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TRNG I HC CN TH KHOA THY SN

GIO TRNH

MIN DCH HC NG VT THU SN

ng Th Hong Oanh on Nht Phng

2007

THNG TIN V TC GI PHM VI V I TNG S DNG CA GIO TRNH


1. THNG TIN V TC GI

H v tn: ng Th Hong Oanh Sinh nm:1969 C quan cng tc: B mn: Sinh hc v Bnh Thu sn Khoa: Thu sn Trng: i hc cn Th a ch Email lin h:

dthoanh@ctu.edu.vn 2. PHM VI V I TNG S DNG Gio trnh c th dng tham kho cho nhng ngnh: Nui trng thu sn v bnh hc thu sn C th dng cho cc trng no: cc trng Cao ng v i hc Cc t kha: vi sinh vt, vi khun, vi-rt, vi nm, nguyn sinh ng vt, min dch, khng nguyn, khng th, Yu cu kin thc trc khi hc mn ny: sinh hc c bn, sinh ho, sinh hc phn t i cng, vi sinh vt hc i cng xut bn in cha, nu c th Nh xut bn no: Gio trnh lu hnh ni b i Hc Cn Th. Cha xut bn chnh thc nh xut bn

GII THIU
Mn min dch hc ng vt thu sn l mn hc c s trong chng trnh o to cho sinh vin chuyn ngnh bnh hc thu sn. Mn hc cung cp nhng kin thc v bn cht, c ch v nhng nhn t nh hng n kh nng t bo v ca c th ngi v ng vt ni chung v cc i tng thu sn ni ring nm chng li cc tc nhn gy bnh. Sinh vin cng s c cung cp nhng kin thc v thnh tu v trin vng ca vic ng dng min dch hc trong chn on v phng nga bnh thu sn. Ni dung phn l thuyt ca mn hc c chia thnh hai phn: Phn 1 trnh by kin thc cn bn v min dch hc bao gm bn cht v c ch ca h thng t v ca c th ngi v ng vt i vi cc tc nhn gy bnh v cc nhn t nh hng n chc nng v hot ng ca h thng ny Phn 2 trnh by s tin ho v c ch hot ng ca h thng min dch/phng v ca c v cc i tng thu sn ch yu. Sinh vin cng s c gii thiu v nhng thnh tu v trin vng ca min dch hc ng dng trong nghin cu bnh thu sn v trong sn xut nui thu sn. Sinh vin s c tip cn vi mt s k thut min dch ph bin c ng dng trong chn on v nghin cu bnh thu sn qua chng trnh thc hnh mn hc. Chng trnh mn hc c xy dng da trn cc sch chuyn kho v min dch hc trong y hc, sinh hc v thu sn. Ngoi ra thng tin t cc cng trnh nghin cu trong v ngoi nc nhm ng dng min dch hc trong chn on v phng bnh thu sn gn y cng c tham kho xy dng ni dung mn hc. Thng tin v cc ti liu tham kho dng bin son gio trnh v cc ti liu c thm c trnh by sau mi chng sinh vin tin tra cu v tham kho.

MC LC
BA .............................................................................................................................1 THNG TIN V TC GI.....................................................................................2 GII THIU .............................................................................................................3 MC LC..................................................................................................................4 Danh sch hnh..........................................................................................................6 Danh sch bng .........................................................................................................7 Phn 1: MIN DCH HC C S..................................................................8 Chng 1:Min dch hc v cc khi nim v min dch hc...............................8 I. Lch s v hng pht trin ca min dch hc ................................................................8 1.Thi k s khai ..............................................................................................................8 2.Giai on u th ca min dch th dch .......................................................................9 3. Giai on u th ca min dch t bo..........................................................................9 4. Giai on min dch phn t.......................................................................................10 5. Xu hng pht trin ....................................................................................................10 II. Khi nim v min dch hc...........................................................................................10 1. Min dch v min dch hc........................................................................................10 2. Cc loi min dch ......................................................................................................10 Ti liu tham kho ..............................................................................................................17 Chng 2 : Cc c quan v t bo tham gia p ng min dch........................18 A. Cc c quan tham gia vo h thng min dch ............................................18 I. C quan gc.....................................................................................................................18 II. Cc c quan lympho tin pht........................................................................................19 1. Tuyn c .....................................................................................................................20 2. Ti Fabricius ...............................................................................................................22 III. C quan lympho th pht..............................................................................................22 1. C quan lympho th pht tp trung c v bc............................................................23 2. C quan lympho th pht phn tn.............................................................................24 IV. S ti tun hon t bo lympho ....................................................................................27 V. Nhng t bo ca p ng min dch khng c hiu...................................................28 1. i thc bo ................................................................................................................28 2. Bch cu trung tnh .....................................................................................................29 3. Bch cu i toan ..........................................................................................................30 4. Bch cu i kim v t bo mast................................................................................30 5. Tiu cu.......................................................................................................................30 6. Nhng t bo dit t nhin..........................................................................................31 7. T bo ni m .............................................................................................................31 8. Hng cu .....................................................................................................................32 VI. Nhng t bo ca p ng min dch c hiu.............................................................32 1. T bo trnh din khng nguyn .................................................................................32 2. Phn t MHC ..............................................................................................................32 3. T bo mono v i thc bo......................................................................................35 4. T bo tua....................................................................................................................35 5. T bo lympho ............................................................................................................36 4

VII. H thng b th ...........................................................................................................42 1. ng khng c hiu................................................................................................43 2. ng hot ha b th c hiu .................................................................................44 3. Cc th th t bo i vi b th ................................................................................46 4. Vai tr sinh hc ca b th .........................................................................................46 Ti liu tham kho ..............................................................................................................47 Chng 3:Khng nguyn v khng th ................................................................48 I. Khng nguyn..................................................................................................................48 1. nh ngha...................................................................................................................48 2. iu kin bt buc ca mt cht khng nguyn .........................................................48 3. Tnh c hiu ca khng nguyn ................................................................................48 4. Cc dng khng nguyn ..............................................................................................49 II. Khng th .......................................................................................................................51 1. nh ngha...................................................................................................................51 2. Bn cht v tnh cht ca khng th ...........................................................................51 3. Cu trc ca khng th min dch...............................................................................51 4.Chc nng sinh hc ca globulin min dch................................................................55 III. Phng php to khng th n dng v a dng........................................................57 1. Chun b khng nguyn ..............................................................................................57 2. Sn xut khng th a dng ........................................................................................57 3. Sn xut khng th n dng......................................................................................58 4. Lm sch khng th ....................................................................................................59 IV. Phn ng kt hp khng nguyn-khng th .................................................................61 1. C ch kt hp khng nguyn-khng th....................................................................61 2. Kt qu sinh hc ca phn ng kt hp khng nguyn-khng th .............................64 Ti liu tham kho ..............................................................................................................66 Phn hai: MIN DCH NG VT THY SN ..........................................67 Chng 4: Min dch hc ng dng trong thu sn............................................67 I. Tin ho h min dch ca ng vt................................................................................67 II. p ng min dch gip xc .......................................................................................68 III. p ng min dch c xng.....................................................................................71 1. C ch bo v khng c hiu ....................................................................................71 2. C ch bo v c hiu ...............................................................................................71 IV. Nghin cu v ng dng ca vc-xin trong phng bnh thu sn ...............................73 1. nh ngha vc-xin......................................................................................................73 2. Lch s pht trin vc-xin ...........................................................................................73 3. C ch hot ng ca vc-xin.....................................................................................74 4. Phn loi vc-xin.........................................................................................................75 5. c tnh c bn ca vc-xin........................................................................................77 6. Yu t nh hng ti vc-xin v hiu qu s dng vc-xin .......................................77 7. Phng thc s dng vc-xin trong nui trng thu sn............................................80 8. Mt s kt qu nghin cu vc-xin c .....................................................................81 V. ng dng min dch hc trong chn an bnh thy sn..............................................81 Ti liu tham kho ..............................................................................................................81 5

Danh sch hnh


Trang Hnh 1.1. p ng min dch tin pht v th pht....................................................... 16 Hnh 2.1. S lc v tr cc c quan min dch ngi................................................ 18 Hnh 2.2. Cc t bo trong tu xng............................................................................ 19 Hnh 2.3. Cu to tuyn c ............................................................................................ 20 Hnh 2.4. Chn lc dng v m trong tuyn c........................................................... 21 Hnh 2.5. Ti Fabricius g .......................................................................................... 22 Hnh 2.6. Nang lympho th pht ................................................................................... 23 Hnh 2.7. Cu trc ca hch........................................................................................... 24 Hnh 2.8. Cu trc ca lch............................................................................................ 25 Hnh 2.9. Cu trc cc t chc min dch di da......................................................... 26 Hnh 2.10. Cu trc cc t chc min dch nim mc................................................ 26 Hnh 2.11. Ti tun hon t bo lympho........................................................................ 27 Hnh 3.1. Ngun gc t bo min dch .......................................................................... 28 Hnh 3.2. Vai tr ca i thc bo trong p ng min dch......................................... 29 Hnh 3.3. T bo NK nhn bit t bo ch khi t bo ny khng c MHC lp I ......... 31 Hnh 3.4. Cu trc phn t MHC................................................................................... 33 Hnh 3.5. Phn t MHC lp I......................................................................................... 34 Hnh 3.6. Phn t MHC lp II ....................................................................................... 35 Hnh 3.7. Phn t CD4 v CD8 ..................................................................................... 37 Hnh 3.8. Kh nng nhn bit khng nguyn ni sinh v ngoi lai ............................... 38 Hnh 3.9. Vai tr ca Th trong p ng min dch........................................................ 39 Hnh 3.10. Hot ho Tc do khng nguyn ca vi-rt..................................................... 40 Hnh 3.11. C s t bo ca s hnh thnh khng th ................................................... 41 Hnh 3.12. H thng b th vi cc cht cu thnh v iu ho.................................... 42 Hnh 3.13. ng hot ho b th khng c hiu ....................................................... 43 Hnh 3.14. ng hot ho b th c hiu .................................................................. 45 Hnh 4.1. Siu khng nguyn......................................................................................... 50 Hnh 4.2. Cu to c bn ca mt khng th ................................................................. 52 6

Hnh 4.3. Cu to ca IgG ............................................................................................. 53 Hnh 4.4. Cu to phn t IgM ...................................................................................... 54 Hnh 4.5. Cu to phn t IgA....................................................................................... 55 Hnh 4.6. Hin tng Oponin ha.................................................................................. 57 Hnh 4.7. Cc lc lin kt khng nguyn-khng th...................................................... 62 Hnh 4.8. Khng th tiu dit vi-rt ni bo .................................................................. 65 Hnh 5.1. S tin ho min dch ng vt .................................................................. 67 Hnh 5.2. C ch hot ho h thng ProPO................................................................... 69 Hnh 5.3. Cc vt en l ni v cutin ca tm b vim, lot v melanin ho ................ 70 Hnh 5.4. C ch chui qua mng t bo vi khun ca cc peptit khng khun. ............ 70 Hnh 5.5. Hin tng thi loi mnh ghp c hi....................................................... 73 Hnh 5.6. C ch hot ng ca vc-xin........................................................................ 75

Danh sch bng


Trang Bng 2.1. Mt s c im so snh gia t bo B v t bo T ...................................... 36 Bng 3.1. Phng php lm sch khng th.................................................................. 60 Bng 4.1. Cc dng bch cu gip xc v chc nng trong p ng min dch......... 68 Bng 4.2. c im Ig ca c xng............................................................................. 72 Bng 4.3. u v nhc im ca cc phng php s dng vc-xin c.................... 80

Phn 1: MIN DCH HC C S


Min dch (Immunity) l trng thi bo v c bit ca c th sinh vt c kh nng nhn ra v gip c th chng li s tn cng ca vi sinh vt hay cc vt cht t bn ngoi v loi thi chng ra khi c th. Min dch l mt qu trnh u tranh lu di xy ra trong mu v cc m ca c th. Ngy nay, min dch hc (Immunology) tr thnh mt ngnh khoa hc pht trin cao. K t khi c nhng pht kin u tin ca Pasteur v vc-xin, lch s min dch hc c dt nn bi nhng pht minh to ln mang du n thi i, thc y s pht trin nhanh chng ca nhiu lnh vc trong sinh hc v y hc. Nhiu gii thng Nobel mi y v y hc v hng lot cc cng trnh nghin cu v min dch, ung th, AIDS, ng dng cc cht ha dc cng nm trong khun kh cc cng trnh nghin cu v min dch.

Chng 1:Min dch hc v cc khi nim v min dch hc


I. Lch s v hng pht trin ca min dch hc
T c xa, con ngi c mt s hiu bit v min dch v ng dng trong vic phng mt s bnh nhim khun. Nhng ti cui th k 19, khi Louis Pasteur ln u tin tm ra vcxin, min dch hc mi c quan tm nhiu hn. Quan im v p ng min dch cng thay i theo tin b ca khoa hc v min dch hc c mi quan h khng kht vi mt s ngnh khoa hc khc nh sinh hc phn t, ha hc phn t, gen hc phn t, v.v. S pht trin ca min dch hc khng nhng lm cho n tr thnh mt mn khoa hc c s ring bit m cn h tr cho cc mn khoa hc khc pht trin vi nhng k thut min dch rt hu dng. thy c nhng thnh tu quan trng ca min dch hc trong tng thi k, c th chia min dch hc ra thnh bn giai on l: (i) thi k s khai; (ii) giai on u th ca min dch dch th; (iii) giai on u th ca min dch t bo v (iv) giai on min dch phn t. 1.Thi k s khai T c xa, con ngi nhn thy mt s bnh ch gp mt s loi, hoc trong cng mt v dch, thm ch trong cng mt iu kin th c c th ny b nng v c th khc b nh. c bit vi mt s bnh ngi khi mc bnh ri khi th sau ny vnh vin khng mc li na, v d nh bnh u ma. Nh vy, h bit ti nhng g m ngy nay chng ta gi l min dch. Vic dng vy u ma phi kh, tn nh v cho ngi lnh ht vo gy min dch c trong y hc c truyn phng ng. Trung Cn ng th ngi ta ly trc tip m ca mn u ma to min dch cho ngi lnh bnh. Tuy nhin, do khng kim sot c liu lng nn c khi h li lm cho bnh nng hn v gy cht ngi hoc to thnh dch trong dn chng. 8

Nm 1798, Edward Jenner dng u ma b thay cho u ma ngi gy min dch cho ngi. Qu trnh ny ghi nhn mt mc quan trng trong s pht trin ca min dch v t y min dch hc bt u c c s khoa hc. Vo nm 1862, Ernst Haeckel pht hin ra hin tng thc bo v sau vi nm (1877) Paul Erlich pht hin ra t bo mast. Sau 100 nm, Louis Pasteur (1879-1885) iu ch thnh cng ba loi vc-xin lm gim c lc vi khun gy bnh t huyt trng g, bnh than v bnh di. Nm 1888, Pierre Roux & Alexandre Yersin to c vc-xin chng c t bch hu. Thnh cng ny cho thy, khng nhng vi khun m ngay c nhng c t ca chng cng c th to p ng min dch. 2.Giai on u th ca min dch th dch Sau khi to c min dch ng vt th nghim, ngi ta dng huyt thanh ca chng nghin cu s tng tc vi cc yu t gy bnh. V th, cc yu t dch th trong thi k ny c tp trung nghin cu rt su. Hng pht trin vc-xin phng cc bnh nhim khun c pht trin mnh v duy tr ti ngy nay. ng thi vi s pht trin ca vc-xin th vic dng huyt thanh chn on v iu tr cng c pht trin cho ti ngy nay. Cc k thut pht hin khng nguyn v khng th dch th lin tc xut hin nh k thut ngng t ca Max von Gruber v Herbert Edward Durham (1896), k thut kt ta ca Kraus (1987). Nm 1898 Bordet pht hin tc dng ca b th v c dng nh mt cht ch th ca kt hp khng nguyn- khng th. T , vic dng huyt thanh min dch nh loi vi sinh vt c ng dng rng ri. Tip , vi k thut min dch in thm, gn phng x hay enzym vo khng th lm tng nhy pht hin khng nguyn hay khng th vi hm lng rt thp gip ch rt nhiu trong chn on. Bn cnh th cc sn phm ca huyt thanh cng c ch to thnh cng nh huyt thanh chng un vn, huyt thanh chng di, chng nc rn. Nhng huyt thanh ny hin vn ang c s dng rng ri. Nm 1917, Karl Landsteiner pht hin ra nhng cht c trng lng phn t nh (Haptens) cng c tnh khng nguyn. Pht hin ny thc y lnh vc ha min dch pht trin mnh. n nm 1929, Heidelberger xut phng php nh lng huyt thanh hc v m t c s ha sinh v cu trc ca khng nguyn l polysaccarid. Nm 1938, Kabat dng in di phn tch cc vng - globulin nhm xc nh cu trc ha hc ca glubolin. Ngy nay ngi ta c th chit tch, tinh khit xc nh cu trc phn t ca khng nguyn v khng th, lm c s cho vic sinh tng hp chng theo con ng ha hc hay sinh hc. 3. Giai on u th ca min dch t bo Nm 1883, Elie Metchnikoff a ra nhng gi thuyt v mt t bo hc ca vic s dng vc-xin. Nm 1891, Robert Koch pht hin ra phn ng b l mt trng thi mn cm mun m trong t bo tham gia l ch yu. Vo nm 1941, Albert Coons ng dng k thut hunh quang pht hin khng nguyn v khng th nm bn trong t bo. Sau vo nm 1942, Karl Landsteiner v Merill Chase cho thy hin tng qu mn mun ch c th c truyn bng bch cu th vai tr ca min dch t bo mi c ch nhiu hn v c pht trin mnh hn. Nm 1948, Astrid Faraeus nhn thy khng th c sn xut ti cc 9

tng bo thuc t bo B. Nm 1964-1968, Anthony Davis v ctv pht hin v s hin din v hp tc ca t bo T v t bo B, y l thi k nh cao ca min dch t bo. T thu ht nhiu nh min dch nghin cu v lnh vc ny. 4. Giai on min dch phn t Vic p dng nhng tin b ca sinh hc phn t vo min dch gip cc nh khoa hc phn tch chi tit cu trc ca khng th, pht hin c vng hng nh v vng thay i trong chui nng v chui nh (Putnam v ctv, 1965), xc nh y trnh t axit amin ca phn t globulin min dch (Immunoglobuline; Edelman v ctv, 1969). Trong thp k 60-70, hng lot phn t quan trng khc trong h thng p ng min dch c xc nh, chit tch v tm hiu cu trc nh cu to ca b th, cu to ca interleukin. Cc nh khoa hc to c cc phn t khng th m phng theo phn t khng th ca con ngi v nht l vic chuyn gen ngi sang cho ln. Thnh cng ny m ra mt hng mi cho min dch tr liu v min dch ghp. 5. Xu hng pht trin Ban u min dch mi ch l mt pht minh trong y hc vi vic tim chng phng bnh. Sau giai on min dch dch th v nhng tin b v k thut cho php con ngi nghin cu su hn mc t bo. Hin ti min dch hc ang c tip tc nghin cu mc phn t. Sinh hc phn t v gen hc phn t gip hiu su hn nhng c ch bn trong t bo. y cng l hai hng chnh ang li cun nhiu cng trnh nghin cu v min dch hc.

