ny gip pht hin kh nng opsonin ha ca huyt thanh mt cch ng tin cy, nhng kt qu thu c khi dng t bo trung tnh ca ngi bnh th kh thay i v i hi phi lm thm xt nghim khc. Mt u im ca k thut ny l c th nh gi huyt thanh bnh nhn vi ngay nhng vi sinh vt m bnh nhn ang nhim. K thut iode ha protein cho php nh gi tnh nguyn vn ca c ch git bng myeloperoxidase - hydrogen peroxide. Enzym ny c th pht hin c nh tnh cht ca n chuyn iodua kali 125I thnh iodua ion c th gn vo protein ni bo. T l 125I t do/125I gn protein cho php nh gi kh nng sn xut enzym ca t bo trung tnh. 12.9. nh typ HLA Khng nguyn bch cu ngi (HLA) l tn dnh cho cc khng nguyn ha hp m (ghp) ch yu ngi. C nhiu khng nguyn ha hp m trn bch cu, trong khng nguyn ca h HLA l quan trng nht. Nhng khng nguyn ny hin din trn tt c cc m ca c th, nhng chng ta ch d dng nh tp HLA trn cc t bo lympho mu ngoi bin v chng ch c mt ln trn nhng t bo ny. Khc vi h thng ABO ca hng cu, khng c khng th anti-HLA t nhin trong c th ngi. Cc sinh phm dng nh tp l khng th c sn xut do qu trnh min dch xy ra trong truyn mu hoc thai k. Th nghim thng dng nht l th nghim gy c lympho bo (lymphocytotoxic test). T bo lymph sng c tch t mu ngoi vi bng ly tm gradient t trng nh cp trn. Dung dch t bo sau c trn vi cc huyt thanh nh tp khc nhau, sau b th (ngi ta thng dng huyt thanh th bnh thng lm

ngun cung cp b th) c thm vo. Sau khi mt thi gian 37 oC, nhng t bo c khng th nhn din s b git bng phn ng ly gii qua trung gian b th. T bo cht c pht hin hin qua kh nng chng khng th ngn cn thuc nhum xm nhp. Nu a s (>90%) cc t bo b git bi mt khng huyt thanh no , th iu c ngha rng chng ta mang HLA tng ng nn b khng th nhn din. Th nghim ny ch c tin hnh thng quy nhng trung tm chuyn khoa chuyn nh tp HLA cho cc trng hp ghp c quan. K thut i hi kh nhiu thi gian, t tin v trnh k nng phi cao cng nh phi c nhiu kinh nghim trong vic c kt qu. Do trc khi ngh lm kt qu xt nghim ny, cn phi xin kin tham vn trc, v khi c nht tr th phi ly mu chng ng v gi ngay n cho la-b. Hin nay, vic nh tp HLA c thc hin bng k thut PCR (polymerase chain reaction) pht hin gen HLA. K thut ny tn km hn nhng c chnh xc v nhy cao hn nhiu so vi cc k thut khc. Kh nhiu bnh cho thy c s phi hp vi nhng khng nguyn HLA nht nh. V d, trong bnh vim t sng dnh khp, c hn 90% bnh nhn dng tnh vi HLA-B27, ngc vi t l thp (8%) ca HLA ny trong nhn dn. y l bnh duy nht m vic nh tp HLA c xem l c ch cho chn on. Trong nhng bnh khc, s phi hp vi HLA t ra yu hn nhiu. Hn na, tn xut gen (tnh c qua mc ph bin ca khng nguyn trong qun th) ngi bnh thng qu cao cho n ni s hin din ca chng khng ni ln c gen c phi hp vi mt bnh no s xy ra hay khng. 12.10. Sn xut khng huyt thanh dng cho cc phng th nghim min dch lm sng Khng huyt thanh c s dng trong nhng th nghim ni trn thng c sn xut trn ng vt bng cch cho tim khng nguyn cn thit. Trc y khng huyt thanh sn xut trn ng c th ch yu l sn phm ca p ng min dch a cln, c ngha l trong khng huyt thanh c nhiu khng th c sn xut t nhiu cln t bo B khc nhau. Mc d cc khng th ny khc nhau v cu trc chi tit ca vng bin i nhng tt c u cho phn ng vi khng nguyn tng ng (ngi ta gi l tnh phn ng n c hiu).

