Chng 1 KHI NIM V MIN DCH HC

I. M u - Sinh vt trong mi trng sng buc phi trao i tch cc vi mi trng tn ti,pht trin v sinh sn. S trao i ny l cn thit tuy nhin n cng thng xuyn mang licc nguy c c hi cho sinh vt bi v mi trng sng lun cha y nhng tc nhn gy bnh, c bit l cc tc nhn vi sinh vt. that khi cc nguy c ny, trong qu trnh tinha sinh vt hnh thnh v hon thin dn cc h thng - chc nng bo v cho chnhmnh, mt trong cc h thng l h thng min dch. Min dch hc l mn hc nghin cu nhng hot ng sinh l cng nh bnh l ca h thng min dch. - H thng min dch c th chia lm h thng min dch khng c hiu (MDKH) v h thng min dch min dch c hiu (MDH). Thut ng min dch khng c hiu cn c cc tn gi khc nh min dch t nhin, min dch bm sinh. Thut ng min dch c hiu cng c cc tn gi khc nh min dch thu c, min dch thch nghi. - Trong lch s tin ha ca h min dch, cc p ng min dch khng c hiu c hnh thnh rt sm v pht trin n lp ng vt c xng sng th cc p ng min dch c hiu mi c hnh thnh. thc hin c chc nng bo v cho c th, hai loi p ng min dch trn hp tc, b tc, khuych i v iu ha hiu qu ca p ng min dch. II. H thng min dch khng c hiu H thng min dch khng c hiu l hng ro bo v u tin ca c th chng li s xm nhp ca vi sinh vt v cc yu t l khc. Chng bao gm cc thnh phn khng chuyn bit (cn mt s chc nng khc) v chuyn bit thc hin chc nng min dch. 1. Cc c ch khng chuyn bit tham gia vo p ng MDKDH 1.1. C ch c hc S nguyn vn ca da nim mc l hng ro bo v, ngn chn s xm nhp ca vi sinh vt. Mi s tn thng nh trong bng, rch da hoc cc th thut tim truyn u lm tng nguy c nhim trng. Ngoi ra cn c cc hot ng c hc ca lp tim mao nhy ca h thng ng h hp trn nhm loi b v tng kh cc vi khun, cht thi ra ngoi. Cc phn x ho, ht hi cng cho kt qu nh vy. S lu thng v nhu ng ca ng tiu ha, ng tit niu, ng mt ngn cn s pht trin ca vi khun. 1.2. C ch ha hc

Trong cc dch tit t nhin c cha cc ha cht c tc dng dit khun khng chuyn bit. V d cc axit bo trong tuyn b, pH thp ca dch m o hn ch s tng trng ca vi khun. toan cao trong dch v c kh nng loi b hu ht cc vi khun. 1.3. C ch sinh hc Trn b mt da, ng tiu ha thng xuyn c mt cc vi khun cng sinh khng gy bnh. Cc vi khun ny ngn cn s pht trin ca cc vi khun gy bnh bng cch cnh tranh cht dinh dng, tit ra cc cht km khun nh colicin i vi vi khun ng rut. Bng 1.1. H thng p ng min dch khng c hiu (khng chuyn bit)

2. Cc c ch chuyn bit tham gia vo p ng MDKDH 2.1. Cc thnh phn dch th 2.1.1. Lysozym L enzym c trong nc mt, nc bt, nc mi, da (trong huyt thanh hm lng rt thp). Lysozym c kh nng ct cu ni phn t ca mng vi khun, do c kh nng lm ly gii mt s vi khun gram dng. Cc vi khun gram m nh c v bc ngoi l peptidoglican nn khng b ly gii trc tip. Tuy nhin khi v ngoi b thng do tc dng ca b th th lysozym s hip lc tn cng mng vi khun. 2.1.2. Cc protein vim L cc protein c to ra trong pha cp ca phn ng vim nh CRP (C-Reactive Protein, a1 antitrypsin, a1antichymotrypsin, haptoglobin). Trong CRP c sn xut sm nht v c th tng gp 100 ln so vi bnh thng. V vy trong lm sng s dng nh lng CRP huyt thanh chn on v theo di vim ni chung. 2.1.3. Interferon (IFN)