II. Khi nim v min dch hc


1. Min dch v min dch hc Min dch l kh nng bo v ca c th chng li cc tc nhn xm nhp t bn ngoi. Tt c mi loi sinh vt trong sinh gii u c t nhiu kh nng t bo v chng li s xm nhp ca bt k vt l bn ngoi no cho d c hi hay khng nhm bo v tnh vn ton c th ca chng. Kh nng t bo v xut hin ngay nhng c th sng thp nht v ngy cng tr nn phong ph v hon thin. Min dch hc l mt mn khoa hc chuyn nghin cu cc qu trnh nhn bit cc cht l (gi l khng nguyn) v hu qu ca s nhn bit (l s p ng min dch). S nhn bit cc cht l v qu trnh p ng min dch c c l do kh nng tng tc ca mt phc h t bo trong h min dch ca c th ngi v ng vt. 2. Cc loi min dch p ng min dch ngi v ng vt c chia lm hai loi l min dch t nhin v min dch thu c. 2.1 Min dch t nhin a. Khi nim Min dch t nhin (bm sinh; native immunity, natural immunity) cn gi l min dch khng c hiu (non-specific immunity) l kh nng t bo v c sn t khi c sinh ra v 10

mang tnh cht di truyn trong cc c th cng loi. Min dch bm sinh khng i hi phi c s tip xc trc ca c th vi mm bnh hay vt l v gi vai tr quan trng khi min dch thu c cha pht huy tc dng. in hnh nh nhiu loi ng vt khng mc bnh ca ngi v ngc li. V d g khng mc bnh than, tru b khng mc bnh giang mai v thng hn ca ngi. Cc bin php khng ca min dch t nhin bao gm hng lot cc hng ro ngn cch nhm ngn cn cc yu t bn ngoi i vo c th. b. Hng ro vt l Bao gm da v cc nim mc ngn cch ni mi vi ngoi mi xung quanh m mi yu t phi vt qua khi mun vo c trong c th. Da gm nhiu lp t bo, trong c lp t bo ngoi cng sng ha, lun c bong ra v i mi, nn to ra c mt cn tr vt l kh vng chc. Nim mc ch c mt lp t bo nhng c tc dng cn tr tt v c tnh n hi cao hn da v c bao ph bi lp mng nhy. Nim mc vi din tch gp 200 ln din tch ca da v li l ch hay c tip xc vi nhiu vt l nht nn hnh thnh mt t chc chng min dch phc tp v c hiu qu nht. Nim dch l cht nhy do nhng tuyn di nim mc tit ra v to nn mt mng bo v lm cho vi sinh vt v cc vt l khng bm c thng vo t bo. Tuy nhin, nim mc khng c kh nng cn tr i vi nhng ht c kch thc di 3 m. c. Hng ro ha hc Ngay trn da v nim mc th hng ro vt l cn c tng cng bi mt s yu t ha hc to ra mt hng ro ngn cn. Trn da nh c cc cht tit to ra axit lactic, axit bo ca m hi v tuyn m di da lm cho mt s vi khun khng tn ti lu c. V d, cho vi khun Bacterium progidisumti tip xc vi da sau 10 pht th ch cn 10% c kh nng gy bnh, sau 20 pht cn 1% v sau 30 pht th khng cn kh nng gy bnh. Ti nim mc, cht nhy che ch b mt t bo khi b enzym neuraminidase ca virut tc ng. ng thi, n cn c kh nng tit ra mt s cht c ch sinh trng ca vi sinh vt nh lysozym l loi enzym muramidase c tc dng ph hy v ca mt s vi khun, c trong nc mt, nc mi v nc bt c th phn gii thnh t bo vi khun. Cht bacterial permeability increasing proteine (BPI) l mt dng protein lm tng tnh thm c th lin kt vi lp lipopolysaccharid (LPS) ca vi khun, sau chc thng mng ca chng v phong b cc men vi khun lm cho chng mt kh nng hot ng. Ngoi ra, cng c nhng cht ca huyt thanh chuyn t lng mch v gian bo ra nim mc nh b th, interferon cng tham gia vo s chng ha hc. Bn cnh cc yu t ho hc c trong da v nim mc, hng ro ha hc cn bao gm cc cht ha tan trong dch sinh hc ca c th. l nhng cht tit ca nhiu loi t bo khc nhau, nhng sn phm chuyn ha ca nhiu c quan nhng u ha tan trong dch sinh hc nh huyt thanh, dch bch huyt, dch gian boTrong huyt thanh c cha lysozym, cc 11

thnh phn ca b th, interferon, cc protein lin kt nh protein phn ng C (C reactive protein). Lysozym: l mt protein mang in tch m c kh nng thy phn cc ni glycosyd mng t bo ca mt s vi khun gram +. B th (Complement): l mt h thng gm nhiu thnh phn do nhiu loi t bo sn xut nhng li tng tc vi nhau c hot ha theo mt chng trnh nht nh. Trong p ng min dch t nhin th b th c hot ha theo con ng khng c hiu (khng cn khng th) bi cc cht nh carbon hydrat, lipopolysaccharic.ca vi khun, nh m chc thng v lm dung gii vi khun. Mt s thnh phn ca b th nh C3a, C5a c tc dng ha ng ng bch cu, gy dn mch, gii phng cc ha cht trung gian t cc ht ca bch cu i kim. Mt s thnh phn khc nh C3b s dnh vo vi khun gip cho cc t bo thc bo d tip cn v tiu dit vi khun. Interferon: (IFN) l mt protein do nhiu t bo tit ra trong min dch khng c hiu. IFN c hot tnh chng mt cch khng c hiu cc vi-rt nhim t bo cng loi. Khi vo trong t bo, vi-rt s hng b my ca t bo hot ng theo hng c li cho chng pht trin nhn ln v t bo dn dn b ph hy. Tuy nhin, nhng t bo b nhim vi-rt li c kh nng sinh ra IFN thm vo cc t bo xung quanh, gip chng khng b vi-rt xm nhp tip. Ngoi ra, IFN cn kch thch cc t bo sn sinh mt protein phong b qu trnh sao chp ca vi-rt khu ARN thng tin v nh m t bo khng b nhim vi-rt na, thm ch vi c vi-rt l. Nh vy, IFN cng c tc dng nh mt loi thuc khng sinh t nhin v ging nh lysozym chng li vi khun. Tuy nhin c ch khng vi-rt ca IFN khc hn vi c ch khng vi khun ca thuc khng sinh. Cc protein lin kt (binding protein): trn mt cc t bo v trong huyt thanh c nhng protein lin kt t nhin vi cc cht nh LPS, lectin, lipit, mannose ca vi khun gy bnh. S lin kt ny s lm hn ch s pht trin ca vi khun. c bit l protein lin kt st nh lactoferrin hay transferrin c nc mt, tinh dch, mt, sa m, trong cc cht tit ph qun, mi, hu, ng tiu ha, trong huyt thanh. Do b lin kt nn nng st t do trong mu v trong cc m thp hn so vi nhu cu cn cho s pht trin ca vi sinh vt, lm cho chng khng sinh trng c. Ngoi ra, da hay d dy c pH mang tnh axit nn c tc dng gy cn tr s sinh tng ca vi sinh vt gy bnh. d. Hng ro t bo y l hng ro quan trng nht v phc tp nht trng h thng min dch bao gm nhiu loi t bo. Tuy nhin gi vai tr quan trong nht l cc thc bo c kh nng nut v tiu ho cc vi sinh vt. Trn nim mc c rt nhiu thc bo di tn ra t ni mi bao gm tiu thc bo (microphage) v i thc bo (macrophage) c c tnh chung l tip cn vi cc yu t l, nut v tiu ho chng gi l qu trnh thc bo. Tiu thc bo l bch cu a nhn trung tnh ca mu, hot ng mnh i vi cc vi khun ngoi t bo. i thc bo l cc t bo 12

mono mu di chuyn ti cc m tr thnh t bo ca h thng vng c tc dng mnh vi cc vi sinh vt c kch thc ln. Qu trnh thc bo (phagocytosis) c chia thnh ba giai on (xem hnh 1.1) nh sau: Ha ng ng: l s di chuyn ca t bo ti vim nh tnh cht sinh hc ca cc cht do vi sinh vt tit ra nh cc peptit-formyl. Cc cht ca vt ch s c hot ha nh: thnh phn b th C3a, C5a Giai on gn: S bm dnh t bo thc bo vi vi sinh vt nh cc th th (receptor) c mt trn t bo vi sinh vt nh mannose, fucose hay axit sialic. Chng s hp dn cc t bo thc bo p ti, hot ha enzym kinase nhm to ra nhng gi tc. Khi thc bo n st th c hin tng dnh mng t bo nh vo nhng protein lin kt. Sau cc t bo thc bo s thay i cc hot ng nh th gi tc, hnh thnh lysosom, tng cng hot ng men. Giai on nut v tiu: u tin, mng t bo b lm vo, cht nguyn sinh s to cc chn gi bao ly vi sinh vt, ri ng kn li to thnh hc thc bo (phagosom) cha cc vi sinh vt. Nh vy, vi sinh vt ang ngoi c chuyn vo bn trong.Tip , giai on tiu s c bt u, cc ht lysosom tin n st cc hc thc bo, xy ra hin tng ha tan mng ca hai tiu th hnh thnh mng chung l phagolysosom, ti y cc vi sinh vt s b tiu do hai qu trnh, mt cn c oxy v mt l do men.

Figure 0.1. Qu trnh i thc bo v tiu dit mt vi khun Trong phagolysosom vi sinh vt s b tiu dit nh hai c ch chnh: C ch khng ph thuc oxy: cc men tiu protein, lysozym, lactoferin.dit vi khun v cui cng l cc men thy phn tiu hon ton vi khun. C ch ph thuc oxy: oxy c s dng mt cch mnh m chuyn thnh cc anion superoxyt (O1/2) v oxyt nit (NO), to nn mt h thng halogen (axit hypochloro, chloramin) c th tiu dit c vi khun ln vi-rt. 13

Qu trnh thc bo c khuch i bi mt s b th hot ha. Ngoi ra, s phng thch ra khi t bo nhng thnh phn ca phagolysosom lm tng phn ng vim cp, tng tnh thm thnh mch v lm dn ti s gia tng mt ca bch cu cc vim. i thc bo s tit ra mt s cytokin gy vim nh Interleukin-1, Interleukin-6 c tc dng ti ch hay gy ra hoi t, stlm tng qu trnh thc bo. Hng ro vi sinh vt cng tham gia tch cc vo cng vic bo v c th. Cc vi sinh vt ny sng trn b mt cng nh bn trong c th. l khu h vi sinh vt bnh thng chng khng gy hi m cn c li cho c th do chng chim trc cc v tr m vi sinh vt gy bnh s n, chng lm gim nng oxy, cnh tranh thc n v tit ra cc cht dit khun... Khu h vi sinh vt bnh thng trong ng tiu ha cn tit ra biotin, riboflavin v mt vi loi vitamin khc cung cp cho c th. Cc t bo c ht i kim nh t bo mast, bch cu a nhn kim tnh s tham gia vo qu trnh vim qua s gii phng cc cht trung gian cha trong nhng ht nh histamin, serotonin thng qua kch thch trc tip. Cn cc t bo c ht i toan nh bch cu toan tnh, tham gia vo vim cng thng qua ni dung ca cc ht y ch yu l protein kim v c kh nng tiu dit u trng ca k sinh trng. Ngoi ra, t bo dit t nhin (natural killer-NK) l mt loi t bo lympho c kh nng tiu dit khng c hiu cc t bo u v t bo b nhim vi-rt bng cht tit ca chng (perforin). IFN do chng tit ra s tng cng hot ng ca thc bo. 2.2 Min dch c hiu a. Cc dng min dch c hiu Min dch c hiu (specific immunity) cn gi l min dch thu c (acquired immunity) l trng thi min dch xut hin sau khi c th tip xc vi khng nguyn (antigen) v c phn ng sinh ra khng th c hiu chng li chng. Min dch thu c c hai c im khc c bn vi min dch t nhin l kh nng nhn dng v tr nh c hiu v khng 14

nguyn (vt l). H thng min dch c hiu c th ghi nh li cc tc nhn gy bnh v ngn cn tc ng gy bnh ca chng ln tip xc lp li tip theo. Min dch c hiu li c chia ra lm hai loi da vo phng thc to ra tnh trng min dch. Min dch ch ng: Min dch ch ng t nhin l trng thi min dch do tip xc ngu nhin vi khng nguyn v vi sinh vt c trong mi trng xung quanh. Min dch ch ng nhn to l trng thi min dch thu c nh tim vc-xin hoc do truyn t bo lympho thng hoc lympho min dch, t khi l do ghp. Min dch th ng t nhin l trng thi min dch thu c do khng th ghp hoc truyn t sa m Min dch th ng nhn to l min dch nh khng th chuyn t bn ngoi do truyn khng huyt thanh.

Min dch th ng: -

b. Cc giai on ca p ng min dch c hiu Khi khng nguyn xm nhp vo c th sng s gp phi s khng t nhin gi p ng min dch khng c hiu. Trong phn ng bo v ny mt s t bo n v tiu c khng nguyn ng mt vai tr rt quan trng bi v chng s trnh din c im ca khng nguyn y vi t bo sinh khng th. Ngoi i thc bo th c nhiu t bo khc cng lm c vic ny nh t bo lympho B nn c gi chung l t bo trnh din khng nguyn (APC-Antigen Presenting Cell). Nu hin tng thc bo l mt phn ca p ng min dch khng c hiu th ng thi cng l bc khi u ca p ng min dch c hiu. p ng min dch c hiu gm c ba giai on: Giai on nhn din khng nguyn Giai on u ca p ng min dch l lm bin i mt khng nguyn c cu trc phc tp thnh nhng peptit nh ch c mt nhm quyt nh khng nguyn (epitop) cc t bo c thm quyn ca h thng min dch c th nhn bit c. Hu ht cc khng nguyn u c x l v trnh din bi APC thng qua nhng phn t MHC (Major Histocompability Complex) c sn trn b mt cc t bo y vi cc th th tng ng trn lympho bo T (TCR- T Cell Receptor). Giai on cm ng Qu trnh trn s l mt tn hiu hot ha t bo lympho T, y l hng lot nhng phn ng bn trong t bo nhm cng c v pht trin s nhn din epitop. S sp xp li cc gen s gip cho t bo tng hp c phn t TCR c cu trc n khp hn vi epitop. S nhn din ny s c khuch i do t bo mi c hot ha tit ra nhng t bo hot ng (cytokin) gy tng sinh cng nh tc ng n nhng t bo khc lm chng tng cng hot ng. Trong , mt s s tr thnh t bo c tr nh tng i bn vng i vi khng nguyn y sn sng phn ng khi tip xc ln sau. Song song vi qu trnh khuch i th qu trnh c ch cng xut hin phn ng khng i qu mc cn thit v p ng mang tnh cht iu ho. 15

Nhng t bo nhn thng tin v tham gia p ng min dch ln u c gi l mn cm, tc l c tip xc vi khng nguyn v sn xut khng th c hiu vi khng nguyn y. Khng th c th nm trn mng ca nhng t bo sinh ra n gi l khng th t bo v do mt qun th t bo lympho T sn xut. Khng th c th ha tan v c vo dch ni mi, l khng th dch th v do nhng t bo lympho B sn sinh. p ng min dch qua trung gian t bo (cell mediated immunoresponse) l p ng c s tham gia ca mt s t bo T, th hin di hnh thc gy c t bo v hnh thc vim kiu qu mn mun. Min dch ny ng vai tr quan trng trong cc bnh do vi sinh vt k sinh bn trong t bo gy ra, trong thi b m ghp v trong min dch chng ung th. p ng min dch th dch (humoral immunoresponse) c th hin bng s sn xut khng th c kh nng tng tc c hiu vi khng nguyn. Min dch ny chng vi sinh vt ngoi t bo v trong th dch ca c th. Giai on hiu ng Khi cc t bo lympho c mn cm sn xut ra cc khng th v kt hp c hiu vi khng nguyn s dn n qu trnh vim v tiu dit khng nguyn y. Trong min dch qua trung gian t bo th s kt hp gia khng nguyn v khng th l do s tip xc trc tip gia t bo lympho T vi t bo ch mang khng nguyn. Lympho T s tit ra cht perfolin dit t bo ny. Nu l khng nguyn ha tan th s kt hp trn xy ra trn mng t bo lympho T, n s c hot ha v tit ra IL-2 hot ha cc t bo c chc nng khc nh lympho B, lympho qu mn.gy vim c hiu.

Hnh 0.1. p ng min dch tin pht v th pht

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p ng min dch tin pht v th pht Mc p ng min dch qua cc giai on tu thuc vo mi mn hay mn cm li. p ng min dch ln u (primary immune response) c thi gian tin pht di, cng p ng yu v thi gian p ng ngn. Mt s t bo T v B c mn cm s tr thnh t bo tr nh (memory cell) nu tip xc li vi khng nguyn s to ra p ng min dch th pht (secondary immune response). p ng min dch th pht c thi gian tim tng ngn hn, cng p ng mnh hn v thi gian duy tr p ng di hn do cc t bo tr nh pht trin nhanh v mnh to thnh mt dng t bo chuyn sn xut ra khng th c hiu.

Ti liu tham kho


1. V Triu An v Jean, C.H. 2001. Min dch hc. Nh xut bn Y hc. 2. Nguyn Ln Dng. 2001. Vi sinh vt hc. Nh xut bn Gio Dc. 3. L Huy Kim. 1998. Bi ging min dch hc th y. Khoa Nng Nghip- i hc Cn Th. 4. Nguyn Ngc Lnh v ctv.1997. Min dch hc. Nh xut bn y hc. 5. Nguyn Vnh Phc. 1978. Gio trnh bnh truyn nhim gia sc. Nh xut bn Nng Nghip.

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Chng 2 : Cc c quan v t bo tham gia p ng min dch A. Cc c quan tham gia vo h thng min dch
H thng min dch rt pht trin loi chim v loi c v, nht l ngi chim trn 1/60 trng lng c th. N gm tt c cc dng bch cu ca h thng to mu m vai tr ch yu thuc vo cc m lympho. l loi m lin kt v n s kt hp vi nhng t bo ca h thng thc bo n nhn v t bo lympho. Cc t bo ca h thng min dch s lun chuyn c mt khp mi ni trong c th, ri t li di nhng hnh thc t chc phn tn hay tp trung thnh m khng c v bc hay dng hch. V mt t chc thnh c quan, h thng min dch c th phn bit ra nhng c quan gc, c quan tin pht v nhng c quan th pht (hnh 2.1).

Hnh A.1. S lc v tr cc c quan min dch ngi

I. C quan gc
Tu xng l c quan gc ca h thng to huyt v cng l ni sn xut ra cc t bo gc (t bo mm) ca h thng min dch nn cn gi l c quan gc. Ni sn xut t bo gc s thay i ty theo tui. ngi, trong nhng tun u ca cuc sng th cc t bo mm nm l phi, sang giai on thai th chng s di chuyn n c tr mm gan, ri sau cng l ty xng.

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Ty xng c hnh thnh bi m lin kt vi nhng mao mch ngon ngoo, nhng t bo ni m, nguyn bo s v t bo m (hnh 2.2). Mng li ngoi t bo bao gm cc si nh collagen hay si lamin Cc t bo sinh mu nm gia cc si reticulin v chu tc ng ca cc yu t sinh trng khc nhau, gi chung l yu t qun th (colony stimulating factor) ty thuc vo dng t bo c sn xut theo nhu cu ca h min dch.

Hnh A.2. Cc t bo trong tu xng

II. Cc c quan lympho tin pht


ngi v ng vt hu nh th c quan lympho tin pht l tuyn c (hnh 2.3). cc ng vt thuc lp chim th c quan lympho tin pht l ti Fabricius (hnh 2.5). C quan ny xut hin sm trong i sng ca phi trc nhng c quan th pht v nm ngoi ng thm nhp v tun hon ca cc khng nguyn, nn s pht trin mnh m ca t bo lympho xy ra y s khng ph thuc vo bt k mt kch thch no ca khng nguyn. Cc c quan tin pht s cho php s bit ha v nhn ln ca t bo lympho gc trong giai on u. ng thi chng c kh nng nhn bit v dung np cc khng nguyn ca bn thn cng nh tng cng tnh a dng cc cu trc nhn bit khng nguyn l. Hot ng ca c quan lympho tin pht ph thuc vo vic thng xuyn c cung cp cc t bo lympho gc t ty xng. Mt t bo khi c bit ho (trng thnh) v ri c quan lympho tin pht th khng quay tr li na, v nhng c quan ny nm ngoi con ng ti tun hon ca cc t bo lympho trng thnh. 19

1. Tuyn c Tuyn c l mt c quan nm pha trn v trc ca trung tht. C cu to gm hai thy ni vi nhau bi mt ci eo gia (hnh 2.3A). Tuyn c l mt c quan lymph-biu m. Cc mm t ti nang gm mt mng nhng t bo biu m v cc t bo lympho cha bit ha t ty xng ti ni c tr. Mi thy ca tuyn c c phn chia thnh nhiu tiu thy bng cc vch ngn, mi tiu thy li c mt vng v ngoi v mt vng ty trung tm (hnh 2.3B).

Hnh A.3. Cu to tuyn c Tuyn c hot ng nh mt c quan gip cho s trng thnh ca cc t bo lympho T v mt pht trin, bit ha v chn lc. Trc khi i vo tuyn c, t bo lympho T cn gi l t bo tin c ch yu ch mang CD33 v CD44 m cha c CD4 v CD8. Ti tuyn c cc t bo lympho T ny c bit ha thnh cc t bo lympho c cc th th vi khng nguyn (gi tt l TCR) nh s xp xp li cc gen bn trong. Nhng t bo no khng hnh thnh TCR c s cht. S pht trin v bit ha cc TCR xy ra ch yu ti vng v ca cc tiu thu tuyn c. Cc t bo c TCR dn dn c nhng du n ca t bo lympho T trng thnh nh cc phn t CD2, CD4 hay CD8 i vo qu trnh chn lc dng v chn lc m trong tuyn c (hnh 2.4) chn ra nhng t bo T c kh nng tng tc vi khng nguyn bo v c th . - Chn lc dng: ti vng v ca tuyn c, t bo tin c c CD4-, CD8- v TCR i vo tip xc vi t bo biu m c mang phn t MHC I v II. Ch nhng t bo no nhn ra cc phn t MHC I v phn t MHC II ca bn thn th c gi li CD4+ v CD8+. S chn lc ny cho php tn ti li nhng t bo c c TCR c kh nng tng tc vi phn t MHC ca t bo biu m thuc tuyn c. N cn kim sot s sp xp li cc gen ca chui. - Chn lc m: i su vo trong vng li ca tuyn c, t bo lympho T c CD4+ hay CD8+ v TCR s tip xc vi khng nguyn ca bn thn cng qua cc phn t MHC. Nhng t bo lympho T no m TCR ca chng c th nhn bit cc peptit ca bn thn do cc phn 20

t MHC ca t bo biu m trnh din s b loi b (nhn t bo tr nn c ng, v thnh mnh nh ri t bo b v ra thnh nhiu mnh).