Hnh 12.14. Nguyn l sn xut khng th n cln

Trong nhng nm va qua ngi ta to ra c mt bc tin quan trng trong sn xut khng th huyt thanh l sn xut khng th n cln, tc l khng th c sn xut bi ch mt dng t bo, v do cc phn t khng th c sn xut ra hon ton ging nhau c vng thay i v vng hng nh ca chng. Nhng khng th n cln ny ch phn ng vi mt quyt nh khng nguyn no trn khng nguyn c dng. Chng ta bit rng hn dch t bo lch ca con vt c gy mn cm, c cha nhiu t bo B chu trch nhim sn xut nhiu khng th chng nhiu epitope khc nhau trn khng nguyn a vo. Nhng t bo B ny c cho lin hp vi mt dng t bo u ty khng sn xut khng th to nn mt t bo lai mang kh nng bt t ca tng bo c tnh. Cc t bo lai sau c tch ra v chn dng (Hnh 12.14). Vic nui cy trn quy m ln c th gip cung cp s lng ng k cc khng th tinh khit v cho phn ng vi chnh xc cao. Nh vo tim nng s dng cho chn on v iu tr mnh, cng ngy ngi ta cng c nhu cu sn xut khng th n cln ngi v ch c nhng khng th ny mi khng to nguy c xy ra

phn ng qu mn. Tuy vy, vic sn xut khng th n cln ngi hin nay vn cn gp nhiu kh khn v k thut.

12.11. K thut DNA ti t hp v min dch lm sng Nhng tin b v sinh hc phn t trong nhng nm qua m ra nhiu ng dng quan trng trong chn on v iu tr cc bnh min dch. Do vy, nhng nh min dch hc lm sang cn phi hiu nhng thut ng v phng php m nhng nh sinh hc phn t ang s dng. 12.11.1. K thut v thut ng Cc enzym endonuclease hn ch (restriction endonuclease) l nhng enzym ly t vi khun c kh nng ct chui DNA ti mt v tr c bit lin quan n mt trnh t nucleotid nht nh. Dng nhng enzym ny vi nhng tnh c hiu khc nhau cho php ct chui DNA thnh tng on, m mi on c cha mt gen c bit cn tch ra khi phn cn li ca phn t DNA (Hnh 12.15).