L mt nhm cc polypeptid c sn xut do cc t bo nhim vi rut tit ra ( Interferon -a v b) hay do cc t bo lympho T hot ha (Interferon-g). Cc interferon c nhiu hot tnh sinh hc nh cn tr s xm nhp v s nhn ln ca vi rut, km hm s tng sinh ca ca mt s t chc u, c kh nng hot ha cc i thc bo v tng biu l cc khng nguyn ha hp m gip cho qu trnh nhn din khng nguyn ca t bo lympho T. Cc hot tnh ny khng c tnh c hiu vi khng nguyn, c th xy ra vi tt c loi vi rut nn interferon c xp vo h thng min dch khng c hiu. 2.1.4. B th (complement, C) H thng b th bao gm khong 25 loi protein huyt thanh tham gia vo c ch khng t nhin ca c th v c p ng min dch c hiu. Trong huyt thanh b th c sn xut di dng khng hot ng v c hai con ng hot ha b th: - Con ng c in: bt u t C1q v khi ng bi phc hp khng nguyn v khng th (KN-KT), trong khng th thuc loi IgG hoc IgM. - Con ng tt: khng ph thuc vo c ch min dch c hiu (khng cn c s hin din ca khng th v khi ng t C3). Cc vi sinh vt v nhiu cht khc c th li hot ha b th theo con ng tt nh trc khun Gram (+) hay gr (-), vi rut Dengue (st xut huyt, nm, k sinh trng, v mt s cht khc nh polysaccharid vi khun (vi khun lao, ph cu). 2.2. Cc thnh phn t bo 2.2.1. Cc bch cu ht Chim a s trong bch cu mu ngoi vi (60-70%), c i sng ngn (3-4 ngy). Trong nhm ny bch cu ht trung tnh chim a s v tham gia tch cc vo phn ng vim, chng c kh nng thc bo v trong bo tng c cc ht cha nhiu enzym tiu m, enzym thy phn nh myeloperoxydase, elastase, cathepsin G, hydrolase, lactoferin, collagenase, lysozym. Cc bch cu i toan c vai tr trong khng i vi k sinh trng, phn ng d ng ti ch. Cc bch cu i kim c vai tr tng t nh t bo mast do trn b mt t bo c cc th th i vi mnh Fc ca khng th IgE (FceR). Cc t bo c hot ha khi c hin tng bt cu (lin kt cho) gia cc IgE v khng nguyn c hiu gii phng v tng hp cc hot cht trung gian nh histamin, serotonin, leucotrien. 2.2.2. Bch cu n nhn - Cc t bo ny c ngun gc t ty xng lu hnh trong h tun hon, nhng khi xm nhp vo cc t chc th bit ha thnh cc i thc bo vi cc tn gi khc nhau nh t bo Kupffer, t bo bch tuc, t bo xe ngn tay. Chng c kh nng thc bo rt mnh nn c vai tr trong dn dp cc vt l, cc t chc b ph hy, t bo gi ci. - Kh nng thc bo ca cc bch cu ht trung tnh , bch cu n nhn / thc bo ph thuc vo s lin kt gia vi sinh vt i vi cc th th b mt ca t bo nh th th i vi C3b.