Hnh A.4. Chn lc dng v m trong tuyn c

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Ngoi ra, cn c cc yu t dch th tham gia tc ng gip hon tt qu trnh bit ha cc t bo lympho trong tuyn c v ti cc c quan lympho ngoi vi khc. Tuy nhin cho n nay c ch ca chng cha c bit r. 2. Ti Fabricius Loi chim c mt c quan c bit l ti Fabricius (hnh 2.5) l c quan lympho-biu m nm mt trong ca l huyt. Nu ct b ti ny trong giai on phi trc khi trng n, s lm ri lon min dch th dch lm gim nng hm lng -glubolin v sinh vt s khng sn xut c khng th khi gy cm nhim vi mm bnh.

Hnh A.5. Ti Fabricius g

III. C quan lympho th pht


Cc t bo lympho T sau khi c bit ho v chn lc tuyn c s ri khi c quan lympho tin pht ny v di chuyn n c tr ti cc c quan lympho th pht lm nhim v khng min dch. S pht trin ca c quan lympho th pht v vy chm hn c quan tin pht. Mt khc c quan lympho th pht ch pht trin y khi c kch thch ca khng nguyn. Chng s khng pht trin nhng con vt nui v trng. Ngoi t bo lympho T n t tuyn c, trong c quan lympho th pht cn c t bo lympho B n t ty xng qua ng mu. Nhng t bo lympho c quan ny thng xuyn ti tun hon v trao i vi cc t bo ca nhng c quan khc qua trung gian dch bch huyt v mu. Ti ngay cc c quan y chng biu l cc kh nng ca mnh khi c dp tip xc vi khng nguyn. Ti mt s vng ca c quan lympho th pht c nhng m t bo c gi l nang gm ch yu l t bo lympho B. Trc khi c s kch thch ca khng nguyn th cc nang ny c gi l nang tin khi. Do cn thi k ngh nn cc t bo lympho cn nh, ci n nm st ci kia to ra mt hnh thi c bit. Nhng sau khi c s kch thch ca khng nguyn th tr chng s pht trin thnh nang th pht gm mt trung tm mm sng c bao quanh bi mt khu thm hn. Khi y nang c th c phn chia thnh 3 vng (hnh 2.6). 22

Vng vnh ngoi m c l o nang gm ton t bo lympho tr nh st cht vi nhau v ang trong thi k phn chia mnh, to ra vng sinh sn ca trung tm mm. Vng vnh th hai cng m c gm nhng t bo lympho trng thi ngh nh trc khi c s kch thch ca khng nguyn. Khu trung tm mm l khu c cc t bo tch bit nhau v thng ang trong thi k phn bo. T bo lympho c bin thnh nguyn bo lympho, l nhng t bo c nguyn sinh cht rt pht trin v l nhng t bo tin thn s tit ra khng th.

Hnh A.6. Nang lympho th pht 1. C quan lympho th pht tp trung c v bc Hch Hch l nhng c quan lympho c ng knh vi mm, hnh trn hay qu u c v bc bn ngoi. Hch c cu trc bi 3 vng c bn l: vng v cha cc nang lympho tin khi hay th pht m ch yu gm t bo B; vng cn v c mt thm t bo lympho T v i thc bo to thnh mt khu vc ph thuc tuyn c ca hch v vng li l khu vc ln trn ca t bo lympho T, t bo lympho B, tng bo v i thc bo (hnh 2.7). Nh s lu thng ca cc hch bch huyt gip cc hch c th kim sot c nhiu lnh vc nh da, c quan su thng qua m k. Cc hch ti nhiu im c th phn tn hay tp trung thnh tng nhm hch nng hay su nhng im giao lu quan trng nh nch, hng, mng treo rut Lch C quan ny nm trong vng tun hon mu v gi mt vai tr quan trng trong vic thanh lc mu. Khng c mch bch huyt ti c quan ny. Lch gi vai tr rt quan trng trong s khng ca c th. V d, nhng a tr b ct b lch th s nhim khun huyt do vi khun gram m xy ra rt nng. 23

Hnh A.7. Cu trc ca hch Lch c cu to bi hai phn l: (1) ty c nhim v loi tr cc ht v cc t bo h do mu a ti m khng gy p ng min dch v (2) ty trng gm nhng ng t bo lympho T v cc nang cha ch yu t bo lympho B (hnh 2.8). Vng trung gian gia ty v ty trng l ni trao i m cc t bo lympho ca mu tun hon c th ri khi tnh mch nm li cc cu to lympho. V mt chc nng, vic nm bt khng nguyn lch xy ra vng ngoi ra do cc t bo li thc hin. Sau 24 gi chng s c chuyn ti trung tm mm ca nang hay ti vng ph thuc tuyn c. Nh vy, lch gi vai tr rt quan trng v s khng ca c th. 2. C quan lympho th pht phn tn Da Da l hng ro vt l ngn cch ni vi ngoi mi v cng l b mt d b tn cng vt l, ha hc hay sinh hc. Da cng l ni thng c a vc-xin vo c th v l ni biu hin p ng min dch bnh l d thy nht. biu b su ca da c y cc loi t bo tham gia vo p ng min dch c hiu v khng c hiu (hnh 2.9). Phn ng min dch da xy ra theo ba thi k: (1) trong pha u ca vim, do ha ng ng bch cu s di chuyn ra ngoi lng mch v tin ti biu b; (2) trong pha th hai, s c s tng tc gia cc t bo trnh din khng nguyn vi cc t bo lympho T di chuyn ti do tc dng ca cytokin. Chng s phn chuyn v hnh thnh mt thm nhim m cn c gi l m ht, cc t bo Langerhans v t bo lympho T c CD8+ vy quanh thnh vng, ri rc l t bo T CD4+ v t bo dng biu b; (3) pha ti tun hon xy ra khi qu trnh vim gii quyt cc yu t xm nhp v c s t iu chnh tr v bnh thng. 24

Hnh A.8. Cu trc ca lch Nim mc Vi din tch rt rng v cu trc tng i mnh gip cho nim mc tr thnh ni tip xc vi nhiu loi khng nguyn nht m ch yu l qua ng tiu ha v h hp. H thng min dch di nim mc cng c mt t chc rt c bit (hnh 2.10) cng ngy cng c ch hn. M lympho min dch di da c th chia ra lm hai loi: M lympho nim mc c t chc (organised mucosa associate lymphoid tissue; O-MALT) to thnh nang t bo di nim mc v thy nhiu rut, ph qun, hc mi, ming v ng sinh dc. Thng th chng tp trung ring l thnh tng m nhng i khi cng tp trung thnh khi nh hch amidan, mng peyer Cu trc ca mi nang l mt trung tm mm sng gm ch yu cc t bo tua c kh nng trnh din khng nguyn v t bo lympho B c IgA, nhng khng thy tng bo tit khng th y. T bo lympho T CD4+ v i thc bo nm ri rc bn trong v xung quanh nhng nhiu nht l bn trn nh v pha gip vi nim mc. ch ny mt s t bo biu m cng thay i hnh thi nh khng c nhu mao c th lm nhim v vn chuyn khng nguyn i qua nn c gi l t bo M (membranous cell).

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Hnh A.9. Cu trc cc t chc min dch di da

Hnh A.10. Cu trc cc t chc min dch nim mc

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M lympho nim mc ri rc (diffuse mucosa associate lymphoid tissue; D-MALT) gm cc t bo lympho B, t bo lympho T v tng bo tit IgA nm ri rc trong gian bo ca ton b nim mc. y l ni tit ra IgA mnh nht v nhiu nht.

IV. S ti tun hon t bo lympho

Hnh A.11. Ti tun hon t bo lympho T bo lympho sau khi ri khi c quan gc n cc c quan th pht, y mt thi gian ri i vo tun hon mu v bch huyt to ra mt s ti tun hon lin tc (hnh 2.11). ng khng nguyn xm nhp vo h thng lympho quyt nh ni xy ra p ng min dch. T di da, nim mc hay dch gian bo cng t bo theo ng mch bch huyt ti v ca hch, vo trong hch v li nh nhng phn t bm dnh. Mt s t bo lympho theo ng mu khi n tnh mch sau mao mch, ch ny th vng cn v c t bo ni m cao (HEV-high endothelium veinule) th nm li di chuyn vo l hch, ri sau cng i ra bng ng mch bch huyt. Cui cng, chng vo ng ngc v vo tun hon mu chung. Nh vy, cc t bo min dch ngoi ng mu cn c thm ng bch huyt. S ti tun hon thng xuyn y cho php phn tn trong ton c th nhng t bo lympho c hun luyn mt cch thch hp nhn bit cc khng nguyn khc nhau, c mn cm, ghi nh li din mo ca khng nguyn v sn sng c hot ha sinh ra khng th khc nhau c hiu chng li cc khng nguyn tng ng. B. Cc t bo tham gia vo h thng min dch H thng min dch bao gm nhiu c quan v nhiu loi t bo phn b khp c th, tc ng qua li vi nhau theo nhiu cch i n p ng min dch cui cng. T bo ch cht tham gia vo p ng min dch l t bo lympho, cho nn bt k t chc no cha t 27

bo lympho v tham gia vo p ng min dch cng u c xem nh t chc lympho. Cc t bo lympho c ngun gc t cc t bo ngun cha bit ho trong ty xng, cn gi l t bo gc. T t bo gc, nhiu dng t bo c chc nng khc nhau c bit ha ri sau tri qua qu trnh thnh thc (chn) khi kt hp vi cc t chc chuyn ha (hnh 2.12). Hai loi t bo chnh ca h thng min dch l t bo lympho v i thc bo.

Hnh A.12. Ngun gc t bo min dch

V. Nhng t bo ca p ng min dch khng c hiu


1. i thc bo i thc bo (macrophage) l cc t bo c kch thc ln c kh nng bt gi, nut v ph hy khng nguyn. i thc bo cng hp tc vi cc t bo lympho sn xut khng th c hiu. i thc bo c hai phn nhm l cc t bo n nhn v cc t bo a nhn c ht (hay bch huyt cu a nhn). T bo a nhn c th bit ha thnh i thc bo. Thut ng i thc bo ch yu dng m t cc thc bo gn c nh trn b mt t chc, cn thut ng bch cu n nhn dng m t thc bo lu ng t do. i thc bo c nhiu trong t chc lympho v lch, cn bch cu n nhn c nhiu trong mu v bch huyt. Khi mt khng nguyn xm nhp vo biu m s tip xc vi thc bo, chng hn i thc bo. T bo ny s bt gi, nut cc t bo c kch thc ln nh vi khun v tit ra enzym thy phn nh proteinase, nuclease, lipase v lysozim tiu ha chng (hnh 2.13). Khi t bo vi khun b phn hy s gii phng ra cc khng nguyn cha trong i thc bo. Cc khng nguyn ny cng vi cc khng nguyn do i thc bo nut trc tip t bn ngoi s c dng bt u giai on sm ca qu trnh tng hp khng th. y i thc bo lm nhim v t bo trnh din khng nguyn (Antigen presenting cell-APC). S d gi nh 28

vy l v chng y khng nguyn l ra b mt to iu kin cho khng nguyn tip cn vi t bo B v t bo T (hnh 3.2). S nhn mt khng nguyn ca hai loi t bo ny l bc khi u ca s to thnh khng th. Khc vi t bo B v t bo T, i thc bo v cc th n nhn khng c kh nng phn bit khng nguyn, do khng mang tnh c hiu. Chng bt gi v nut bt c vt l no m chng gp bt k c tnh khng nguyn hay khng. Tuy nhin, trong thc t v nhiu cao phn t l khng nguyn v cc t bo l c cha nhiu khng nguyn, cho nn phn ln cc ht l do cc t bo ny nut cng l khng nguyn.

Hnh A.13. Vai tr ca i thc bo trong p ng min dch ng tc trnh din khng nguyn ca i thc bo ng vai tr rt quan trng trong sn xut khng th, bi v mt s ln khng nguyn ch c th kch thch cc t bo lympho thng qua i thc bo. 2. Bch cu trung tnh Bch cu trung tnh (Neutrophil) l loi bch cu c nhiu nht trong mu ngoi vi, c sn sinh t t bo m trong ty xng di s kch thch ca cc yu t nh GCSF (granulocyte colony stimulating factor), GM-CSF( granulocyte macrophage colony stimulating factor), IL-3 (interleukin- 3). Chng ch tn ti trong mu khong 10 gi ri i ra khi lng mch ti 29

m. c tnh c khong 100 t t bo ny lun chuyn trong h tun hon v n s tng 10 ln khi c hin tng vim cp tnh. Bch cu trung tnh khi cn non th cha men myeloperoxydase, hydroxylase nhng khi gi th cha ch yu l lysozym v lactoferrin. Kh nng ti sinh cc ht ny sau khi s dng th hu nh khng c bi v cc bch cu trung tnh trng thnh thiu mng li ni nguyn sinh th. Trn b mt ca chng cng c cc th th vi cc cht ng ha ng lm chng c th di chuyn. ng thi n cng c cc th th vi Fc ca Ig, C3b ca b th, cc yu t sinh trng Trong phn ng vim th cc bch cu trung tnh s chuyn ra st thnh mch v chui ra khi lng mch ti vim m chng s gi vai tr ch cht. Tuy nhin, bch cu trung tnh ch c lp MHC I nn khng c nhim v trnh din khng nguyn. Do cng c kh nng n nhng l nhng t bo nh nn bch cu trung tnh cn c gi l tiu thc bo (microphage) nhm phn bit vi i thc bo. Tt c nhng thay i v hnh thi, chc nng ca chng l nhm tiu dit nhng cht ch. 3. Bch cu i toan i sng ca bch cu i toan (Eosinophil) tng i ngn, trong h tun hon chng ch chim khong 1-3 % s bch cu. Bch cu i toan c nhiu trong m hn l trong mu, v cng c ngun gc t ty xng. Bch cu i toan cha protein ch yu c tnh cht kim (major basic protein-MBP) v protein ti in m (major cationic protein-MCP) lm cho chng bt mu axit nh eosin. Cc protein ch yu c tc dng c t bo, nht l i vi cc k sinh trng. Tuy nhin, k sinh trng c kch thc ln nn cc bch cu i toan u tin s tip cn vi chng v sau s tit ra cc cht c ti ch tip xc. 4. Bch cu i kim v t bo mast T t bo gc l CFU-GEMM (Colony forming Unit granulocyte erythrocyte macrophage monocyte) ca ty xng nhng do tc dng ca IL-4 nn bch cu i kim (Basophil) v t bo mast c nhng ht bt mu kim xanh thm cha histamin, heparin, arylsulfat, glucuronidase nn c chc nng ging nhau. Tuy nhin, bch cu i kim ch yu c trong mu cn t bo mast th c trong m. c trng ca c hai loi t bo ny l u c th th mnh vi IgE, cho nn d khng th ny rt t dng ha tan trong mu nhng li thng xuyn c mt trn t bo kim. Khi khng th ny kt hp c hiu vi khng nguyn th s to nn mt tn hiu i vo trong t bo lm cho cc ht i kim b y ra gip mng, v v phng thch ra ngoi cc cht trung gian c sn hay mi c hnh thnh. y l hin tng mt ht m c ch v vai tr ca chng rt quan trng. Cc cht trung gian nh lipit l sn phm ca s chuyn ha ca axit arachidonic v PAF acete (platelet activating factor), chng rt quan trng trong tng tc t bo trong p ng min dch t nhin hay min dch thu c. Axit arachidonic c gii phng t phospholipit nh phospholipase A2 hay C, chuyn ha thnh prostaglanin nh enzym 5-cyclooxygenase v thnh leucotrien nh 5lipooxygenase l nhng cht gy vn mch rt mnh trong vim. 5. Tiu cu Tiu cu (platelet, thrombocyte) bt ngun t cc mu tiu cu ln trong ty xng. Ngoi vai tr ch cht ca chng trong qu trnh ng mu th tiu cu cn tham gia vo trong p 30

ng min dch. c bit, trong vim chng gy ng mu ti ch v tit ra cc cht vn mch. ng thi, chng c biu l cc phn t MHC lp I v cc th th c i tnh vi IgE. 6. Nhng t bo dit t nhin Nhng t bo dit t nhin (Natural killer-NK) l nhng t bo c ngun gc cha r rng, chng c nhn bit nh l mt t bo lympho to khng c TCR hay BCR nh t bo lympho nhng li c cha ht perforin v granzym. Chng chim khong 4-10% tng s nhng t bo lympho trong mu (hnh 2.14).

Hnh A.14. T bo NK nhn bit t bo ch khi t bo ny khng c MHC lp I T bo NK hot ng khi tip xc vi cc t bo khng c hoc khng biu l phn t MHC lp I trn b mt, v d nh t bo b nhim vi-rt. l do trn b mt ca chng c mt loi th th c gi l KIR (killer cell inhibitory receptor). Bnh thng khi tip xc vi t bo c phn t MHC lp I th hot ng ca chng b c ch. Khi cc t bo NK hot ng ngha l tn hiu gy hot ha chng trnh dung gii t bo i vi nhng t bo t hay khng c MHC lp I. Khi y mt loi th th khc gi l KAR (killer activated receptor) s hot ng sn xut ra perforin gy dung gii t bo ch. T bo NK c th th vi Fc ca IgG nn l thnh phn t bo ca hin tng gy c t bo ph thuc khng th (antibody dependant cellular cytotoxicity-ADCC). Khi c hot ha bi IL-2 n c gi l LAK (lymphocyte activated killer) c kh nng tiu dit mt s t bo u. 7. T bo ni m Ngoi nhim v lt mt trong ca thnh mch mu, cc t bo ni m cn tham gia tch cc trong iu bin p ng ca cc t bo vim tun hon. Chng l bn l ca nhng thay i vn mch v tnh sinh hc t bo mch khi b kch thch bi mt s cytokin. Chng tit ra 31

nhng phn t bm dnh gip cho tiu cu vn t, cc bch cu trong mu c th tp trung ra pha ngai v thot mch. Khi c hot ha th xut hin phn t MHC lp II mi trn mng mt, gip chng tr thnh t bo c kh nng trnh din khng nguyn. S tng cng chuyn ha lipit mng ti ni m s sn sinh ra cc prostaglandin v leucotrien tham gia vo qu trnh thay i vn mch ti ch. Bn thn ni m cn tit ra IL-1, GM-CSF l nhng cht quan trng trong qu trnh iu bin tng sinh t bo m ch yu l bch cu trong vim. 8. Hng cu Hng cu (Red blood cell, Erythrocyte) mu ngoi vi l t bo mt nhn m nhim v c bn l vn chuyn oxy nhng hin nay ngi ta thy chng c th th CR1 vi b th gip vn chuyn phc hp min dch ti ni o thi.

VI. Nhng t bo ca p ng min dch c hiu


1. T bo trnh din khng nguyn T bo trnh din khng nguyn (antigen presenting cells-APC) l nhng t bo c kh nng x l phn t khng nguyn to thnh nhng peptit nh ri a chng ra ngoi mng t bo trnh din chng vi t bo lympho tng ng. Chng gm cc t bo bnh thng c biu l phn t MHC lp II trn mng ngoi v c thy nhiu nht l cc t bo lympho B, cc t bo ca h thng i thc bo hay cc t bo mono (Monocyte). Ngoi ra, mt s t bo c tua v t bo khi b hot ha mnh nh t bo ni m, t bo lympho T cng c kh nng trnh din khng nguyn. 2. Phn t MHC Phn t MHC (major histocompability complex) l mt phc hp ha hp m (hnh 2.15), c vai tr quan trng trong qu trnh trnh din khng nguyn v p ng min dch. Cm gen MHC l mt vng cha rt nhiu gen a hnh. Sn phm ca cc vng gen ny gi l khng nguyn MHC biu l trn b mt nhiu loi t bo trong c th. Vi tr ca cm gen MHC c chng minh mt cch y khi cc t bo T c hiu khng nhn ra cc khng nguyn ha tan m ch nhn bit cc khng nguyn c x l v trnh din trn mng APC kt hp vi cc phn t MHC.