Hnh 12.15. Lp bn gen bng k thut Southern Blot

Trong k thut Southern blot, cc on DNA, sau khi c ct bi bng endonuclease hn ch, c cho in di trn gel agarose, nhng on nh th di chuyn xa hn nhng on ln. Trong s nhng on ny s c on c cha gen m ta quan tm. Bng cch dng cht kim ta c th lm tch i cc on dsDNA ra thnh cc ssDNA. Sau khi blot cc ssDNA sang giy nitrocellulose, ta cho on DNA chui n mi c tch lai vi mt on ssDNA b sung tng ng nh du. Sau khi ra v quan st di n c pht x (autoradiography) thy c pht x v tr no th l v tr c cha on gen m ta quan tm. C nhiu bnh di truyn, s khuyt tt ca gen khng th bit v vic tm gen khuyt tt ny cng khng thc hin c. Trong trng hp ny, gen gy bnh c th lin kt cht ch vi v tr nhn din ca mt endo-nuclease hn ch no . Dng cc endonuclease bit d ton b genome ngi c th gip tm ra cc v tr endonuclease mi hoc loi b nhng v tr ang tn ti. Nh vy, nhng on DNA to c do mt enzym hn ch nht nh s c nhng chiu di khc nhau trn nhng ngi khc nhau. Ngi ta gi iu ny l tnh a dng v chiu di on hn ch (restriction fragment length polymorphism, RFLP), v tnh cht ny c di truyn n gin theo kiu Mendel. RFLP cung cp cho ta mt lng ln cc du n lin kt (linkage marker) tm ra cc gen gy bnh trong gia nh, m khng cn phi bit g v bn thn gen c. K thut DNA ti t hp (recombinant DNA technology) da vo vic s dng plasmid nh cc phng tin truyn cc on DNA l, v d gen ngi. Plasmid l nhng mnh DNA hnh trn, nh, xut hin t nhin trong bo tng ca vi khun. Dng mt endonuclease c hiu c th m vng plasmid ny v gn vo mt on gen ngi, v nh vy l ta to ra mt phn t DNA lai (hybrid DNA) c chc nng sinh hc ring. Nu sau plasmid a c vo mt loi vi khun no (v d E. coli) th ta c th cho nui cy vi khun sn xut ra mt loi cc bn sao on DNA gn vo plasmid . K thut DNA ti t hp thng c dng sn xut cc ch phm sinh hc tnh khit s dng trong chn on hoc iu tr hoc mt s mc ch sinh hc khc. 12.11.2. ng dng chn on K thut khuych i DNA cung cp cho chng ta mt phng tin chn on trc sinh (prenatal diagnosis) chnh xc i vi cc bnh di truyn. Vt phm dng cho chn on l mu m ly c t gai nhau, t k thut soi thai (fetoscopy) hoc chc ti i (amniocentesis). K thut ny cng

gip chn on giai on tin lm sng nhng bnh nhim sc th c thi k khi bnh mun, bnh ph n lin quan gii tnh, k c nhng thiu ht min dch di truyn. Ngi ta ghi nhn rng cc th nghim gen ang c s dng ngy cng nhiu cho vic chn on bnh. Vic pht hin ra hin tng ti sp xp (rearrangement) ca cc gen immunoglobulin v ca gen th th t bo T (TCR gene) cung cp cho chng ta mt cng c mi phn tch ngun gc ca nhng t bo lympho c tnh khng mang cc du n kinh in ca t bo B v t bo T, tm ngun gc ca t bo ung th trong bnh bch cu t bo dng tc (hairy cell leukemia) v nhng cn tng d di cc nguyn bo trong bnh bch cu ty mn. Ngoi ra, th nghim gen cng gip ta phn bit cc bnh tng sinh lympho a cln v n cln. 12.11.3. ng dng i u tr K thut DNA ti t hp mang li nhiu tin b trong iu tr thng qua vic tng hp cc hp cht sinh hc hoc liu php gen. Sinh tng hp c c tin hnh bng cch gn mt gen ngi vo mt plasmid lm vt truyn v sau cho nhn ln thnh cln. C nhiu loi hormone (v d insulin) v thuc iu ha min dch (v d interferon) c tng hp theo cch ny. Mt ng dng quan trng ca phng php ny s l ng dng trong sn xut vc xin. Mt khi chng ta xc nh c nhng khng nguyn vi khun c kh nng gy min dch bo v th chng ta c th to cln c vi nhng gen tng ng. Mt vc-xin ti t hp c sn xut v dng ph bin l vc xin vim gan B. Hin nay cc nh nghin cu ang c gng tm ra nhng vc xin c hiu qu khc nhm chng li cc bnh nhim trng ph bin trn th gii nh vc-xin st rt v HIV. Mt mc ch ca cng ngh gen l thay th c nhng gen b khim khuyt trong c th con ngi. Liu php gen hin ang cn nhiu tranh ci nhng nhng ri lon min dch nh thiu ht adenosine deaminase hoc purine nucleoside phosphorylase ang l nhng ng c vin quan trng u tin cho vic s dng liu php ny iu tr.