- Mi khi vi sinh vt c nhp ni bo trong cc ti, tip theo l s ha mng vi cc th tiu bo. Qu trnh dit khun xy ra theo hai phng thc ph thuc oxy hoc khng ph thuc oxy to ra cc sn phm nh: O2 -, H2O2, OCl-, OH- v 1O2, lysozym, lactoferin, cathepsin G, enzym tiu m. - Ngoi ra cc t bo n nhn/i thc bo cn tham gia ch ng p ng min dch c hiu bng cch bit ha thnh cc t bo c chc nng trnh din KN cho cc t bo lympho T v tit ra cc cytokin (IL1, TNF,...) m u cho p ng min dch c hiu. 2.2.3. T bo NK (natural killer cells) C mt trong tun hon ngoi vi v c t l t 5-15% cc t bo lympho. V hnh thi th n ging t bo lympho nhng c nhng ht ln trong bo tng, t bo NK khng c cc du n (marker) b mt ca t bo lympho T v t bo lympho B. T bo NK c kh nng dit cc t bo ung th, t bo nhim vi rut m khng cn c mn cm trc v khng b gii hn bi phc hp ha hp m (khng c tnh c hiu). III. H thng min dch c hiu 1. Cc thuc tnh c bn ca MDH 1.1. Tnh c hiu p ng min dch c hiu c ngha l cc khng th hay cc t bo lympho T hiu qu ch c th gn vi khng nguyn hay chnh xc l cc quyt nh khng nguyn c tip xc trc . V d: nu ta tim chng phng bnh un vn th hot tnh min dch ch bo v cho c th chng li bnh un vn m thi. 1.2. Tnh phn bit cu trc bn thn v cu trc l Bnh thng h thng min dch khng to ra p ng min dch gy tn thng cho cc cu trc bn thn trong khi chng li c kh nng thi loi cc cu trc ngoi lai t c thkhc (khng cng thuc tnh di truyn). 1.3. Tr nh min dch p ng min dch c to ra khi tip xc vi khng nguyn ln th nht khc vi p ng min dch khi tip xc vi chnh khng nguyn ln th hai c gi l p ng th pht : p ng min dch th pht xy ra nhanh hn, mnh hn v c th chuyn th ng bng cch truyn cc t bo lympho mn cm. 2. Cc yu t dch th tham gia p ng MDH Khng th l yu t dch th tham gia vo p ng min dch c hiu v c hai dng: - Dng lu hnh t do trong dch th c kh nng kt hp vi cc khng nguyn (QKN) ho tan c hiu dn n cc thay i sinh hc.

- Dng biu l trn b mt cc t bo lympho B, c vai tr l th th khng nguyn ca t bo B cn c gi l cc globulin b mt (sIg). V bn cht, khng th l mt globulin v chng c nhng c im cu trc thc hin c chc nng min dch nn c gi l globulin min dch (immunoglobulin). Cn c vo s di chuyn trn in trng ngi ta cn gi chng vi tn chung l globulin gamma, tuy nhin thc t cn c cc lp di chuyn trn in trng thuc c khu vc globulin a v b. Cc globulin min dch c kh nng nhn dng rt nhiu quyt nh khng nguyn khc nhau. Khi kt hp vi khng nguyn c hiu, khng th c kh nng hot ha b th v khi b th c hot ha s dn n nhiu hot tnh sinh hc khc nh hin tng opsonin ha to iu kin d cho thc bo, ly gii t bo ch, trung ha cc c t ca vi khun, gy c t bo ph thuc khng th (ADCC). 3. Cc thnh phn t bo tham gia p ng MDH Cc t bo tham gia p ng min dch c hiu ch yu l cc t bo lympho c ngun gc t t bo mm trong ty xng, sau bit ha theo hai con ng khc nhau to nn hai qun th lympho c chc nng khc nhau: t bo lympho T v t bo lympho B. T bo lympho T bit ha tuyn c, chu trch nhim v p ng min dch qua trung gian t bo trong khi t bo lympho B bit ha trong ti Fabricius loi chim v trong ty xng cc ng vt cp cao khc, khi cc th th b mt t bo lympho B kt hp vi cc khng nguyn c hiu v cng vi cc tn hiu khc s lm cho t bo lympho B tng sinh ri bit ha thnh cc tng bo sn xut ra khng th c tnh c hiu tng ng. Ngoi ra thc hin c chc nng min dch c hiu cn c cc t bo khc cng tham gia vo nh t bo trnh din khng nguyn, dng bo, bch cu ht trung tnh..v..v.. 4. Cc phng thc p ng MDH C ch p ng min dch c hiu c th hin hoc bng cch to ra cc khng th hoc qua trung gian ca cc t bo lympho T hoc c hai. Phng thc p ng kiu no ty thuc bn cht v v tr xm nhp ca khng nguyn. 4.1. Min dch dch th Cc khng th c th bt ng cc vi sinh vt, ngn cn kh nng dnh ca vi sinh vt vi cc th th trn b mt ca t bo thc bo, trung ha c t, hot ha b th lm ly gii t bo ch, hin tng opsonin ha lm d cho s thc bo. Khng th c to ra bi cc tng bo do s bit ha v tng sinh dng t bo lympho B c kch thch bi cc khng nguyn. S tng tc gia khng nguyn v t bo lympho B c th xy ra bi hai c ch:ph thuc t bo lympho T hoc khng ph thuc t bo lympho T.