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Hnh A.15. Cu trc phn t MHC a. Phn t MHC lp I: l cc glycoprotein, gm hai loi chui a peptit. Chui (chui nng) do gen MHC m ha, c u tn cng l amin ngoi bo, mt on ngn k nc xuyn mng v nhm tn cng l cacboxyl khong 30 axit amin nm trong tng bo. Chui khng do gen MHC m ha, gn khng ng ha tr vi phn ngoi bo ca chui m khng gn trc tip vi t bo. Trn phn t MHC I c chia thnh bn vng c cu trc ring bit nh trnh by hnh 2.16 Vng gn peptit: chc nng chnh ca cc phn t MHC l gn cc on peptit l t bo T nhn bit v c hot ha nhm tiu dit cc vi khun khc nhau trong mi trng sng. Vng ging Ig: c bo ton cao gia cc phn t MHC lp I ging nh vng hng nh ca Ig. Cc t bo T CD8+ ch hot ng c khi gn vi phn hng nh ca phn t MHC lp I. V th, cc t bo T CD8+ b gii hn hot ng trong cc phn t MHC lp I. Vng xuyn mng: l mt chui a peptit vi vng k nc khong 25 axit amin v i qua vng k nc ca mng huyt tng (plasma). Mng plasma c hai lp lipit neo cc phn t MHC vo trong mng t bo. Vng tng bo: khng c bo tn tt trong cc phn t MHC lp I khc nhau. Tham gia vo qu trnh iu ha tng tc gia cc phn t MHC I vi cc protein mng khc hay vi cc protein khung t bo. ng thi, ng vai tr quan trng trong vic lu hnh ca cc phn t ni bo.

33

Hnh A.16. Phn t MHC lp I b. Phn t MHC lp II: cng c hai chui a peptit v kt hp khng ng ha tr vi nhau, chui ln hn chui do c glycosyl ha nhiu hn (hnh 2.17). C hai u c u tn amin ngoi bo, u tn cacboxyl ni bo v u do gen MHC m ha. Cc phn t MHC lp II cng c chia lm bn vng nh phn t MHC lp I. Vng gn peptit: cc on ngoi bo ca c hai chui v u c chia thnh hai on nh khong 90 axit amin. Hai chui 1 v 1 to thnh nn l c 8 lp hai cnh 1 v 1 to nn rnh gn peptit. Tnh a hnh ca gen MHC II nm trong cu trc 1 v 1 ca rnh peptit, to cc b mt c cu trc ha hc c hiu ca rnh. T , quyt dnh tnh c hiu v i tnh gn peptit ca rnh. Vng ging Ig: c hai on 2 v 2 ca lp II u c cu ni disulphua bn trong chui, cc phn t ny cng thuc gia nh h Ig. Chui 2 v 2 v c bn th khng a hnh nhng khc bit nhau trong cc cm gen. Cc phn t T CD4+ gn vo vng khng a hnh ny, do ch p ng min dch gii hn trong phn t MHC lp II. Cc tng tc ny rt mnh v ch b ph v trong cc iu kin phn t b bin tnh. Cc vng xuyn mng v vng trong tng bo: vng xuyn mng ca 2 v 2 c 25 axit amin k nc. Tch mch bng papain c th tch on ngoi bo vi vng xuyn mng m khng b ri lon cu trc. Vng xuyn mng ca c hai chui ny u tn cng bng cc axit amin kim, tip theo l mt ci ui i nc ngn trong bo tng, to thnh u tn cacboxyl ca chui a peptit. Chng ta cn bit rt t v vng ni bo tng ca cc phn t 34

MHC lp II. Cc phn t ny c th c vai tr trong dn truyn tn hiu v vng ni bo c th c vai tr chuyn thng tin mng.

Hnh A.17. Phn t MHC lp II 3. T bo mono v i thc bo Cc t bo ny c kh nng a cc khng nguyn t ngoi vo trong hc thc bo (phagosom). Mt mt s hp nht phagosom v lysosom thnh phagolysosom, cho php qu trnh thoi bin khng nguyn thnh nhng peptit sinh mn cm. Mt khc, ngay ti mng li ni nguyn sinh ca chng cc phn t MHC II c sn xut v c a ti sp nhp vi mng ca phagolysosom, t s l ra trn b mt cc chui , v mi c th nhn peptit sinh mn cm. Phagolysosom di chuyn ra pha ngoi ca t bo v mng ca phagolysosom s ha nhp vi mng nguyn sinh cht ngoi t bo, kt qu l peptit nm trn phn t MHC ra ngoi mng s cng tip xc vi TCR ca t bo lympho T. i thc bo c coi l nhng t bo trnh din khng nguyn chnh, khi ngh th c phn t MHC II nhng sau khi c hot ha bi INF- t t bo T th chng mi xut hin nhiu v khi tip xc vi t bo lympho T h tr th n s tit ra IL-1, IL-6 v TNF (tumor necrosis factor). Ngoi ra, trn b mt i thc bo cn c nhng phn t bm dnh h tr cho s tng tc gia i thc bo v t bo T. 4. T bo tua C mt khp cc m (tr no v gic mc) nhng ch yu l trong da, hch, lch v tuyn c. Trn mng chng u c nhng phn t MHC II. Sau khi nut khng nguyn th chng 35

tr nn trn tra v di chuyn ti hch gn nht vo trong v, chuyn thnh t bo c chn xen k. Chng x l khng nguyn thnh cc a peptit khong 20 axit amin v trnh khng nguyn cho phn t MHC II ngoi mng. S trnh din ny tn ti trong nhiu ngy. i tng c trnh din l TCR ca t bo lympho T CD4 5. T bo lympho T bo lympho (lymphocyte) phn tn khp c th trong h tun hon mu v bch huyt, cng l mt trong nhng t bo c s lng cao nht ca ng vt c v. ngi ln trung bnh c 1012 t bo lympho. C hai loi t bo lympho cn cho p ng min dch l t bo lympho bo B (t bo B) v t bo lympho T (t bo T). Tuy c hai u c bit ha t t bo ngun nhng qu trnh chn ca t bo B c thc hin trong ty xng (Bonemarrow nn k hiu l B). gia cm, t bo B chn trong mt c quan chc nng chuyn ha, gi l ti Bursa Fabricius (Bursa ngha l ti, cng bt u bng ch B), l mt tuyn ng tiu ha pha di. T bo T chn trong c quan chc nng l tuyn c (Thymus, nn k hiu l T). Do ty xng v tuyn c c vai tr ln trong s pht trin ban u v chn ca t bo B v t bo T, nn chng c gi l cc c quan lympho trung tm. Sau khi chn, t bo T v B phn tn khp c th thng qua h tun hon mu v bch huyt, ri n c tr ti hch lympho hoc lch. Cc c quan ny c gi l c quan lympho ngoi vi. Chng nm trong h tun hon mu v bch huyt, hot ng nh mt b my lc. i thc bo lm nhim v by khng nguyn khi chng i qua cc c quan ny, cng y cc t bo B v t bo T thc hin p ng min dch. T bo B thc hin tng tc vi khng nguyn v to khng th. T bo B khc vi t bo T ch trn b mt ca n c cha khng th. Khng th b mt ny s dng sao ra cc khng th m t bo B s sinh ra trong qu trnh pht trin sau ny. Trn b mt tt c t bo T u c th th c hiu vi khng nguyn nn t bo T c kh nng tng tc c hiu vi khng nguyn. Bng A.1. Mt s c im so snh gia t bo B v t bo T T bo T Ngun gc: Tu xng Ni chn: Tuyn c Thi gian sng: Vi thng n vi nm Lu ng C th th t bo T Tnh c hiu vi khng nguyn hp Khi c khng nguyn kch thch s tin hnh tng sinh H tr t bo B sn xut khng th T bo B Ngun gc: Tu xng Ni chn: Tu xng Thi gian sng: Vi ngy n vi tun Khng Lu ng C th th vi b th Tnh c hiu vi khng nguyn hp Khi c khng nguyn kch thch s tin hnh tng sinh to plasma v t bo tr nh Sn sinh ra khng th

36

T bo lympho T Qun th t bo T li c bit ha thnh cc tiu qun th c chc nng khc nhau gi l cc qun th t bo T phn lp. C hai qun th phn lp chnh ca t bo T phn bit vi nhau bi s c mt ca cc protein th th CD4 v CD8 (hnh 2.18). Qun th t bo T CD4 li c bit ha thnh hai phn lp na c chc nng khc nhau. Mt loi gi l t bo T h tr, k hiu l Th ( T helper) c nhim v kch thch t bo B sn xut nhiu khng th. Mt loi l t bo T qu mn mun, k hiu l TDTH ( Delayed type hypersensitivity). T bo TDTH tham gia vo cc phn ng trung gian t bo T, nhng khng tng tc vi t bo B m chu trch nhim hot ha cc t bo khng c hiu, chng hn nh i thc bo. Qun th t bo T CD8 cng li bit ha t nht ra lm hai phn lp. Mt loi l t bo T c, k hiu l TC ( T- cytotoxic) lm nhim v tng tc v ph hy trc tip cc t bo c khng nguyn trn b mt. C mt loi t bo T c ch, k hiu l Ts (T- suppressor) lm nhim v iu ha p ng min dch, c ch tc ng ca cc t bo min dch nh t bo B.

Hnh A.18. Phn t CD4 v CD8 T bo T vi nhiu phn nhm nn thc hin c cc chc nng c bn v ton din nht ca p ng min dch l: nhn bit khng nguyn (Th v Tc), iu ha v kim sot mc p ng min dch (Th v Ts), loi tr khng nguyn (Tc v TDTH). Chc nng nhn bit khng nguyn: Kh nng nhn bit khng nguyn ca t bo T l cho ton h min dch, trong khi th t bo B ch nhn bit khng nguyn cho ring min dch th dch. Khi khng nguyn ngoi lai xm nhp vo c th th hu ht u b i thc bo bt gi, tiu i thnh nhng mnh peptit v trnh din ln mt. Mt loi phn t m trch vic ny l MHC lp II do i thc bo sinh ra. T bo c trch vic nhn bit khng nguyn do MHC lp II trnh ra l T CD4 hay t bo h tr Th. Phn t CD4 c th gn c hiu vi phn t MHC lp II nn Th c iu kin tip cn vi mnh khng nguyn c trnh din. Khi khng nguyn l ni sinh (mt thnh phn ca t bo c th) cng s c t bo lympho nhn ra. V d, axit nhn ca virt c th ci cm vo DNA ca t bo ch, nhng cc khng nguyn ca vi-rt vn c trnh din ln b mt ca t bo. Thc hin c vic ny l nh t bo ch sn sinh c phn t MHC lp I. C kh nng lin kt c hiu vi MHC lp I chnh l CD8 ca t bo T, 37

y l nhm gy c nn cn c gi l t bo Tc (cytotoxic). Sau khi nhn ra khng nguyn ni sinh th n s dit t bo ch bng cc c t (hnh 2.19).

Hnh A.19. Kh nng nhn bit khng nguyn ni sinh v ngoi lai Chc nng iu ha v kim sot min dch: Th chi phi hon ton cc hot ng hiu ng, tc l hot ng ca cc t bo min dch k c chc nng loi tr khng nguyn, v d sn xut khng th ca t bo B, vai tr gy c ca t bo Tc v vai tr gy vim ca t bo TDTH (hnh 2.20). Th s tit ra cc interleukin thch hp nhm gip cho s sn sinh mc ca cc t bo hiu ng, gip cho chng hot ng mc loi tr khng nguyn. S hot ng ca Th s c kim sot nh chnh cc sn phm v hiu qu ca t bo hiu ng. Chc nng kim sot do t bo Ts m trch, y l phn nhm ca t bo T c CD8. Nh vy Ts gn gi vi Tc c nhim v c ch phn ng loi tr khng nguyn khi phn ng ny t ra qu mnh. Ngoi ra, Ts cn km hm sut i nhng qun th Th t phn ng, tc l nhng Th c tim nng chng li khng nguyn ca chnh c th ch. Nh vy m c th khng mc nhiu bnh t min. Chc nng loi tr khng nguyn Chc nng loi tr khng nguyn do hai phn nhm t bo T c CD8 thc hin l Tc v T DTH. i tng ch yu m Tc chng li l nhng t bo bn thn c mang khng nguyn ni sinh, tc l hnh thnh t trong ni bo nh t bo nhim vi-rt, mt s vi khun, cc n bo c kh nng xm nhp ni bo hoc cc t bo b ung th ha. ng thi, Tc cng chng c cc t bo ghp d gen. Tn hiu hot ha Tc l vic to ra cc cp lin kt CD8MHC I, TCR-khng nguyn. Sau , IL-2 s bm vo cc th th ph hp trn b mt Tc. S hot ha Tc c th hin thng qua vic tit ra cc c t nh TNF (tumor necrosis 38

factor) gy hoi t u. Cc cht do Tc tit ra s gy hy hoi t bo xung quanh, l cc t bo trnh din khng nguyn ln b mt m Tc tip cn (hnh 2.21). Khi c nhiu c cht c tit ra trong mu th s lan ra ton thn nht l trong ung th nng, st rt c tnh, cm nng v nhng bnh c khng nguyn ni sinh khc. Nh vy, Tc s gip cho c th chng li cc bnh nh vi-rt, vi khun, nm v cc n bo k sinh ni bo. Ngoi ra, Tc cn c kh nng to ra t bo tr nh gip c th min dch c mt s bnh sut i nh u ma, si, thy u, vim gan

Hnh A.20. Vai tr ca Th trong p ng min dch TDTH (delayed type hypersensitivity, qu mn mun) l mt nhnh ca Th cng c CD4. TDTH s to ra mt vim nhm lu tr khng nguyn li v sau loi chng ti ch. TDTH cng c kh nng nhn bit cc khng nguyn ngoi lai v y cng l tn hiu TDTH c hot ha, sau l s kch thch ca IL-2. Vic hot ha ny c th hin ch TDTH tp trung vo ni c khng nguyn v sinh sn rt cao ti ni ny ri sn xut ra cc lymphokin ring c tc dng thu ht i thc bo ti trc tip loi thi khng nguyn.

39

Hnh A.21. Hot ho Tc do khng nguyn ca vi-rt Ngoi ra, min dch t bo cn chi phi c s sn sinh khng th dch th ca lympho B. T bo B ph thuc vo min dch dch th nhng li chu s chi phi ca Th, c bit l i vi cc khng nguyn ph thuc tuyn c. Th s tit ra cht BCGF (B cell growth factor, yu t sinh si t bo B, IL-4) gip cho qun th sinh ra khng th chng li khng nguyn m Th nhn bit. T bo lympho B Khi c mt yu t l xm nhp vo c th, h thng min dch c nhim v nhn bit, sau c nhng hot ng hiu qu tip theo loi tr n nhm mc ch bo v ton vn c th. p ng min dch dch th v p ng min dch t bo l hai phng thc m h thng min dch s dng. i vi p ng min dch dch th, th cc khng th ha tan, chnh xc hn l cc globulin min dch m ng trch nhim ny. Cc globulin min dch do t bo plasma m c bit ha t t bo B sn xut. T bo lympho B l t bo sinh khng th. gia cm hot ng ca t bo B ph thuc vo ti Fabricius. ngi, cc t bo tin thn ca t bo B c trong gan bo thai v trong ty xng ca ngi trng thnh. Sau vo mu ngoi vi ri n c ng ti vng v ngoi ca hch ngoi vi, u ty trng ca lch, to ra cc nang lympho. Khi cc khng nguyn xm nhp th c th din ra p ng min dch thng qua i thc bo. i thc bo s di chuyn ti cc hch lympho gn nht v mang theo nhng khng nguyn x l truyn thng tin cho t bo B, ri cui cng s bin chng thnh t bo mn cm. Sau , nhng t bo ny tr thnh nhng nguyn tng bo v pht trin thnh nhng qun th ti nhng hch a phng v i n cc hch khc trong ton c th. Lc ny cc hch lympho th cc nang s ni rng ra v xut hin tm im mm. Mt s nguyn tng bo s chuyn thnh t bo plasma sn xut ra khng th. Mi dng t bo plasma ch sn xut mt kiu globulin min dch. Qu trnh tng sinh, bit ha t bo lympho B thnh t bo plasma sn sinh ra globulin min dch c nghin cu nhiu v c nhng hiu bit nht nh v n.

40

Di knh hin vi in t, cc t bo B c b mt x x, ni gai l cc globulin b mt (surface immunoglobuline-SIg). Qu trnh tng sinh, bit ha lympho bo B thnh t bo plasma din ra km theo s thay i SIg thng qua hai bc (hnh 2.22). Giai on I: cc t bo ngun pht trin thnh tin t bo B cha c SIg m ch c IgM trong bo tng, sau mi pht trin thnh t bo B cha chn nhng c SIg. Cc t bo ny tip tc pht trin thnh t bo B chn vi s xut hin ca SIg v SIgD. Mi t bo B c khong 0,5-1,5.105 phn t SIg v chng hot ng nh cc th th tip nhn khng nguyn. Tuy nhin, n y t bo B vn cha tit c khng th. giai on ny th s pht trin ca t bo B khng cn s kch thch ca khng nguyn v s h tr ca t bo T. Giai on II: cc t bo B chn, tng sinh v bit ha thnh t bo plasma. Trong giai on ny chng cn c s kch thch ca khng nguyn v s hp tc ca t bo Th. Cc khng nguyn sau khi vo c th s chn lc v gn vi cc t bo B chn c cc SIg thch hp, y l mt iu kin c bn cho s pht trin mt p ng min dch dch th. Phc hp khng nguyn-SIg s c chuyn vo trong t bo. Lc ny cc t B s tri qua qu trnh tng sinh, bit ha thnh dng t bo plasma tit ra khng th dch th, chng c cu trc ging nh SIg m khng nguyn chn lc nhng c i tnh cao hn khi kt hp vi khng nguyn c hiu. Trong khi mt s bit ha thnh t bo plasma th mt s khc s chuyn thnh t bo tr nh gip cho qu trnh p ng min dch ln sau vi chnh khng nguyn nhanh v mnh hn.

Hnh A.22. C s t bo ca s hnh thnh khng th 41

VII. H thng b th
Trong p ng min dch mt s thnh phn huyt tng tham gia vo s tiu dit, o thi yu t gy bnh v k c phc hp khng nguyn-khng th. Nhng phn t ny to thnh tng h thng hot ng theo kiu dy chuyn c s t iu ha va khuch i va c ch sao cho phn ng t mc thch hp vi yu cu. B th (Complement) thuc v h thng min dch dch th bm sinh (khng c hiu). B th tham gia vo phn ng vim v s khng chng nhim khun. Cc cht gy hot ha chim 5% protein huyt thanh m trong thnh phn C3 l nhiu nht (hnh 2.23). B th c hot ha theo hai con ng ch yu l ng c in (classial pathway) v con ng khc (alterne pathway). S d nh vy l do con ng u tin mc d l pht hin trc nhng v mt tin ha th n c sau. V th, xu hng hin nay li chia theo c ch hot ha ca b th m c hai hnh thc l ng c hiu v ng khng c hiu. C hai con ng u t v chung l C3 i vo mt con ng hiu ng chung s dng n cc thnh phn cui cng ca b th. Cc protein gy hot ha, c ch hay u ha tham gia vo mi giai on s nm ngay trong huyt tng hay trn b mt t bo ngun. Tuy nhin, gn y con ng th ba c cp l con ng lectin ca thc vt v collectin ng vt. l nhng cht c kh nng hot ha b th t C4 v C2 khng qua C1 nh ng c hiu v cng khng i qua C3 nh ng khng c hiu

Hnh A.23. H thng b th vi cc cht cu thnh v iu ho .

42

1. ng khng c hiu a. Cc yu t gy hot ha Cc vi sinh vt v nhiu cht khc khi cha gy mn cm c th nhng li c th hot ha theo con ng ny nh trc khun gram dng hay gram m, vi-rt, nm (Candida albicans), k sinh trng (Trypanosoma, Schistosoma) v mt s cht khc nh polysaccharid hay ni c t ca vi khun, zymosan, inulin, huyt cu t, bi, Ngoi ra, nhng protein gn vi mannose, protein phn ng C cng lm vi khun lin kt c vi b th theo con ng khng c hiu. Mt mng t bo cng c kh nng hot ha khi n cng cha t axit sialic. Ngoi ra, con ng c hiu c th c hot ha bi cc phc hp vn t ca IgG hay IgA (hnh 2.24). b. Cc yu t cu thnh ng khng c hiu C3: trong huyt tng mt phn C3 nguyn s thng xuyn b dung gii bi cc protease lu hnh, to ra nhng lng nh C3b di dng lin kt nc. C3b s c nh ln thnh ca cc vi sinh vt hay t bo h hi khi b nhim, ng thi s tc ng ln yu t B vi s c mt ca Mg2+.