Hnh 1.1. C ch hot ng ca globulin min dch i vi tc nhn gy bnh 4.1.1. p ng min dch dch th khng ph thuc t bo lympho T p ng ny c quyt nh bi cu trc ca khng nguyn, c bit l cc phn t c cu trc trng lp vi cc quyt nh khng nguyn lp li, v d nhim trng Streptococcus pneumoniae. Do tnh cht cu trc nh vy s lm cho cc t bo thc bo nhn din d dng cc quyt nh khng nguyn

v to nn nhng lin kt cho, kch thch s hot ha t bo lympho B bit ha thnh tng bo sn xut khng th . Nh vy s hot ha t bo B lc khi u l khng ph thuc t bo lympho T, khng th to ra ch yu l IgM v khng c tr nh min dch v p ng min dch khng bn vng. 4.1.2. p ng min dch dch th ph thuc t bo lympho T p ng ny c vai tr rt ln trong min dch chng nhim trng c c t, v d bnh bch hu v un vn. Khi khng nguyn kt hp vi cc th th b mt t bo, s c nhp ni bo trong cc ti thc bo (phagosome). y khng nguyn s phn ct thnh cc peptid bi cc enzym t bo. Sau cc peptid s c vn chuyn n b mt t bo cng vi phn t ha hp m ch yu bc II, gi tt l MHC bc II. Phn t MHC trnh din peptid khng nguyn vi th th c hiu ca t bo lymphoTCD4+ (t boTh2) gi tt l TCR (T cellreceptor).

Hnh 1.2. Cc hnh thc p ng min dch dch th 4.2. p ng min dch qua trung gian t bo p ng min dch qua trung gian t bo c th thc hin qua hai c ch: (1) lin quan n t bo lympho TCD4+ ( t bo Th1 ) nhn din khng nguyn do phn t MHC bc II trnh din trn b mt

cc i thc bo, (2) lin quan n t bo lympho TCD8+( t bo T c tay gi tt l t bo Tc), nhn din khng nguyn do phn t MHC bc I trnh din trn cc t bo c nhn . 4.2.1. Vi sinh vt gn ti thc bo (p ng ca t bo lympho TCD4+) Khi cc vi khun lao, vi khun hi xm nhp vo c th, vi sinh vt lp tc c thc bo. Trong t bo cc vi khun pht trin cc c ch ngn cn s ph hy ca i thc bo v d sn xut fibronectin, cc enzym kh con ng dit khun cn oxy, ngn cn ha mng vi cc th tiu bo. Cc vi khun nhn ln trong cc ti ni bo v sn xut cc peptid , cc peptid s c vn chuyn n mng v c phn t MHC bc II trnh din vi t bo Th1. T bo Th1 sn xut IL-2, IFN-g, TNF (tumour necrosis factor) tc ng tr li i thc bo, ring IFN-g v TNF-a hip ng tc ng trn hai con ng dit khun ca i thc bo (ph thuc oxy v khng ph thuc oxy). TNF-a c vai tr to u ht, yu t ha hng ng cc bch cu v bc l cc yu t dnh trn b mt cc t bo ni mc gip cc bch cu xuyn mach.

Hnh 1.3. p ng min dch c hiu i vi mycobacterium 4.2.2. Khng nguyn vi sinh vt t do trong bo tng (p ng ca t bo TCD8+)

Ph bin nht l cc khng nguyn vi rut, mc du mt s vi khun nh Listeria monocytogenes c th thot khi cc ti ni bo vo bo tng. Cc vi rut vo t bo bng cch gn vo cc th th c hiu, v d th th CD21 i vi virut Epstein- Barr, th th CD4 i vi phn t gp120 ca HIV,... V tr phn b cc th th l mt trong cc yu t quyt nh i tnh t chc ca vi sinh vt. V d : cc vi rut bnh di gn vi th th acetylcholin c cc tip hp thn kinh, do c kh nng truyn mm bnh n thn kinh trung ng. Mt khi vo t bo , cc virut sao chp v dch m, cc protein ca vi rut vo bo tng v vn chuyn n h li ni m th , sau chng c vn chuyn cng phn t MHC bc I n mng t bo trong nhng ci ti. Phc hp peptid KN-MHC c nhn din bi cc th th c hiu vi khng nguyn c trn t bo lympho TCD8+ (Tc), nhng t bo ny c kh nng tiu dit t bo ch bng cc enzym t t bo lympho Tc vo t bo ch v gy cht t bo (apoptosis). Ngoi ra cn c c ch th hai thng qua cc cytokin TNF-a, IFN-g do t bo lympho Tc tit ra s iu bin s tng hp protein t boch gy cht t bo.

Hnh 1.4. p ng min dch c hiu i vi cc vi rt IV. ng dng gy min dch phng nga nhim trng Ngn nga bnh bng c ch min dch chng t s hiu bit v bnh nhim trnghoc kh nng min dch ca lch s loi ngi, v d dng vy u ma ngi nhm ngn nga bnh u ma c nhc n t 590 nm trc cng nguyn ti Trung Quc. Ngy ra i ca ngnh min dch hc nh du bi s thnh cng ca Edward Jenner trong chng nga u ma (1798) v gn mt th k sau, ngi ta hiu bit v vn chng nga nh nhng thnh cng ca L. Pasteur. Thi k ng ghi nh cho vic gy min dch ngi l nm 1885. Cu b Joseph Meister c tim vc xin chng bnh ch di ln u tin. 1. Min dch ch ng Min dch ch ng t cn bn trn c ch min dch tng ng vi s khng vi tc nhn vi sinh vt, c th thc hin c m khng c nguy c gy nhim trng cho vt ch. Mc p ng c c ph thuc vo min dch t nhin i vi bnh. V d cc khng th lu hnh trong mu trc tip i vi ph cu khun s ngn cn kh nng nhim bnh nng do chng lm cho vi khun nhy cm hn vi cc c ch thc bo. Kch thch p ng min dch c th thc hin vi polysacarid vch t bo vi khun m khng cn gy nhim vi ph cu khun thc s. Khi c gy mn cm vi khng nguyn, c th s khi ng mt lot p ng mc t bo v dch th, in hnh vi nhng tnh cht: c hiu, a dng, hiu ng phn t vc tr nh min dch 2. Min dch th ng Min dch th ng do s dng khng th c hiu. Thc t thng dng iu tr cc bnh gy ra bi c t nh un vn, khng th chng nc c ca rn. Min dch th ng thng ngn do khng th b ging ho trong khi p ng min dch ch ng khng c to ra, khng c tr nh min dch nn vt ch khng c bo v trong ln nhim sau. Min dch th ng xy ra thi k s sinh do khng th thuc lp IgG ca m truyn qua nhau thai cung cp tm thi kh nng bo v i vi nhim trng trong thi k u sau sinh. Mt khi khng th ca m ging ho th a tr s nhy cm nhim trng tr khi n pht trin c p ng min dch ch ng. Min dch th ng s dng globulin min dch ngi, huyt thanh ng vt hoc huyt tng v cc ch phm ca chng. Cn quan tm n cc phn ng phn v, bnh huyt thanh, nhim trng km theo nh nhim vi rut vim gan B..v..v.. 3. Nguyn tc khng nguyn ca mt s loi vc xin 3.1. Vc xin vi rut v vi khun bt hot hoc gim c lc Cc vc xin vi khun gim c lc nh lao, cc chng v hi Salmonnella typhi, Vibrio cholerae, Bordetella pertussis. Vc xin ny thng c hiu qu hn ch v thi gian min dch ngn. Cc vc xin vi rut gim c lc c v hiu qu hn, ng.i ta chit xut vi rut gim hot t mi trng nui cy