Hnh A.24. ng hot ho b th khng c hiu Yu t B: l mt protein tham gia vo con ng khuch i. Di tc dng ca C3b th yu t B s tch ra thnh Ba v Bb. Khi c mt ca Mg2+ th s to phc hp C3b-Bb c hot tnh nh protease lm tch thm phn t C3 thnh C3b. Phn ng vn tip din v c tnh khuch i lm sn sinh ra nhiu C3b-Bb. Yu t D: hot ng ngay trc khi c hot ha, tch yu t B thnh Bb gip cho s hot ha hnh thnh phc hp C3b-Bb. 43

Khi trn b mt hot ha cha t axit sialic th s d c nh yu t B, lm cho phn ng pht trin mnh hn. Khi c nhiu axit sialic th do yu t H s lm bong C3b ra khi mng t bo v nh m bo v t bo khi s ly gii. Nh vy, tt c hnh thnh mt vng khuch i cho php hot ha i C3 thnh C3b c th ph bc ton b v vi khun, ng thi c tc dng nh mt enzym chuyn C5. c. Cc yu t iu ha Yu t P (properdin) gip n nh phc hp C3-Bb. Yu t H lm r cc phc hp C3-Bb. Yu t I l cht bt hot C3b thnh C3bi ri thnh C3bdg. CR1 c trn nhiu loi t bo c th c nh C3b v lm gim nng C3b trong huyt tng. DAF (decay accelerating factor) l mt cht thuc mng v lm bt hot C3b-Bb cng nh C4b ng c hiu. MCP (membrane cofactor protein) cng l mt protein mng v c tc dng nh DAF. Nh vy, mt vi sinh vt hay mt s cht c kh nng hot ha b th theo con ng khng c hiu, ngha l khng cn khng th v bt u t C3 i n C5 v i vo con ng hiu ng chung. 2. ng hot ha b th c hiu a. Cc yu t gy hot ha Cc yu t hot ha b th theo con ng c hiu c trong huyt thanh di tnh trng nguyn s khng c chc nng sinh hc. Cn phi c mt kch thch hot ha chng m ch yu l phc hp khng nguyn- khng th, trong khng th l IgM c phn Fc c th th vi b th hay IgG vn t cng hot ha b th theo con ng ny (hnh 2.25). Con ng c hiu cng c th c hot ha bi cc tc dng ph ca mt s yu t t vi-rt, vi khun gram m Salmonella hay E.coli, Neisseria, plasmin, thrombin, cht protein phn ng C, phc cht protamin-heparin v polysaccharid. b. Cc yu t tham gia hot ha C1q, c trng lng phn t cao l 400.000 dalton, hot ha c th cn mt phn t IgM hay hai phn t IgG gn k nhau. C1r, c hai phn t ny th c nh ln mt phn t C1q, tip theo l hai phn t C1s. C1s, khi 1C1q + 2C1r+ 2C1s to thnh mt phc hp protein c hot nng enzym v tc ng ln cu thnh tip theo C4. Tuy nhin, giai on ny cn c mt ca Ca2+. C4, C1s s tch phn t C4 thnh C4a c hot nng phn v v C4b lin kt vi Fab ca khng th hay vi nhn t ch. 44

C2, C1s cng vi C4 s tch mt phn t ca C2 to thnh C2b c hot tnh nh mt kitin v C2a s cng vi C4b gn vo ch. T hp ny cn c mt ca Mg2+ to thnh C3 di dng phc hp C4b-C2a lm cho t hp khng th v C1 c th tch khi ch m qu trnh hot ha vn tip din. C3 b tch thnh C3a v C3b di tc dng ca phc hp C2b-C2a, C3a c hot nng gy phn v v ha ng ng trong khi C3b c nh ln ch nh mt cu thio-este bn trong, tng i n nh. Sau khi cu ny c m ra th C3b c nh mt cch ng ha tr ln trn mng t bo. Nhng cht ny li b bt hot bi yu t I thnh C3bi ri tch ra thnh phn t ln C3c t do v mt phn t C3dg cn li trn ch m sau ny c th chuyn thnh C3d.

Hnh A.25. ng hot ho b th c hiu

c. Nhng yu t iu ha qu trnh hot ha Nh vy qu trnh hot ha ti y c khuch i ngy cng mnh cho nn cn nhng yu t iu ha km hm bt phn ng, l nhng protein iu ha. Protein trong huyt tng: cht c ch C1 (C1-inh) s c ch hot ha C1, tch C1 hot ha v c ch vic tch C4 bi C1s. Tnh trng thiu C1-inh bm sinh l ngun gc ca bnh ph thn kinh mch. Yu t I s tch C4b thnh C4c v C4d dng khng hot ng. Yu t I cn lm bt hot C3b thnh C3bi ri thnh C3dg. C4bp (binding protein) s tch phc hp C4b2a v c s dng nh ng yu t cho yo t I. Cacboxypeptidase N s gy dung gii b th v C3a, C4a v C5a. 45

Trn t bo: DAF (decay accelerating factor) l yu t tng nhanh thoi ha. MCP (membrane cofactor protein) l protein ng yu t mng. Hai yu t ny c trn mng t bo nn c ch hot ha b th ngay trn nhng t bo no c mang chng. 3. Cc th th t bo i vi b th Trn mt mt s t bo c nhng phn t lin kt c vi mt s cu thnh ca b th gi l th th ca b th (complement receptor-CR). CR1: cc th th vi C3b hay C4b c trn b mt hng cu, tiu cu, bch cu a nhn trung tnh v toan tnh, t bo mono v i thc bo, t bo lympho B v T4, t bo c nhn cu thn. Chng cho php vn chuyn cc phc hp min dch nh hng cu ti i thc bo gan. Hin tng cc i thc bo c bm dnh min dch vi cc ht mang C3b cho php tiu cc phc hp y. S c mt ca khng th s lm tng phn ng thm hng chc ln. CR2: cc th th vi C3d c trn cc t bo lympho B, t bo tua hch v t bo nim mc mi hu. Chnh cc th th y m vi-rt xm nhp c vo trong c th v gy nhim cc t bo lympho B. Chng kch thch cc t bo y thng qua cc phc hp min dch c ph C3d. CR3: cc th th i vi C3bi c trn cc t bo mono, i thc bo, cc t bo trung tnh, t bo tua hch. Chng gip cho hin tng bm dnh v thc bo cc ht c ph C3bi. CR4: c trn cc bch cu trung tnh, tiu cu, t bo mast v i thc bo m. Chng gip cho s bm dnh v thc bo cc phc hp min dch ph C3bi. Ngoi ra, cng c cc th th vi cc mnh nh C3a, C4a, C5a cc t bo mast, t bo mono, i thc bo, bch cu a nhn trung tnh v tiu cu. Khi cc th th y c hot ha th cng ko theo hin tng vim. 4. Vai tr sinh hc ca b th Trong phn ng vim: mt s cu thnh ca b th c kch c nh, ha tan v c vai tr quan trng trong phn ng vim. C3a, C4a v C5a c trng lng phn t khong 10.000 dalton c gi l anaphylatoxin, chng c th c nh trn cc bch cu kim tnh v t bo mast dn n s phng thch histamin v lm dn mch. y l yu t u tin ca phn ng vim. C2b th c kh nng lm tng thnh mch. C5a c kh nng ha ng ng dng tnh i vi bch cu trung tnh v lm vn t bch cu a nhn ngay ti ni c hot ha b th. Cc cu thnh C5, C6, C7 c nh trn mng hay cc phc hp min dch cng thu ht cc bch cu a nhn. S khng chng nhim khun: b th gy ly gii cc vi sinh vt hay tham gia vo qu trnh gy c nh khng th. Cc yu t gy nhim bn ngoi t bo c ph b th hoc do hot ha trc tip hay thng qua cc khng th chng vi khun c c nh trn b th. Cui cng do s tham gia ca cc phc hp tn cng mng m c s dung gii cc vi sinh vt khc nhau nh vi khun, vi-rt hay k sinh trng. l hot ng ly gii t bo trc tip ca b th vi s tham gia ca cc cu thnh sau cng. Ngoi chc nng chng nhim khun, b th cn ly gii hng cu hay bch cu. c im ny c th dng pht hin in vitro cc khng th chu trch nhim phn ng dung gii hng cu bn trong mch mu. 46

Chuyn ha cc phc hp min dch: s thi tr cc phc hp min dch c d dng hn nhiu b th. Vic n gin c nh b th theo ng c hiu c ch s hnh thnh nhng phc hp min dch c kh to v theo ng khng c hiu th gip chng d ha tan hn. Nht l cc phc hp tun hon mt khi c ph bi C3b th c th bm dnh trn hng cu, ri c chuyn ch n tn cc t bo Kuppfer gan, y th chng s b thc bo bi cc t bo y. Tham gia kim sot p ng min dch: t bo lympho B c cc th th CR2 vi C3d. Nh vy, khi hnh thnh cc phc hp min dch c b th bao ph th s gy kch thch v c mt vai tr nht nh trong p ng min dch. Trn t bo T cng c C3dR nhng cha r vai tr.

Ti liu tham kho


1. V Triu An v Jean, C.H. 2001. Min dch hc. Nh xut bn Y hc. 2. Nguyn Ln Dng. 2001. Vi sinh vt hc. Nh xut bn Gio Dc. 3. L Huy Kim. 1998. Bi ging min dch hc th y. Khoa Nng Nghip- i hc Cn Th. 4. Nguyn Ngc Lnh v ctv.1997. Min dch hc. Nh xut bn y hc. 5. Madigan, M.T., Martinko, J.M. and Parker, J., 2002. Biology of Microorganisms. Tenth edition, Prenhall. 6. Ngc Lin, 1999. Min dch hc c s. Nh xut bn i hc Quc gia H ni.

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Chng 3:Khng nguyn v khng th


I. Khng nguyn
1. nh ngha Bt k mt cht no khi a vo c th ng vt iu kin thch hp gy ra p ng min dch c gi l cht sinh min dch. Bt c mt cht no khi gn vi thnh phn ca p ng min dch (khng th, t bo lympho hoc c hai) c gi l khng nguyn. Tt c cc cht sinh min dch u l khng nguyn, song mt s cht c coi l khng nguyn nhng khng gy p ng min dch. V d: hapten l cht c khi lng phn t thp (nh cc phn t ng, axit amin, polime nh v cht khng sinh) c th gn vi khng th c hiu nhng bn thn n khng kch thch to khng th. 2. iu kin bt buc ca mt cht khng nguyn Tnh l: Cht c coi l khng nguyn trc ht phi l mt cht l vi c th, bi v bnh thng c th khng c phn ng bo v vi cc cht ca bn thn. Cht cng l vi c th bao nhiu, kh nng kch thch to khng th cng mnh by nhiu. Khi lng phn t ln: Nhn chung khng nguyn c khi lng phn t ln hn 10000 dalton. Nu nh hn 1.000 dalton (penixilin, progesteron, aspirin...) th khng c tnh sinh min dch. T 1.000 n 6.000 dalton (insulin) c th c hoc khng c kh nng p ng min. Cu trc phn t phc tp: Mt cht c tnh sinh min dch phi c cu trc ha- l tng i phc tp th tnh sinh min dch cng cao. V d polilizin l mt polime c khi lng phn t 30000 dalton nhng khng gy p ng min dch v c cu trc n gin, trong khi hapten tuy c khi lng phn t nh v khng c tnh sinh min dch, nhng khi gn vi cht c khi lng phn t cao (chng hn protein) li tr thnh cht sinh min dch. Nh vy mt cht mun c tnh sinh min dch phi t ba tiu chun: tnh l, khi lng phn t ln v cu trc phc tp. Nu thiu mt trong ba tiu chun ny th cht phi c gn vi cht mang lm tng khi lng phn t hoc c mc phc tp v cu trc. 3. Tnh c hiu ca khng nguyn S lin kt gia khng nguyn vi khng th hay gia khng nguyn vi t bo lympho lun mang tnh c hiu cao. Tnh c hiu ny tng t nh gia enzym v c cht, ngha l phi lun khp vi nhau nh kha vi cha. Khng th hay t bo lympho khng phi lin kt vi ton b phn t khng nguyn m ch vi nhng phn nht nh ca khng nguyn (cn gi l quyt nh khng nguyn hay epitop). Phn tng ng vi n trn mi khng th gi l v tr kt hp khng nguyn (hay paratop). Phn tng ng vi quyt nh khng nguyn nm trn t bo lympho gi l th th. Chng hn th th ca t bo T l TCR (T cell receptor).

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Kch thc ca epitop khong 7*12*35 A, gm 5-7 axit amin. Paratop l TCR cng c kch thc tng t. Mi epitop ch gn c hiu vi mt paratop ca khng th hoc TCR v ch sinh ra mt dng khng th c hiu. Mt khng nguyn c nhiu epitop khc nhau s to thnh nhiu dng khng th tng ng vi tng epitop. 4. Cc dng khng nguyn a. Theo mi quan h vt ch c p ng Khng nguyn d loi: khng nguyn d loi l nhng khng nguyn ly t con vt khc loi i vi con vt c mn cm sinh ra khng th. Vic mn cm cng d khi c s khc bit v loi cng mnh. Khng nguyn d gen: trong cng mt loi, khng nguyn d gen c mt mt s c th m khng c nhng c th khc. l do a dng gen hc ngay bn trong mt loi. Khng nguyn l nhng cht ca c th sn xut ra v cu trc ca chng c m ha trong b gen. Khng nguyn d gen c th thu c khi mn cm cng loi hay khc loi. Khng nguyn t nhn: l sn phm ca mt p ng min dch khng bnh thng nhn bit mt khng nguyn ca ngay bn thn mnh. V d, khi tim hng cu ca mt con chut sang con chut khc cng chng loi th khng c p ng. Nhng khi tim hng cu chut cng cho chut nht th s xut hin khng th chng hng cu chut cng m ng thi c c khng th chng li hng cu ca chut nht. Khng nguyn idiotyp: do cu trc thay i khc nhau ca vng cc k thay i ngay trn b mt cc th th t bo lympho cng nh cc globulin min dch lm cho nhng vng tr nn l ngay i vi bn thn. Cho nn, khi mt khng th xut hin th vng thay i ny tr thnh khng nguyn i vi bn thn. Tuy nhin loi khng nguyn ny rt hn ch. b. Theo typ p ng min dch Khng nguyn ph thuc tuyn c: ch gy min dch khi tuyn c cn nguyn vn, thng c bn cht protein nn d to nn mt p ng min dch tin pht v th pht bng IgG. Mun c p ng min dch xy ra th cn phi c ba loi t bo tham gia l: (i) t bo APC; (ii) t bo lympho Th c hiu v (iii) t bo Tc hay t bo lympho B. Khng nguyn khng ph thuc tuyn c: vic sn xut khng th khng cn ph thuc t bo T v p ng y ch i hi s hin din ca t bo lympho B c hiu l . Trn b mt t bo ny c mt phn t cm th CD1 c cu trc tng t phn t MHC lp II lm cng vic trnh din khng nguyn. Cc khng nguyn ny thng l glucid vi cc nhm quyt nh khng nguyn cng khng ph thuc tuyn c. c. Theo bn cht ha hc - Cc glucid: cc polyosid ni chung cng nh l phn glucid ca cc glycoprotein l nhng khng nguyn mnh. V d khng nguyn ca nhiu vi sinh vt v cc nhm mu m tnh cc hiu do cc nhm ng khc nhau quyt nh. l nhng polysaccharic vi cu trc phn t a dng nn c tnh khng nguyn mnh. 49

- Cc lipid: phn ln cc cht ny gm mt chui n CH2 k nc nn khng c tnh khng nguyn. Nhng khi chng c thm phn glucid hay protein th li c tnh khng nguyn. V d, hp cht cardiolipin l cht chit t ty lp th c tim ca b m ngi mc bnh giang mai c xut hin khng th chng li cht y. Cho nn cardiolipin c dng pht hin bnh giang mai do rt nhy v r tin. - Cc protein: khi c trng lng phn t ln hn 4.000 dalton th cc polypeptit hay protein l nhng khng nguyn tt nht. Cu trc phc tp ca chng lm cho chng c nhiu nhm quyt nh khng nguyn khc nhau. Vasopressin c trng lng phn t 1000 dalton vi chn acid amin l cht nh nht gy c min dch. - Cc axit nucleic: rt kh c c khng th chng li axit nucleic khi mn cm cho con vt. Ngc li, trong mt s bnh t min nh ban ri rc cp th xut hin nhiu loi khng th chng axit nucleic.

Hnh 0.1. Siu khng nguyn - Cc cht tng hp: cc cht c cu trc tng hp khc nhau c th tr thnh khng nguyn khi chng c trng lng phn t ln hay khi chng lin kt vi nhng protein mang ti. Cu trc tng hp xc nh tnh khng nguyn v tnh c hiu ca cc cht tng hp ang c cc nh nghin cu ch n. Thuc c th l khng nguyn gy ra nhng phn ng d ng thy trong bnh l ngi. - Cc siu khng nguyn: l loi khng nguyn c bit gy hot ha t bo min dch m khng cn phn t MHC lp II do t bo APC trnh din nh thng l. Chng kt hp thng vi trnh t peptit ca mt s TCR c bit. Cho nn, nhng phn t y khng cn c nhn bit mt cch c hiu m vn tc dng ln nhiu dng t bo T c mang cu trc nh chui ca TCR (hnh 3.1).

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II. Khng th
1. nh ngha Khng th l cc globulin trong mu ca ng vt, c kh nng lin kt c hiu vi khng nguyn kch thch sinh ra n. Khng th theo nh ngha trn y gi l khng th min dch (immunoglobulin, k hiu l Ig) hay khng th c hiu. Khng th ch yu c tm thy trong huyt thanh ca ng vt, do vy huyt thanh cha khng th c hiu khng nguyn c gi l khng huyt thanh. Khng th cn c tm thy trong cc th dch khc ca c th nh sa. Nhng khng th c sn trong sa hay huyt tng ca ngi v ng vt t trc khi c s tip xc vi khng nguyn c gi l khng th t nhin hay khng th khng c hiu. 2. Bn cht v tnh cht ca khng th Trong huyt thanh ca ngi v ng vt c v cha albumin, , v globulin th globulin l khng th. V bn cht khng th l protein nn cc tc nhn ha, l nh nhit , axit, kim,... c th lm bin tnh protein th cng c th ph hy khng th. Hot tnh khng th ph thuc vo pH mi trng v nhiu yu t khc. Ngoi ra cc cht nh Sunphat amon, Sunphat Natri, cn 5o c th kt ta c khng th. Tuy nhin nhng cht ny khng lm mt tnh cht ca khng th nn ngi ta s dng chng tinh khit khng th. 3. Cu trc ca khng th min dch Tt c cc Ig u c cu trc ging nhau gm c hai chui nh (ngn) v hai chui nng (di), c gn vi nhau bi cu disunphua (S-S) (hnh 3.2). Trnh t axit amin khng th ging ht nhau theo tng i chui nng v tng i chui nh. C phn t c cu to i xng. Di tc dng ca enzym phn gii protein (papain) phn t Ig c phn gii thnh ba mnh nh. Hai mnh nh cha ton b chui nh cng vi na chui nng c u amin NH2). y l ni gn vi khng nguyn v c gi l on Fab (Fragment of antigen binding). Mnh cn li l hai na c u carboxyl (-COOH) ca hai chui nng. Phn ny khng gn c vi khng nguyn nhng c kh nng kt tinh nn gi l phn Fc (Fragment crystallizable) (hnh 3.2).

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Hnh 0.2. Cu to c bn ca mt khng th Da vo c tnh sinh l, ha hc v min dch hc ngi ta chia khng th ra thnh 5 loi l: IgG, IgA, IgM, IgD v IgE. IgG ngi, IgG l khng th lu hnh ph bin nht chim 80% tng s Ig trong huyt thanh. IgG c khi lng phn t 160.000, hng s lng 7S cha 2,5 cacbonhydrat. IgG cha 4 chui polipeptit. Mi chui nh cha 212 axit amin, cn chui nng cha khong 450 axit amin. Phn t IgG c hai v tr kt hp khng nguyn nn c hai ha tr. V tr ny chim khong 1% din tch b mt ca IgG. IgG cng cn cha mt lng nh cacbonhydrat, gm ch yu l ng hexoz v hexozamin. Cacbonhydrat khng lin quan n v tr kt hp khng nguyn. Cc chui nh: mi chui nh ca IgG cha hai vng axit amin. Mt vng nm pha u amin c trt t axit amin c th thay i gi l vng bin i (VL). Vng nm pha u cacboxyl c trt t amin khng thay i gi l vng c nh (CL) (hnh 3.3). Trt t axit amin vng c nh ca chui nh lun ging nhau k c cc IgG kt hp vi cc khng nguyn khc nhau. S d nh vy v phn c nh ny ch c mt trong hai kiu trt t axit amin l trt t lamda () hoc trt t kappa (K). Mt phn t IgG ch cha hoc hai chui nh lamda hoc hai chui nh kappa m khng bao gi cha c hai loi. Ngc li, vng bin i ca chui nh, trt t axit amin lun khc nhau, k c i vi cc Ig do cng mt t bo sinh ra. 52

Cc chui nng: mi chui nng IgG cha bn vng axit amin gm mt vng bin i (VH) v ba vng c nh (CH1, CH2 v CH3) (hnh 3.3). on c u amin (ni c v tr kt hp khng nguyn) c trt t axit amin bin i nn bo m tnh a dng ca phn t. Vng c nh nm gia CH1 v CH2 ca chui nng gi l khp ni, c tc dng nh chic bn l lm cho phn t c cu to hnh ch Y.

Hnh 0.3. Cu to ca IgG IgG gn vi b th v i vo nhau thai nn c th truyn t m sang thai. IgG ngi c bn phn lp (isotype) khc nhau l IgG1, IgG2, IgG3 v IgG4. Cc phn lp ny khc nhau phn ca chui nng v s lng cu ni disunphua gn gia hai chui nng. Cc phn lp IgG nh trn cng c chut nhng khng c th. IgM IgM chim 5-10% tng globulin ca huyt thanh, globulin ln nht, c khi lung phn t 900.000, hng s lng 19S v cha 10% cacbonhydrat. IgM c cu to gm hai chui nh kappa hoc lamda v hai chui nng muy nn c k hiu l K22 hoc 22. Nm globulin cm li vi nhau thnh ngi sao nm cnh nh cu ni disunphua v chui peptit nh (chui J) nn IgM c ti 10 v tr kt hp khng nguyn (hnh 3.4). V th IgM c hot tnh hn hot tnh ca IgG t 60 n 180 ln. IgM xut hin sm, u tin trong cc bnh vi-rt, sau IgG xut hin mun v thay th IgM. IgM cng p ng vi polysaccharit v nhy ca nhiu loi vi khun nn c dng chng cc vi khun ny. IgM c trn b mt t bo lympho B v lm nhim v nh th th dnh cho khng nguyn.

53

Hnh 0.4. Cu to phn t IgM IgA IgA c khi lng phn t 140.000- 300.000, hng s lng 7S. Cu to gm hai chui nh kappa hoc lamda v hai chui nng nn c k hiu l K22 hoc 22. IgA tn ti dng n, dng dime hoc dng trime gn vi nhau nh chui peptit J (hnh 3.5). Trong huyt thanh ngi c t IgA, ch yu IgA c trong dch nhy. Chng c tng hp ch yu nh t bo B trong nim mc rut, ng h hp v thc hin chc nng chng vi khun trn b mt nim mc. IgD IgD chim 0.2-1% tng globulin v c nng trong huyt thanh rt thp (0.5-40 mg/100ml). Cu to gm hai chui nh kappa hoc lamda v hai chui nng delta, nn c k hiu l K22, 22. IgD c trn b mt t bo B, c th lm nhim v nh th th dnh cho khng nguyn. IgE IgE c khi lng phn t 180.000, hng s lng 8S. Cu to gm hai chui nh kappa hoc lamda v hai chui nng epsilon, c k hiu l K22, 22. Nng trong huyt thanh rt thp, ch bng 1/50.000 nng IgG, nhng s c tng ln nhanh khi b d ng hoc nhim k sinh (giun).

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Hnh 0.5. Cu to phn t IgA 4.Chc nng sinh hc ca globulin min dch Chc nng sinh hc ca phn t Ig trong h thng min dch l nhn bit ci l v tc ng ln n. Vng thay i V l v tr ca phn t Ig lm nhim v nhn bit, cn vng C lm nhim v tng tc vi cc phn t v cc t bo khc hon thnh mt cch c hiu qu vic loi tr yu t l. a. Chc nng nhn bit Chc nng nhn bit c thc hin thng qua vic phn t Ig kt hp c hiu vi nhm quyt nh khng nguyn. V tr kt hp nm vng V ca chui nng v chui nh, u tn cng NH2. y, chui polypeptit c gp li v to ra cu trc gp np vi nhng on tng i n nh xen k nhng on cc k thay i. Nhng vng ny cm st vo nhau to ra mt ci ti trong cc phn t nh ca nhm quyt nh khng nguyn c th lt vo. Phn t Ig c cu trc i xng, nn c hai v tr kt hp khng nguyn hon ton ging nhau. Nh vy, mi nhm quyt nh khng nguyn s c mt b mt ph hp, n c th hin qua s c mt v trnh t tng axit amin vng cc k thay i cng nh cu trc khng gian ca n. Ngoi ra, cu trc Ig cn c h tr bi mt on peptit gi l on khp ni vng V vi vng C. on khp ny c tc dng nh chic bn l lm cho phn t c cu to hnh ch Y lm tng tnh mm mi gia hai vng ca phn t Ig c th quay i xng nhau. Vi cu trc nh vy nn Ig d dng trong vic kt hp vi khng nguyn c hiu do phn t IgG c th iu chnh dn ra hay khp li gip cho vic gn ph hp vi hai quyt nh khng nguyn. b. Chc nng sinh hc th pht c hiu qu a. Hot ha b th Khng th kt hp c hiu vi khng nguyn hnh thnh nn phc hp khng nguynkhng th, lm thay i cu hnh khng gian ca phn t Ig v bc l v tr kt hp vi b 55

th. Kh nng hot ha b th ch c IgM v IgG. Tuy nhin, khng phi tt c cc IgG u c kh nng hot ho b th nh nhau m ph thuc vo cu trc nh IgG1, IgG2, IgG3 hay IgG4. Chiu di v tnh mm mi ca vng bn l c lin quan cht ch vi kh nng hot ha b th. i vi IgG, hot ha c b th th cn phi c hai phn t kt hp vi quyt nh khng nguyn nm k nhau trn b mt t bo. Cn IgM th ch cn bn thn vn c kh nng hot ha b th do chng c ti hai mnh Fc k nhau, gip n tr thnh Ig c kh nng hot ha b th mnh nht. b. Tng tc vi cc t bo khc Phn Fc ca phn t Ig thuc mt s lp v lp di c kh nng gn vi mt s t bo khc nh: - Cc phn t IgE, IgG1, IgG3, IgG4: c kh nng gn ln b mt t bo mast v bch cu i kim thng qua nhng th th ca chng vi phn Fc. Khi phn Fab ca nhng Ig ny kt hp vi khng nguyn s hot ha cc t bo ny lm cho cc ht bn trong t bo phng thch cc ho cht trung gian nh steronin, histamin lm tng tnh thm ca mao mch, co c trn. Do , khng th trong mu v cc t bo thc bo d dng lt qua thnh mch ti ni c khng nguyn xm nhp. - Cc i thc bo v bch cu trung tnh: cc t bo ny cng c th th vi phn Fc ca cc phn t IgG v IgM. Nu khng nguyn l vi khun hay n bo ph bi IgG hay IgM th s b cc thc bo bt v nut. i thc bo v bch cu trung tnh khng ch c th th vi Fc m chng cn c th th vi b th nn kh nng thc bo s c tng cng, nu cc phn t IgG v IgM c gn b th. Hin tng ny c gi l opsonin ha. Khi phn t Ig c phn Fab nhn bit, kt hp c hiu vi khng nguyn l. Trn c s , khng nguyn s b tp trung, khu tr li. Thng qua Fc th cc t bo khc c huy ng ti. Kt qu, di hnh thc mt vim c hiu s lm cho khng nguyn l b loi tr mt cch mnh m v c hiu qu (hnh 3.6).

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Hnh 0.6. Hin tng Oponin ha

III. Phng php to khng th n dng v a dng


1. Chun b khng nguyn Vic chun b khng th a dng i hi phi c khng nguyn sch. Cn khng th n dng c sn xut t khng nguyn cha sch. Cc protein ha tan l ra s p ng mnh c th bin ha thnh nhng khng nguyn c th bi s lin kt chng vi c cht rn. Axit nucleic bnh thng khng gy ra min dch nhng khi lin kt vi protein mang n th s gy ra min dch. Cacbohydrat loi n gin th thng c tnh min dch yu v cn thit lin kt vi mt protein mang n. Carbohydrat cng ln th c th gi ra s p ng bnh thng nhng khng gy ra p ng th cp. Khng nguyn c th c chun b bng nhiu cch nh: (i) nghin ph hu cc m vi nhng ht thy tinh hoc (ii) tch chit bng cc phn t khi ta mui hay cht ty ra. Phng php c chn ph thuc vo khng nguyn ha tan hay khng ha tan v thnh phn ca khng nguyn l protein, cacbohydrat hay axit nucleic. Cc khng nguyn c th c tch chit v lm sch theo trng lng ca chng hoc theo kch thc thng qua qu trnh in di trn gel. 2. Sn xut khng th a dng Cc khng th a dng c to nn bng cch tim cht gy min dch (khng nguyn) vo sinh vt v sau mt thi gian thch hp th s tch huyt thanh tng ng. S p ng min dch s ph thuc vo lng v bn cht khng nguyn cng nh kh nng p ng min dch ca vt c tim vi khng nguyn . Thng thng, trong ln tim u tin th khng th sinh ra cha IgM vi nng rt thp, ln tim th hai th nng khng th IgG t mc trung bnh. Tuy nhin, trong nhng ln k tip s lm tng nng ca khng th IgG ng k.

57

a. Chun b hn hp t dc khng nguyn Khng nguyn c trn vi t dc trc khi tim vi mc ch l lm cho khng nguyn gii phng t t kch thch h thng sinh min dch ca sinh vt. chun b t dc khng nguyn th thng trn dung dch khng nguyn vi t dc Freund tng ng vi nhau. Ngoi t dc Freund th cng c th dng mt s khc nh Titermax vi liu 50500ml/ng vt. Tuy nhin, vi nhng t bo sng th khng cn thit phi b sung t dc . b.Con ng gy min dch Phng php chung thng l gy min dch cho th l tim di da bi v mt lng ln c th tim vo ng vt v khng th c hiu c th c dn qua bi phng php ny. Tim tnh mch c th trn th, s p ng nhanh v mnh bi v khng nguyn i vo mu v nhanh chng ti cc c quan sinh min sinh nh lch, gan v phi. Tuy nhin, tim tnh mch khng thch hp lm trong ln tim u tin v khng nguyn c hiu d b loi tr bi nhng cht ha hc th nh azide sodium i qua ng phi. 3. Sn xut khng th n dng Huyt thanh cha mt dy cc khng th v chng c hiu vi cc khng nguyn khc nhau. Khi ng vt c gy min dch th khong 1/10 khng th tun hon c hiu vi khng nguyn. Cc khng th c sn xut bi tng bo t t bo B c bit ha. Mi t bo B b m c kh nng sn xut cc khng th c hiu. Cc khng th c bi tit bi dng t bo lympho B th ging ht nhau v y cng l ngun gc ca cc t bo ng nht. Song cc t bo tng bo c i sng tng i ngn v cng khng th ln ln c trong nui cy. Nm 1975, Kohler v Milstein pht trin k thut cho php tng bo c ha vo cc t bo ung th myeloma to ra cc t bo lai v ln ln. Cc t bo ny c kh nng ln ln khng hn ch m vn sn xut ra khng th c hiu gi l khng th n dng (Monoclonal antibody- MAB). Cc khng th n dng c th c sn xut t khng nguyn khng sch bng cch chn la cc dng t bo n gin sau khi hp nht. Chng c th c chun b chng li s thay i rng ri cc phn t gy min dch nh protein, cacbohydrat, axit nucleic hoc phi hp gia chng. Cc khng th n dng c hnh thnh ch c hiu vi mt yu t quyt nh ca phn t gy min dch. V th, c th c dng tch yu t quyt nh y. Thm vo dng t bo lai s cung cp mt cch khng hn ch khng th trong dch ni ca t bo.

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Hnh 0.7. Sn sut khng th n dng chut Nhiu dng myeloma c th c sn sinh bng cch tim cho chut du khong vo mng bng. Dng t bo myeloma c chn la rt k l chng khng c kch thch h thng min dch sinh ra khng th. Cc t bo lai c th c chun b bi s hp nht t bo myeloma v cc t bo sn xut khng th m cc t bo ny c tch ra t cc loi chut khc nhau. Tuy nhin, thnh cng nht l hai loi t bo ny n t mt dng chut. 4. Lm sch khng th C nhiu phng php lm sch khng th (bng 3.1) v s la chn chnh xc phng php s ty thuc vo s lng cc thay i v cc loi khng th.

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Bng 0.1. Phng php lm sch khng th K thut Sunphat amon Caprylic acid Ph hp u im Nhc im To ra khng th cha c sch lm, cn kt hp vi cc phng php khc

C ch cho vic m R, m c, thun tin c v lm sch mt vi mt lng ln v phn khng th t tt d thc hin c cc ngun v cc mu

Hu ch vi IgG t R, thun tin i vi To ra khng th tt c cc ngun v mt lng ln v cng khng sch v cn cc mu d lm kt hp vi cc k thut khc C ch cho vic m R, thun tin i vi c v lm sch mt mt lng ln v cng phn khng th t tt d lm c cc ngun v cc mu To ra khng th khng sch v cn kt hp vi cc k thut khc

DEAE

Hydroxyapti C ch cho tt c cc m c, khng thm Sinh ra khng th te khng th t cc tch khng th v khng sch lm ngun khng th c phc hi trong dng dng ngay Lc gel Thch hp cho IgM t Tch IgM t cc khng Kh nng thp v tt c cc ngun th khc trong huyt cn pha long. thanh a dng Khng th to ra khng sch. Ascites, polycloral To khng th gn nh Tri qua nhiu giai sch, r v thun tin on. vi lng ln

Ammonium

Caprylic acid Sunphat amon Protein A

Ascites, sera

polyclonal to ra khng th gn Tri qua nhiu giai nh sch, r v thun on. tin vi lng ln Rt t tin v khng ph hp cho tt c cc mu v cc lp

IgG lin kt vi To ra khng th sch, protein A t tt c cc cc bc lm n gin ngun v ph hp vi lng ln Polyclonal sera

Ct i lc khng

To ra khng th sch t tin, tn nhiu v sn sinh ra khng bc v ihi 60

nguyn Ct i lc chng Ig

th c hiu

khng nguyn sch

Khng th chut, cu To ra khng lp v t v tn nhiu v d. Khng th lp mu c hiu bc. di lp c hiu t huyt thanh n dng v khng th n dng chut

IV. Phn ng kt hp khng nguyn-khng th


Nhiu phn ng min dch ph thuc vo phn ng khng nguyn-khng th. Khng th phn ng c hiu vi khng nguyn kch thch sinh ra n. Do khng th c trong huyt thanh nn nhng nghin cu in vitro v tng tc gia khng nguyn v khng th c s dng huyt thanh c gi l huyt thanh hc. V khng th khng nhn thy c bng mt thng nn khng th ch c th c xc nh khi chng gn vi khng nguyn c hiu. Phn ng khng nguyn-khng th c th c xc nh thng qua s kt ta, s ngng kt, s c nh b th, s pht hunh quang, hot tnh enzym hay gn vi ng v phng x. C nhiu phng php khc nhau xc nh mi tng quan gia khng nguyn v khng th. 1. C ch kt hp khng nguyn-khng th Khi em khng th trn vi khng nguyn c hiu tng ng th hai th s kt hp vi nhau, nhiu khi c th thy c bng mt thng di hnh thc ln bng, kt ta hay ngng kt. S kt hp ny d khng phi l lin kt ng ha tr nhng li c nhiu lc tc dng v th chng cng tr nn kh mnh. Chng ph thuc vo khong cch gia hai phn t:

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Hnh 0.8. Cc lc lin kt khng nguyn-khng th Lc tnh in c thc hin gia mt nhm mang in ca paratop vi mt nhm mang in tri du trn epitop, v d, gia COO- v NH3+. Lc ny i hi mt khong cch thch hp gia hai nhm t tr s ti a. V th, n t l nghch vi bnh phng khong cch (1/d2), nn nu khong cch tng th lc ny gim i rt nhanh. Do , gia khng th v khng nguyn phi gn th mi pht huy c tc dng (hnh 3.7). Lc ca cu ni hydro to ra gia nguyn t H+ trn phn t khng nguyn hay khng th vi O1- hay N1-. Lc ny ty thuc vo cc axit amin i din nhau, bi v thc cht n cng l lc ht tnh in (hnh 3.7). Lc k nc do s kt hp gia cc nhm k nc trn phn t khng nguyn v khng th lm cho phn t nc khng xen vo gia c v b y ra ngoi. Ngi ta cho rng, lc ny chi phi 50% lc lin kt gia khng nguyn v khng th (hnh 3.7). Lc Vander Walls do m my in t quanh nguyn t theo t l 1/d7 (hnh 3.7)

Nh vy, cc lc trn nu ring l th hon ton khng mnh chng li va chm do chuyn ng nhit. Do , chng phi lin kt li vi nhau th mi c th to thnh phc hp khng nguyn- khng th. Ngoi ra, cc cu hnh paratop phi ph hp cao vi epitop sao cho cc lc y ng thi xut hin, khong cch gia hai bn phi thch hp cc lc cng t gi tr cc i. a. Tnh cht chung ca s kt hp - Tnh c hiu: mt v tr khng th ch c th kt hp vi mt epitop khng nguyn m thi v mang tnh cht c hiu. 62

- Tnh kh hi: phc hp khng nguyn-khng th c th b tch ra bi nhit , khi toan ha mi trng (pH<3) hay tng hm lng ion. Nh vy, lin kt khng nguyn-khng th l kh hi v c th tch khng th ra khi khng nguyn in vitro ngay khi hnh thnh in vitro. Th d, tin hnh tch khng th t hng cu xc nh tnh c hiu ca cc khng th t mn chng hng cu. b. nh tnh v nh lng khng th Kha cnh nh tnh Tnh phn ng ca mt khng th c c trng bi i tnh v ho tnh: i tnh ca khng th i vi mt khng nguyn c hiu l cng ca cc lc lin kt phc hp khng th-khng nguyn. N cng mnh khi tnh b sung ba chiu cng cht ch gia v tr kt hp khng th vi epitop khng nguyn. Kt qu l cc lc ht nhau mi c iu in pht huy ht sc ko st cc phn t li vi nhau. Mi lin kt gia khng nguyn v khng th l mt cn bng c th vit nh sau: Khng nguyn + Khng th Khng nguyn-khng th + Nhit Hng s lin kt bn trong hay l hng s i tnh nh gi i tnh i vi khng nguyn c vit nh sau: K = (nng ca phc hp KN-KT)/((nng KN t do)-(nng KT t do)) Khng th i tnh cao/khng nguyn (1010 n 1013 1.mol-1) Khng th i tnh thp/khng nguyn (107 n 1010 1.mol-1) Rexepto t bo/hormon (109 n 1011 1.mol-1) Cht ti huyt thanh/hormon (109 n 1011 1.mol-1) Enzym/c cht (104 n 106 1.mol-1) Albumin/thuc (104 n 106 1.mol-1) Gi tr cao ca cc hng s lin kt cc phc hp min dch khng nguyn-khng th cho php gii thch nhy cm ca cc k thut nh lng min dch. Ho tnh ca mt khng th i vi mt khng nguyn c hiu quyt nh tc xut hin hin tng kt ta, ngng kt hay mt phn ng khng nguyn-khng th no khc. Ho tnh ny ph thuc vo hng s lin kt, ha tr ca khng th, s epitop, nhit , pH v lc ion ca mi trng. Trong qu trnh mn cm, i tnh v ho tnh ca khng th tng v trong khng th cng v sau cng xut hin nhiu v tr kt hp v tnh b cu vi epitop cng cht ch. Kha cnh nh lng C th nh lng mt khng th khi c mt khng nguyn tinh khit hoc thun nht. Ngi ta c th dng mt ng biu din so snh chun t mt dung dch khng nguyn bit vi mt huyt thanh min dch a gi hay t mt khng th n dng c hiu vi khng nguyn y. Nhn chung, vic nh lng mt khng th trong mt huyt thanh theo ng ngha khoa hc th khng lm c v l do khng nguyn thng c nhiu epitop 63