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chuyn t bo nhiu ln nh bi lit, si, st vng. Cc vcxin vi rut bt hot nh cm, ch di v vim no Nht bn B. Cc vc xin vi rut thng cho p ng min dch c hiu lu di, c th cho tr c kh nng bo v sut i . 3.2. Vc xin tinh khit S dng khng nguyn tinh khit ngn nga bnh gy ra do c t vi khun. V d gii c t (toxoide) v hi m khng lm mt tnh khng nguyn, dng trong vacxin bch hu v un vn. S dng khng nguyn polysacarid ca ph cu khun, tuy nhin polysacarid khng kch thch to ra cc t bo c tr nh min dch. Vc xin vim gan vi rut B s dng cc peptid khng nguyn v bng phng php ti t hp gen bng cng ngh sinh hc. 3.3. Vc xin tng hp Da trn s tng hp nhng ng phn (polymer) chui thng hoc nhnh (3-10 axit amin) da trn cu trc bit ca khng nguyn vi sinh vt. Tuy nhin bn thn peptid tng hp thng sinh min dch yu do phi gn vi protein kch thch p ng min dch . 3.4. Vc xin vec t vi rut sng Ngi ta a gen m ho khng nguyn vi rut gy bnh vo c th vt ch thng qua mt vi rut khc lnh tnh. Nh vy vi rut c s dng nh ngun khng nguyn trong c nhn . Tim vc xin vi rut ny vo trong nhiu loi vt gy c p ng min dch dch th ln t bo i vi khng nguyn do gen l sn xut, tuy nhin cho n nay vn cha c th nghim ngi bi v s an ton nhng trin vng ca n th khng cn bn ci.

Chng 2 T CHC V T BO CA H MIN DCH

I. T chc lympho T chc lympho gm c cc t bo lympho, t bo biu m v cc t bo m c phn b vo mt t chc c lp c nang bao bc hoc c phn b di dng mt t chc lympho lan ta khng c nang bao bc. Cc t chc lympho cha cc t bo lympho cc giai on pht trin khc nhau c phn loi thnh: - T chc lympho s cp (trung ng): gm tuyn c, ti Fabricius ( loi lng v) hoc ty xng ( ng vt c v). - T chc lympho th cp (ngoi vi): gm lch, hch bch huyt v t chc lympho lin kt vi nim mc. 1. T chc lympho s cp T chc lympho s cp l ni m qu trnh bit ha ca cc t bo lympho khng cn s kch thch ca khng nguyn.