khc nhau. Trong cng mt khng huyt thanh a dng, c nhiu khng th c hiu i vi cng mt khng nguyn to thnh mt phc hp vi nhng phn t c i tnh khc nhau. Ch c nhng khng nguyn n dng thun nht v tnh cht l hc v kt hp vi cng mt epitop th mi c th cho php tin hnh mt nh lng tht s. Trn thc t, vic xc nh hm lng mt khng th hay khng nguyn thng ch l bn nh lng bng cch pha long dn cht phn ng nh o theo h s hai, ri cho thm vo cht phn ng nng khng thay i. Kt qu c biu din bng pha long cui cng m cn thy phn ng dng tnh hoc bi hiu gi l s o ca pha long y. Tuy nhin, phng php ny t chnh xc. Khi cn nh gi nng khng th trong hai mu huyt thanh th ch c th coi nh l s khc bit c ngha khi c s khc trn hai pha long m phi c lm trong cng mt iu kin th nghim. c. Cc loi phn ng khng nguyn-khng th Mt s phn ng khng nguyn-khng th c th quan st c khi lm th nghim nh kt ta hay ngng kt cc phc hp khng nguyn-khng th. ng thi, cng thy s ly gii ca khng nguyn ch. Tuy nhin, cng c mt s phn ng khng nguyn-khng th khng nhn thy trc tip c. Khi , ngi ta phi dng nhng mo thc nghim phn ng c th biu l ra nh nh du khng th bng cht hunh quang, bng mt cht ng v phng x hay bng mt enzym. 2. Kt qu sinh hc ca phn ng kt hp khng nguyn-khng th Khi b khng th kt hp, khng nguyn khng b bin i v mt cu trc ha hc nhng b thay i v mt tnh cht sinh hc. Vi khun hay vi-rt mang khng nguyn khi b khng th c hiu kt hp s mt kh nng nhn ln lm ri lon chuyn ha ni bo, thoi bin v d b thc bo hay b th tiu dit. a. Lm bt hot cc phn t c hot tnh Cc phn t khng nguyn c hot tnh nhng khi b khng th kt hp th s mt i hot tnh. C ch kh hot tnh khng nguyn ca khng th c th l: (i) ti khng th kt hp tI v tr hot ng ca phn t khng nguyn lm v tr ny b che ph nn khng th tip xc c i tng tc ng na; (ii) cu hnh ca v tr c hot tnh b bin dng lm cho n khng cn c hiu na v (iii) phn t c hot tnh thay i v hnh th khng gian. T lu, ngi ta bit sn xut khng th chng c t nh un vn, bch hu dng trong phng bnh v iu tr. Trong bnh l, khng th chng insulin, thyroglobulin gy suy gim chc nng ca tuyn ty, tuyn gip. Khng th chng enzym c tc dng kh hot tnh enzym. b. Bt hot vi-rt Khng th lm cho vi-rt mt kh nng kt hp vi th th ca t bo ch, nn khng thm nhp c vo ni bo v s nhanh chng cht ngoi bo. C ch ny c dng nh gi hiu lc khng th bng cch nui cy t bo ch vi vi-rt v khng th. Nu khng th c hiu lc th t bo ch s khng cht. Trng hp vi-rt lt vo ni bo, khng th vn c kh nng gy bt hot chng theo mt c ch khc. Vi-rt tn ti v pht trin trong 64

t bo s hnh thnh mt s khng nguyn a ln b mt t bo v b khng th kt hp. Mc d khng th khng trc tip tiu dit vi-rt nhng c tc dng hp dn i thc bo v t bo NK n tiu dit c t bo nhim ln vi-rt cha bn trong. y l c ch gy c t bo thng qua khng th (hnh 3.8). c. Bt hot vi khun, k sinh trng hay u trng k sinh trng Khi kt hp vi khng th th xon khun s mt kh nng di ng v tc nhn ln ca vi khun b gim i mt cch r rt hoc mt hn (khng to c khun lc khi nui cy trong mi trng thch). Cc qu trnh trao i cht qua mng v chuyn ha ni bo b ri lon hay gin on v thm ch b dng hn lm cho vi khun b cht. Cc k sinh trng n bo v mt k sinh trng s a bo nh st rt, amip, giun ch, cng b khng th dit trc tip v cng theo c ch dit vi khun. Nhiu loi u trng giun, sn b IgG v IgA rut lm chm hay ngng pht trin, gim t l n v trng thnh hoc khng thm nhp c qua nim mc rut. S kt hp ny s to iu kin cho bch cu a axit v i thc bo tiu dit chng.

Hnh 0.9. Khng th tiu dit vi-rt ni bo d. Tp trung khng nguyn Bng cch gy ta hay gy ngng kt, khng th c vai tr lm cho khng nguyn t dng phn tn tr thnh dng tp trung hn ch kh nng lan rng ca khng nguyn. ng thi, to iu kin quy t cc bin php bo v khng c hiu vo ni khng nguyn tp trung.

65

Ti liu tham kho


1. V Triu An v Jean, C.H. 2001. Min dch hc. Nh xut bn Y hc. 2. Nguyn Ln Dng. 2001. Vi sinh vt hc. Nh xut bn Gio Dc. 3. L Huy Kim. 1998. Bi ging min dch hc th y. Khoa Nng Nghip- i hc Cn Th. 4. Nguyn Ngc Lnh v ctv.1997. Min dch hc. Nh xut bn y hc. 5. Madigan, M.T., Martinko, J.M. and Parker, J., 2002. Biology of Microorganisms. Tenth edition, Prenhall. 6. Ngc Lin, 1999. Min dch hc c s. Nh xut bn i hc Quc gia H ni.

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Phn hai: MIN DCH NG VT THY SN Chng 4: Min dch hc ng dng trong thu sn
I. Tin ho h min dch ca ng vt
Mi sinh vt u c kh nng t v nhm chng li s xm nhp ca bt k mt vt l no t bn ngoi. Kh nng u tranh sinh tn vn c mi sinh vt, trong qu trnh p ng min dch l quan trng v phc tp nht (hnh 4.1).

Hnh 0.1. S tin ho min dch ng vt T nhng sinh vt tin ha thp nht trong sinh gii, cha c cu to t bo hon chnh nh nhm nguyn sinh ng vt c nhng th hin kh nng t bo v c th. V d qu trnh thc bo bt cc vt l lm thc n amip, s thi loi mnh ghp san h, hin tng dung np duy nht cc c th cng chng loi to thnh mt khi qun th hi min. Nhm ng vt c khoang th tin ha hn nn cc du hiu v p ng min cng bt u th hin r nt hn nh nhm cu gai xut hin cc t bo tham gia vo qu trnh thc bo, c kh nng nh cc mnh ghp v nhng phn t gy dnh. Nhm mc th hin r cc 67

t bo gc, cu trc ca phn t MHC v cc lympho bo. gip xc, vai tr ca b th cng c th hin r trong qu trnh p ng min dch (hnh 4.1). nhm giun xut hin cc t bo chuyn bit nh opsonin, lysin v nhng phn t gy dnh. nhuyn th mc d c s tin ha cao hn nhng xu hng v p ng min dch li chm i, th hin r nt nht l khng xy ra hin tng thi loi mnh ghp. Lp c l lp tin ha nht v c cu trc ca h thng min dch hon chnh nht thu sinh vt. u tin l nhm c khng hm c h thng cc t bo lympho v vai tr ca khng th. Nhm c sn th xut hin cc c quan sinh min dch nh lch, tuyn c, Ig, t bo T, t bo plasma, IgM. Nhm c xng th c qun th t bo T, t bo B v Ig (hnh 4.1). ng vt lng c c Ig, t bo T, IgM, IgG. Lp chim th c ti bursa, Ig M, IgG, IgA. Cui cng l ng vt bc cao th c y 5 loi khng th IgA, IgA, IgM, IgE, IgD.

II. p ng min dch gip xc


Trong h thng min dch ca gip xc thiu nhng yu t cn thit cho p ng min dch c hiu nh t bo lympho T, phn t MHC v Ig cho nn s khng c th gip xc ch yu da vo cc c ch p ng min dch khng c hiu. p ng min dch khng c hiu gip xc c thc hin ch yu bi cc t bo mu chuyn ho nh thc bo (bng 4.1), qu trnh phong to v s sn sinh cc cht khng khun hay dit khun. Bng 0.1. Cc dng bch cu gip xc v chc nng trong p ng min dch Chc nng Bch cu Khng ht Bn ht C ht Thc bo C Hn ch Khng Phong ta Khng C Rt hn ch c t bo Cha bit C C Hot ha h thng ProPO Khng C C

gip xc, ngoi cc c ch p ng min dch t nhin tng t nh ng vt c xng sng chng cn c mt s c ch p ng min dch kh c th l kh nng hnh thnh khi u, kh nng phong b, kh nng sn sinh cc protein khng khun (cn gi l cc peptit khng khun, phn ng ng mu c th b kch thch bi LPS ca vi khun, kh nng s dng cc enzym thu phn, cc cht khng vi nguyn sinh ng vt v c bit l h thng Prophenoloxydase. H thng Prophenoloxydase C ch ca qu trnh Phenoloxidase c trnh by hnh 4.2. Khi vi sinh vt hay vt cht l vt qua c hng ro vt l lt vo trong c th ca gip xc th chng gp phi bch cu, hin tng thc bo xy ra s lm kch hot enzym protease c trong huyt thanh. Enzym ny cng vi hin tng thc bo xy ra bch cu l tn hiu kch hot men prophenoloxidase thnh dng hot ha phenoloxidase.

68

Hnh 0.2. C ch hot ho h thng ProPO Khi men ny hot ha th n s chi phi qu trnh sn sinh ra quinone melanin mt cch mnh m v tp trung ngay nn sinh vt hay vt l tn cng vo v bao ly chng. Kt qu ca qu trnh ny thng l hin tng melanin ho trn v cutin ca gip xc (hnh 4.3). Ngoi ra, khi enzym protease hot ng n cn kch thch qu trnh opsonin ho thu ht cc thc bo tp trung li ch y. V th, thc y hin tng thc bo c din ra mt cch mnh m hn.

69

Hnh 0.3. Cc vt en l ni v cutin ca tm b vim, lot v melanin ho Cc peptit khng khun (antimicrobial peptides-AMPs) Peptit khng khun l mt dng p ng min dch t nhin ph bin thc vt, ng vt c v khng c xng sng. Chng c kh nng khng khun, khng c t v c vi trng hp c kh nng khng nm.

Hnh 0.4. C ch chui qua mng t bo vi khun ca cc peptit khng khun. Peptit khng khun l nhng phn t nh t 15-75 amino axit (hnh 4.4) c kh nng tng tc trc tip vi b mt t bo vi sinh vt to nn nhng l thng v lm cht t bo vi sinh vt (hnh 4.4). Cu trc c bit ca chng lm cho vi sinh vt kh c th pht trin kh nng khng nh trng hp khng thuc khng sinh v do s khc nhau v cu to mng t bo vi sinh vt v mng t bo vt ch nn cc peptit khng khun c th tiu dit mm bnh m khng lm hi n vt ch. 70

III. p ng min dch c xng


1. C ch bo v khng c hiu a. Cc hng ro b mt Dch nhn: l mt yu t c th v bao ph ton c th ca c. Dch nhn khng nhng gip c gim c ma st trong qu trnh vn chuyn m cn ng vai tr quan trng trong qu trnh bo v c th chng li s xm nhm ca vi sinh vt hay cc vt l t mi trng vo c th c. V d, hin tng tut nht trn c bng tng s lm cho c d nhim bnh hn. Da: da c tng i khc vi cc ng vt trn cn l khng ho sng, nhng kh nng phc hi ca da rt nhanh do s hnh thnh lp t bo Malpighi huy ng t vng ln cn. Phn ng ph i cc t bo Malpighi v lp biu b cng rt nhanh, gip cho da tr thnh mt hng ro vt l tng i vng chc bo v c th. Ngoi ra, mt loi c c vy th chnh h thng ny s bo v da v c th c c vng chc hn. Mang: l c quan c bit v khc hn vi cc ng vt trn cn. Mang l ni thc hin qu trnh h hp c bn ca c, cng l ni tip xc thng xuyn vi cc sinh vt ca bn ngoi mi trng. Cho nn, mang l con ng xm nhim quan trng ca mm bnh. Tuy nhin, mang th c s tp trung ca i thc bo rt cao. N cng c bao ph bi dch nhn v s xut hin ca cc t bo Malpighi gip cho mang c kh nng thc hic c chc nng chng li cc sinh vt t bn ngoi mi trng b. Yu t min dch khng c hiu H thng min dch khng c hiu ca c cng bao gm cc nhn t c ch sinh trng nh transferin, interferon, lysin trong b th, protein phn ng C v lectin. Hng ro t bo nh i thc bo, bch cu trung tnh, bch cu i toan v i kim cng ng mt vai tr rt quan trng trong p ng min dch c hiu c. Tuy nhin, s hiu bit v chc nng v c ch hot ho cc t bo ny c cn hn ch so vi ngi v ng vt bc cao. 2. C ch bo v c hiu a. C quan lympho Thn c xem l c quan lympho ngoi vi c, ni xy ra qu trnh bt gi, x l v trnh din khng nguyn cho h thng p ng min dch. H thng min dch ca c xng th c hnh thnh tng i hon chnh hn gip xc, n c c p ng min dch c hiu ln khng c hiu. Cc t bo lympho tham gia vo qu trnh p ng min dch cng c ngun gc v chc nng gn ging nh ng vt trn cn.Trong qu trnh p ng min dch th vn c s to thnh khng th dng Sig (xem bng 4.2), cc thng tin ny cng c ghi nh li sn sng cho vic to khng th trong ln tip xc sau vi khng nguyn.

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Bng 0.2. c im Ig ca c xng Nng trong huyt thanh (mg/ml) % tng s protein huyt thanh Thi gian bn hu trong mu (ngy) Hng s lng (s) Tetramer Monomer Khi lng phn t (kDa) Tetramer Monomer Chui nng Chui nh Hm lng cacbonhydrat b. p ng min dch dch th Khi khng nguyn xm nhp vo trong c th c th s b cc t bo trnh din khng nguyn bt gi, x l v trnh din yu t quyt nh khng nguyn ln b mt lm kch hot cc t bo lympho T. Sau , t bo lympho T s tc ng ln lympho bo B, chuyn t bo ny thnh tng bo sn sinh ra khng th. Tng bo bt u xut hin v s lng tng mnh lit trong lch v thn khong 1 tun sau khi c kch thch ca khng nguyn. Khng th huyt thanh thng xut hin ngay trc thi im s lng tng bo t cc i khong ngy th 10-15 v hm lng Ig tng ln mnh lit t cc i khong ngy th 20-30 sau khi tim khng nguyn. Nh vy, So vi ng vt c v, pha mn cm c ko di hn, nhng thi gian duy tr hm lng khng th li lu di hn. c. Min dch qua trung gian t bo Cc c im min dch qua trung gian t bo ng vt c v u c c, tuy nhin h thng ny cha c nghin cu k c. Cc phn ng thi loi mnh ghp c xng l cp tnh (hnh 4.5) nhng cha r c ch. d. p ng min dch cc b mang Mang ng vai tr quan trng trong vic tip th khng nguyn, c bit l cc khng nguyn khng ho tan. mang c rt nhiu t bo lympho, i thc bo v tng bo c tr. Mang c kh nng sn xut khng th ti ch ng vai tr khng quan trng i vi cc bnh mang do vi khun. 72 650-850 160 70-75 20-25 Ti a 16% 13-17 7 2-7 6-15 12-16

Hnh 0.5. Hin tng thi loi mnh ghp c hi e. p ng min dch cc b da Ig c pht hin trong dch nht da c. C bng chng cho thy chng khng c ngun gc t khng huyt thanh v c gi nh rng y l cc sn phm c sn xut ti ch. ng thi cng c s hin din ca t bo lympho, tng bo v i thc bo lp biu b da c. S c mt ca cc t bo ny da c cho thy vic hnh thnh phn ng min dch cc b c th xy ra y. f. p ng min dch cc b dch nhy Khi gy min dch bng cch ngm hoc cho n c th kch thch vic hnh thnh khng th trong lp dch nhy m khng lm gia tng khng th trong huyt thanh. c chp, i b phn khng th dch nhy da l tetramer. IgM dch nhy v huyt thanh c cc chui nng v nh ging nhau v u phn ng vi cc khng th khng IgM huyt thanh. Tuy nhin, mt s khng th n dng khng IgM dch nhy li khng phn ng vi IgM huyt thanh. Vic s dng khng th n dng khng IgM dch nhy gip pht hin c t bo sn xut khng th trong mang v rut c chp c gy min dch bng cch cho n vin nang cha vi khun Vibrio b bt hot ho, nhng li khng pht hin c cc t bo ny c chp c gy min dch bng cch tim vo c. Nh vy c chp, c mt dng IgM chuyn bit c sn xut bi mt tiu qun th cc tng bo trong cc m tit dch nhy.

IV. Nghin cu v ng dng ca vc-xin trong phng bnh thu sn


1. nh ngha vc-xin Vc-xin l ch phm c tnh khng nguyn dng to min dch c hiu ch ng, nhm tng sc khng ca c th i vi mt (s) tc nhn gy bnh c th. Thut ng vc-xin xut pht t vaccinia, loi vi-rt gy bnh u b nhng khi em chng cho ngi li gip nga c bnh u ma (ting Latinh vacca ngha l "con b ci"). Vic dng vc-xin phng bnh gi chung l chng nga hay tim phng hoc tim chng, mc d vc-xin khng nhng c cy (chng), tim m cn c th c a vo c th qua ng ming. 2. Lch s pht trin vc-xin tng phng bnh c hnh thnh cch y kh lu, ngay t thi thng c ngi Trung Quc dng vy u sy kh, nghin nh b vo mi ngi phng bnh u ma. Th dn Chu phi dng thanh kim chc vo phi ca b ang mc bnh vim phi, ri rch vo da chn ca con b khe phng bnh vim phi cho b. Tuy nhin, Edward Jenner, mt bc s ngi Anh c cng nhn l ngi u tin dng vc-xin nga bnh u ma cho ngi ngay t khi ngi ta cn cha bit bn cht ca tc nhn gy bnh (nm 1796). Kinh nghim dn gian cho thy nhng nng dn vt sa b c th b ly bnh u b, 73

nhng sau khi khi bnh, h tr nn min nhim i vi bnh ny. Da vo , Jenner chit ly dch t cc vt u b trn cnh tay ca mt bnh nhn ri cy dch ny vo cnh tay ca cu b 8 tui khe mnh cng lng tn l James Phipps. Sau Phipps c nhng triu chng ca bnh u b. 48 ngy sau, Phipps khi hn bnh u b, Jenner lin tim cht c cha mm bnh u ma cho Phipps, nhng Phipps khng h mc bnh ny. Cch lm ca Jenner xt theo cc tiu chun y c ngy nay th khng ph hp, nhng r rng l mt hnh ng c tnh khai ph v a tr c chng nga khng c bnh. Thi ca Jenner, cc vi-rt cha c khm ph v vai tr gy bnh ca vi khun cha c bit. Thi im 1798, khi Jenner cng b kt qu th nghim ca mnh, ngi ta ch hnh dung l c cc "mm bnh" gy nn s truyn nhim. Tm mi nm sau, Louis Pasteur vi cc cng trnh nghin cu v vi sinh hc v min dch hc m ng cho nhng kin thc hin i v vc-xin. Louis Pasteur nghin cu bnh t huyt trng ang tn st n g. ng cy cc vi khun ny trong phng th nghim ri em tim cho g. Kt qu l nhng con g b tim cht sch. Ma h nm 1878, ng chun b mt bnh dung dch nui cy vi khun dng huyn ph, ri , i ngh mt. Khi tr v, ng li trch ly huyn ph em tim cho g. Ln ny th by g ch b bnh nh ri c n cng khe li. Pasteur hiu ra rng khi ng i vng, m vi khun trong huyn ph b bin tnh, suy yu i. ng ly vi khun ny (bnh thng) em tim cho nhng con g va tri qua th nghim trn v nhng con cha h b chch vi khun. Kt qu l nhng con no tng c chch vi khun (bin tnh) th c kh nng khng li mm bnh, s cn li cht ht. Qua , Pasteur xc nhn cc gi thuyt ca Jenner v m ng cho khoa min dch hc hin i. T , chng nga y li nhiu bnh nh trit tiu bnh u ma trn ton cu, thanh ton gn nh hon ton bnh bi lit, gim ng k cc bnh si, bch hu, ho g, bnh ban o, thy u, quai b, thng hn v un vn v.v. Nguyn tc vn khng c g thay i l gy min dch bng mt vi khun hoc vi-rt gim c lc, hoc vi mt protein c hiu c tnh khng nguyn gy ra mt p ng min dch, ri to mt tr nh min dch c hiu, to ra hiu qu khng cho c th v sau khi tc nhn gy bnh xm nhp vi y c tnh. Ngi ta cn hng ti trin vng dng vc-xin iu tr mt s bnh cn nan y nh ung th, AIDS v.v. 3. C ch hot ng ca vc-xin C ch hot ng ca vc-xin c thc hin da trn c s ca p ng min dch c hiu tin pht v th pht. H min dch trc tin nhn din vc-xin l mt vt l (khng nguyn) nn tin hnh cc p ng min dch tiu dit khng nguyn ng thi cng ghi nh khng nguyn. V sau, khi tc nhn gy bnh thc th xm nhp vo c th c th, h min dch t th sn sng tn cng tc nhn gy bnh nhanh chng hn v hu hiu hn (bng cch huy ng nhiu thnh phn ca h min dch, c bit l nh thc cc t bo lympho nh) (hnh 4.6).

74

Hnh 0.6. C ch hot ng ca vc-xin 4. Phn loi vc-xin Vc-xin c th l cc vi-rt hoc vi khun sng, gim c lc, khi a vo c th khng gy bnh hoc gy bnh rt nh. Vc-xin cng c th l cc vi sinh vt b bt hot, cht hoc ch l nhng sn phm tinh ch t vi sinh vt. a. Cc loi vc-xin kinh in Vc-xin bt hot l cc vi sinh vt gy bnh b git bng ha cht hoc bng nhit (nh formaline, - propiolacton, cn, nhit , UV, tia X). Cc yu t trn ch lm cht mm bnh nhng khng lm bin tnh protein nn vn gi c c tnh ca mm bnh. c tnh ca loi vc-xin ny khi a vo c th th chm sinh ra khng th (khong 7-14 ngy). Th d: cc vc-xin chng cm, t, dch hch v vim gan siu vi A. Hu ht cc vc-xin loi ny ch gy p ng min dch khng hon ton v ngn hn, cn phi tim nhc nhiu ln. Tuy nhin an ton ca vc-xin ny rt cao. Vc-xin sng, gim c lc l cc vi sinh vt c nui cy di nhng iu kin c bit nhm lm gim c tnh c hi ca chng. y l loi vc-xin c tnh min dch tc thi v c th dng dp tt nhng dch ang bc pht. Tuy nhin, vc-xin ny lun phi c theo di k v c lc do vi sinh vt rt d dng b t bin, nn an ton ca vc-xin ny tng i khng nh. Vc-xin ny khng nn dng cho cc sinh vt c tnh trng suy gim min dch nh suy dinh dng, ang dng nhng cht c ch min dchl do l trong hon cnh y sc khng min dch yu nn vi sinh vt c kh nng phc hi li c lc v sinh bnh. Vc-xin ti t hp: vi cng ngh gen hin i, ngi ta ct on gen tng hp nn protein c trng cho vi sinh vt gy bnh, ghp gen ny vo vi khun hay t bo nui cy to ra protein c hiu cho mm bnh, dng protein ny tim chng to min dch c hiu. Dng vc-xin ny an ton, t tc dng ph, kh nng min dch cao. Mt in hnh ca vcxin dng ny l vc-xin phng vim gan vi-rt B th h II v III.

75

Cc "toxoid" l cc hp cht c b bt hot trch t cc vi sinh vt (trong trng hp chnh cc c cht ny l phng tin gy bnh ca vi sinh vt). Chng c tim cho vt ch khc (nh nga) to khng th, ri chit ly khng th ny cha bnh. Th d: cc huyt thanh nga un vn v bch hu. b. Mt s loi vc-xin mi ang nghin cu Cc vc-xin ny cn c xem l vc-xin ca tng lai, c 6 hng pht trin chnh hin nay: S dng cc t dc (adjuvant) mi, nhm gy ra loi p ng min dch mong mun. Th d, cht nhm phosphate v cc oligonucleotide cha CpG demethyl ha a vo vc-xin khin p ng min dch pht trin theo hng dch th (to khng th) thay v t bo. Vc-xin khm: s dng mt sinh th quen bit hn ch hin tng "phn tc dng", th d dng vi-rt vaccinia mang mt s yu t ca vi-rt vim gan B hay vi-rt di. Vc-xin polypeptidique: tng cng tnh sinh min dch nh lin kt tt hn vi cc phn t MHC: peptit nhn to 1/2 ging vi-rt, 1/2 kia gn MHC; on peptit m phng 1 quyt nh khng nguyn (epitop). Anti-idiotype: idiotype l cu trc khng gian ca khng th ti v tr gn khng nguyn, c hiu vi khng nguyn tng ng. Anti-idiotype l cc khng th c hiu i vi idiotype, do anti-idiotype xt v mt c hiu li tng t vi khng nguyn. Vy, thay v dng khng nguyn X lm vc-xin, ngi ta dng idiotype anti-anti-X. Vc-xin ADN: ADN ca tc nhn gy bnh c biu hin bi t bo ngi c chng nga. Li th ca vc-xin ny l r, bn, d sn xut ra s lng ln nn thch hp cho nhng chng trnh tim chng rng ri. Ngoi ra, chng cn gip nh hng p ng min dch l tc nhn gy bnh ngoi bo c trnh din qua MHC II, dn n p ng CD4 (p ng min dch dch th). Khi khng nguyn ca tc nhn c chnh c th ngi biu hin, n s c trnh din qua MHC I, lc ny p ng min dch t bo qua CD8 c kch thch. Tuy nhin phng php ny l con dao hai li bi l t bo mang ADN l c nguy c b nhn din l "tnh l", sinh ra bnh t min.

c. Vc-xin dng iu tr Mt trong nhng hng nghin cu mi l min dch liu php, bao gm min dch liu php th ng v ch ng (tc vc-xin liu php). Ngi ta hy vng l phng php ny s cha c nhng bnh nh ung th, AIDS v bnh Alzheimer. Trong thy sn, vc-xin c dng ch yu di dng vc-xin cht. Tuy nhin, trong tng lai th c xu hng nghin cu v pht trin cc loi vc-xin theo cc xu hng: 1. Ti t hp di truyn: tng hp cc ADN c cu trc ging nh cc ADN ca cc khng nguyn c hiu lc, sau a vo c th sinh vt. 2. Nng cao tnh sinh min dch ca khng nguyn bng cch lm l ra cc yu t quyt nh khng nguyn (trnh t axit amin ngn) vi t bo T. 76

5. c tnh c bn ca vc-xin Vc-xin khi c s dng tim truyn cho vt ch th phi m bo bn c tnh c bn l tnh sinh min dch, tnh khng nguyn, hiu lc v khng c lc. Tnh sinh min dch: l kh nng gy ra p ng min dch, dch th. Tnh ny ph thuc vo c khng nguyn ln c th nhn kch thch y. p ng ca vt ch cn ty thuc vo loi, ng tim truyn v c a ca bn thn sinh vt. Thc nghim cho thy, cng mt khng nguyn nhng nhng sinh vt khc nhau s cho nhng p ng khc nhau. Vc-xin a qua nim mc s sinh ra nhiu khng th IgA c hiu lc bo v ng tiu ha, tim qua da rt tt cho p ng min dch qua trung gian t bo. p ng min dch cn ph thuc vo tui, tnh trng sc khe ca sinh vt. Tnh khng nguyn: l kh nng gy ra p ng min dch bng khng th dch th hay t bo v phn ng kt hp c hiu vi n. Hapten cn phi lin kt vi cht mang ti, epitop cn phi kt hp vi mt protein mang ti v hi l cc t cht hay cc vc-xin khc nh vc-xin u ma hay trn nhiu vc-xin khc nhau. Tnh hiu lc: cc khng th to ra khng phi ci no cng c hiu lc tiu dit c yu t gy bnh. Yu t gy bnh c nhiu khng nguyn khc nhau nn trong bo ch vc-xin trc tin phi lm sao cho p ng min dch chng li nhng nhm quyt nh khng nguyn, ngha l nh vo th yu t gy bnh b tiu dit hay khng cn kh nng gy bnh na. V th vic xc nh cc khng nguyn hay cc yu t quyt nh khng nguyn s gip cho vc-xin tinh khit hn v tin ti vic tng hp nhn to cc vc-xin. V d: cc loi khng th do vi-rt vim gan B sinh ra th ch c khng th chng li khng nguyn b mt HBs l c tc dng bo v, cn khng th chng v nhn HBc khng c tc dng y. Tnh hiu lc c nh gi trn bnh din c th v trn bnh din tp th thng qua thc nghim. Vc-xin gy c min dch trn 60% th c coi l c hiu lc. Trong vic nh gi qun th th hiu lc ca vc-xin ph thuc rt nhiu vo vic bo qun, vn chuyn v cch s dng vc-xin. Tnh v hi: vc-xin cn phi c th nghim nhiu ln trong phng th nghim trc khi ng dng i tr. Tn sut v mc nng nh ca cc phn ng ph phi c xc nh trc khi s dng.

6. Yu t nh hng ti vc-xin v hiu qu s dng vc-xin a. Cc yu t nh hng Nhit : Tnh min dch ca c chu nh hng ca nhit trong vi giai on nht nh ca qu trnh hnh thnh p ng min dch c bit l giai on hot ho t bo T h tr. Thng thng, trong phm vi thch ng ca loi, khi nhit cng cao th p ng min dch cng nhanh v cng s cng cao. Khi nhit thp th giai on lag phase cng ko di v lng khng th c th b nh hng, suy gim hoc hon ton b trit tiu. Ngoi ra, nhit thp cn gy ra hin tng c ch kh nng sn xut nhn t hot ho i thc bo ca cc t bo T. Do s lm suy yu c ch min dch qua trung gian t bo. ng thi, hin tng st gim nhit t ngt c th dn n s v cm min dch. Bn cht ca s c ch min dch ny vn cha c bit r. 77

Tnh ma v: H thng min dch ca c c nhng thi k b c ch lin quan n ma v m khng n thun ch do nhit thp. Th d, c r bin Sebastiscus marmoratus p ng min dch con ci thnh thc vo ma sinh sn (ma ng) li thp hn con c v cc c th cha thnh thc. Yu t kim loi: Cc kim loi Nhm, Arsen, Caimi, Crm, ng, Ch, Thu ngn, Nickel, Km km hm p ng min dch i vi ng vt thu sn. Cc ion kim loi s kt hp vi protein min dch to thnh mt phc hp rt bn. V th s ngn cn p ng min dch ca c th nh lm gim hot ho thc bo, gim nng khng th trong mu, gim s lng t bo lympho v ng thi s lm tng tnh mn cm vi vi-rt v vi khun gy bnh. Hydrocacbon thm: Cc hydrocacbon thm nh Phenol, Benzen, Polychlorinated biphenils, Chlorinated dioxin, Polynuclear aromatic hydrocacbons (PAHs) gy suy gim sc khng ca c do lm st gim khng th v hot tnh i thc bo, lm tng agglutinin khng c hiu. Bi v cc hydrocacbon thm s kt hp vo th th t bo gy c ch phn ng oxy ho-kh. Nng dc: Cc cht nng dc (nh DDT, Endrin, Malathion,) c kh nng gy hoi t tuyn c, lm suy gim hot tnh thc bo, gim s lng t bo B v suy gim hm lng Ig. V th, ch cn mt liu thp ca cc cht dit c, thuc dit cn trng & bo v thc vt, cng c th gy suy gim p ng min dch ca nhiu loi c. nh hng ca ho dc v thuc khng sinh: Cc ha dc v thuc khng sinh cng c tc ng km hm n tnh sinh min dch ca c th. Trn c hi, khi s dng Oxytetracyclin th s lm suy gim t bo lympho B, s dng Aflatoxin B-1 s lm mt t bo B nh, cn s dng Cortisol/Kenalog-40 th lm gim s lng t bo B. Trn c chm chu u th s dng Hydrocortisoe lm gim tnh trng thc bo. Sc: Stress s nh hng trc trip ln thn kinh trung ng, kch thch tit ra chlomaffin v ng thi kch thch no thy tit ra ACTH. Sau ACTH s tc ng ln tuyn gip thn v kch thch tuyn ny tit ra cortisol. Cortisol v chlomaffin s c tc ng km hm h tun hon, nn hin tng ti phn b nng lng khng c m bo lm nh hng n s sinh sn v sinh trng ca cc i thc bo. Cc c quan ti sinh min dch nh tuyn c, tin thn v lch cng b nh hng lm cho vic sn xut cc t bo lympho b st gim. S tun hon s nh hng ti vic vn chuyn cc yu t p ng min dch ti cc c quan ngoi vi nh mang, da v cc c quan min dch b yu i, lm cho tc nhn gy bnh s d dng tn cng hn. b. Hiu qu s dng vc-xin C c khoa hc ca vic s dng vc-xin trong cng tc phng chng dch bnh l s hnh thnh p ng min dch thch nghi ca sinh vt nh tnh c hiu v kh nng nh. Nh vy, mc ch ca vic s dng vc-xin l ch ng to cho c th c sc khng i vi mt tc nhn gy bnh nht nh, hn ch nguy c nhim bnh do tc nhn ny gy ra. Tiu chun nh gi mt vc-xin Tnh an ton ca vc-xin: th hin khi a vc-xin vo c th sinh vt s khng to phn ng ph, vi sinh vt khng phc hi c lc (i vi vc-xin s dng l vc-xin sng), ng thi khng tc ng tiu cc n mi trng. 78

Kh nng sinh min dch: ty thuc bn cht khng nguyn v c im loi m phi s dng vc-xin cho ph hp C hiu qu bo v: sau khi tim vc-xin vo c th th vc-xin phi kch thch c h thng min dch to khng th v khng th sinh ra phi c tnh c hiu vi tc nhn gy bnh tng ng. ng thi, thi gian bo v ca vc-xin phi m bo v ph hp vi i tng nui.

Phng php nh gi hiu lc ca mt vc-xin Cc yu cu b tr th nghim Mi nhm c th nghim phi trn 25 con, lp li phi ln hn 2 ln Gy nhim bnh thc nghim trong khong thi gian t 2560 ngy sau khi s dng vc-xin bng phng php tm T l nhim bnh nhm i chng (A) phi trn 60% trong thi gian kim nh T l nhim bnh nhm c s dng vc-xin (B) khng vt qu 24% Phi kim tra ton b c nhim bnh thc nghim. T l c nhim bnh do nguyn nhn khc khng vt qu 10%.

Cc ch s nh gi hiu qu bo v ca vc-xin T l sinh tn tng i (Relative Percent Survival-RPS) (%) Cng thc tnh RPS: RPS = (1- (t l c th nghim b nhim/t l c i chng b nhim)) x 100 Yu cu: RPS 60% nh gi theo ch s RPS thch hp cho vic kim nh hiu qu vc-xin trong phng th nghim v cc thc nghim ngoi hin trng. Gia tng liu gy cht 50% (LD50 Lethal Dose) y l th nghim ch ph hp trong iu kin phng th nghim v cc yu cu b tr th nghim tng t nh trng hp nh gi ch s RPS. Cng thc tnh LD50 (theo Reed v Muench, 1938) LD50 = Mc gy t l nhim bnh ca c trn 50% thp nht - s ni suy (p.d) p.d = (L%-50)/(L%-H%) Trong : L%: t l c nhim bnh thp nht trn 50% H%: t l c nhim bnh cao nht di 50% Yu cu: gi tr LD50 ca nhm c th nghim c s dng vc-xin phi cao hn gi tr nhm c i chng 100 ln. 79

7. Phng thc s dng vc-xin trong nui trng thu sn a. Tim y l phng php c th b sung nhng t dc nhm lm tng hiu lc ca vc-xin s dng. Tuy nhin, gp phi mt s kh khn v vic gy m v bt gi i tng khi thy sn khi tim vc-xin nn d dng gy sc cho c (bng 4.3). Hn na, ch ng dng c i vi c trn 15g. khc phc, c th s dng kim tim t ng bm thuc theo mt h thng dy truyn, vi cng sut khong 1.000 c/gi. b. Cho n y l mt phng php c ng dng rng ri cc trang tri nui c v phng php ny n gin, d ng dng v khng gy sc cho c. Tuy nhin, cn mt lng vc-xin ln nn lm tng chi ph u t. Hn na, liu lng vc-xin khng m bo gia cc c th trong qun n v khng nguyn d dng b ph hy khi qua bao t v rut trc (bng 4.3). c. Ngm Ngm l phng php n gin v nhanh v ch cn c vi giy khi cho c tip xc vi vcxin. u tin, vc-xin c pha long sn trong nc, sau bt c ngm khong 30-60 giy. Kh nng hp th cc khng nguyn theo phng php ngm th t c hiu qu (bng 4.3). C ch hp th khng nguyn cha bit c chn chn, nhng ngi ta thy rng mang l con ng chnh cc hp th cc khng nguyn, bn cnh th da v cc c quan ng bn cng c tham gia vo qu trnh thp th cc khng nguyn. C nhiu loi bnh th c quan min dch ca c khng chng c theo phng php ny. Ngoi vic lin quan n c ch hp th khng nguyn cn ph thuc vo kh nng p ng min dch t nhin v iu kin t nhin ca th nghim. d.Tm vc-xin Nhm hn ch lm sc cho c theo phng php ngm, ngi ta s dng phng php tm vc-xin cho c bng cch nh t t vc-xin vo thng tr c. Tuy nhin, phng php ny i hi mt lng ln vc-xin v thi gian l khong 1 gi (bng 6.3). e. Phun vc-xin y l phng php c pht trin ng thi vi phng php ngm. Vc-xin c phun hoc c dn bng h thng bn t ng thng qua bng truyn chy qua di nhng vi phun vc-xin. Phun vc-xin c kh nng gy sc c v kt qu c th bin ng (bng 4.3). Bng 0.3. u v nhc im ca cc phng php s dng vc-xin c Phng php Tim u im Hiu lc tt nht v c th dng t dc t tiu tn vc-xin Tm, ngm, nhng, phun C th dng cho c con 80 Nhc im Khng th tim c <15g. Tn nhn cng, thi gian v d dng lm sc c Tiu tn nhiu vc-xin

Thi gian ngn, s lng c nhiu Khng hiu qu cho c ln

Cho n

Khng gy sc c Khng cn thit b chuyn dng

Hiu qu khng n nh Kh kim sot c lng vc-xin

8. Mt s kt qu nghin cu vc-xin c Vic s dng vc-xin phng bnh nhim khun trn c hi Nauy c chng minh l c hiu lc t nm 1993. Vc-xin c kh nng bo h n c nui vi t l sng trn 90% v lm gim chi ph sn xut cn 10% so vi khi s dng thuc khng sinh phng bnh. Tuy nhin, vic pht trin vc-xin va c hiu lc va c gi thnh h thng khng d dng. Hin ti trn th trng ch c mt vi loi vc-xin dng tim chng nga mt vi bnh nhim khun thy sn. Thng gp l vc-xin u ch bng cch lm cht hoc lm yu vi khun c c lc. Hin ti ngi ta ang khm ph kh nng lm tinh khit cc khng th t cc mm bnh hoc to khng th qua cc thao tc gen (cn gi l vc-xin ti t hp) v vcxin ADN. Vc-xin ADN c rt nhiu u im nh chun b rt n gin v c th c sn xut s lng ln. Hn na, vc-xin ADN rt bn v c th tn ti nhng iu kin nhit bt li to iu kin d dng trong vn chuyn, lu gi v phn phi. Vc-xin ADN cn c u im v kha cnh min nhim do h min dch nhn bit khng nguyn ADN tng t nh nhn bit vi-rt v vi khun ni bo nn rt c hiu lc trong vic bo h c vi cc trng hp nhim vi-rt v vi khun. Mt s loi vc-xin ADN phng bnh vi-rt (hematopoietic necrosis virus, viral hemorrhagic septicemia) v vi khun (bacterial kidney disease) c th nghim c hi. Tuy nhin, vic ng dng vc-xin ADN vo sn xut vn cn i hi s kim nh v tnh an ton v kh nng bo h ca vc-xin ADN.

V. ng dng min dch hc trong chn an bnh thy sn


Nguyn l v k thut min dch ng dng trong chn an bnh thy sn c trnh by chi tit trong chng 3, gio trnh nguyn l v k thut chn an bnh thy sn (ng Th Hang Oanh, 2007). Cc k thut min dch ng dng trong chn an bnh ng vt thy sn ch yu l s dng khng th pht hin protein khng nguyn ca vi-rt, vi khun, k sinh trng hay nm hoc nhng p ng ca vt ch vi vi-rt, vi khun, k sinh trng hay nm trong mu huyt thanh. Trng tm ca cc k thut min dch ny l xc nh s tip xc ca vt ch vi mm bnh, tuy nhin, cc k thut ny cung cp t thng tin v tnh trng nhim bnh ca vt ch hoc ca c n thy sn nui.

Ti liu tham kho


1. Cng Ty thuc th Y Trung ng II. 1998. Vaccine v Thuc th Y. Nh xut bn Nng Nghip. 2. Ellis, A.E. 1988. Fish vaccination. London San Diego New York Berkeley. 3. L Huy Kim. 1998. Bi ging min dch hc th y. Khoa Nng Nghip- i hc Cn Th. 4. Nguyn Ngc Lanh v ctv.1997. Min dch hc. Nh xut bn y hc. 5. ng Th Hang Oanh. 2007. Nguyn l v k thut chn an bnh thy sn. Gio trnh i hc. 81

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