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Tt c cc t bo ca h min dch u c sinh ra trong ty xng t cc t bo mm (stem cells). Mt qun th cc t bo mm tin thn ca t bo lympho T ( pre -T cells) s ri ty theo ng mu n mt t chc c hai thy di c, l Tuyn c, ti y chng tip tc bit ha thnh cc t bo lympho T trng thnh (mature T cells). Mt qun th cc t bo mm khc tin thn ca t bo lympho B (pre-B cells) s i n ti Fabricius hay tip tc li ty xng bit ha thnh cc t bo lympho B trng thnh (mature B cells). Nh vy, tuyn c v ti Fabricius (hoc ty xng) l nhng t chc lympho s cp m cc t bo lym pho n c tr u tin v khi ri khi ni y, chng thu c nhng yu t di truyn quan trng cho php chng nhn bit c cc khng nguyn t thn dung np v nhn bit cc khng nguyn l loi b. C th ni t chc lympho s cp nh mt loi trng hc dnh ring hun luyn cc t bo lympho. Chnh ti ty xng m cc t bo lympho B c c cc Ig (Immunoglobulin) u tin v cng chnh ti tuyn c m cc t bo lympho T c c cc cht tip nhn khng nguyn (T cell receptor,TCR) u tin xut hin trn mng t bo. 1.1. Tuyn c (Thymus) 1.1.1. Cu trc Trong qu trnh pht trin ca c th, tuyn c l t chc lympho c hnh thnh sm nht vo khong tun l th 6 ca thai k, t t l ln nht vo thi s sinh v bt u thoi trin vo tui dy th nhng khng bao gi bin mt hon ton. V cu trc th tuyn c ng vt c v l mt t chc lympho biu m, nm trong lng ngc pha trc tim v cc mch mu ln, phn lm 2 thy, mi thy li phn lm nhiu tiu thy ngn cch vi nhau bi mt b t chc lin kt. V phng din m hc, tuyn c c chia thnh 2 vng: vng v v vng ty. Cc t bo biu m ca tuyn ni vi nhau thnh mt mng li, tha tht vng v nhng li dy c vng ty m c l chng c chc nng trong qu trnh bit ha ca cc t bo lympho. Ngoi ra trn mng li t bo biu m cn c cc t bo dng bch tuc (interdigitating cells) mang nhiu phn t MHCII m ngi ta cho rng chng cn thit cho cc t bo lympho trong vic hc nhn bit khng nguyn t thn. Trong vng ty cng thy cc tiu th Hassal, chc nng cha c bit, c th l ni cha cc t bo biu m b thoi ha. Cc t bo lympho khi cha ri khi tuyn c th c gi chung l cc t bo tuyn c (thymocytes) c s phn b kh khc bit. vng v, cc t bo tuyn c phn b dy c vi rt nhiu hnh nh phn chia (c lng s phn chia cao gp 7 ln hn cc ni khc). vng ty, t bo tuyn c tha tht hn v c kch thc nh, y chnh l cc t bo lympho T trng thnh chun b ri tuyn c i vo tun hon n c tr ti cc t chc lympho th cp.

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1.1.2. Chc nng Th nghim ca Miller ct b tuyn c chut nht s sinh nhn thy chut con c cc biu hin nh mt kh nng thi loi mnh ghp, gim r rt p ng min dch to khng th i vi mt s ln khng nguyn (khng nguyn ph thuc tuyn c), gim s lng t bo lympho T trong mu v trong cc t chc lympho th cp. Sau khi nui t 2 n 3 thng, chut khng ln, lng x, a chy ko di,... gi l mc bnh ci (wasting disease). Nh vy r rng tuyn c l trng hc o to v hun luyn cc t bo tuyn c non tr tr thnh cc t bo lympho T trng thnh m nhim nhiu chc nng chuyn bit, c bit l chng chu trch nhim trong p ng min dch qua trung gian t bo (cell mediated immunity) v iu ha p ng min dch. 1.2. Ti Fabricius (Bursa Fabricius) 1.2.1. Cu trc Ti Fabricius ch thy loi lng v, y cng l mt t chc dng lympho biu m c hnh thnh sm nhng cng thoi trin sm. Khi u, n l mt ci ti lng hp, thng vi nhp (cloaca), nim mc c v thanh mc tip lin vi cc thnh phn tng ng ca ng tiu ha nhng cc lin bo y khng c cc t bo tit nhy. Ti ny sinh ra cc chi l cc nang lympho biu m cng chia lm 2 vng: + Vng ty gm cc lin bo l cc t bo li, i thc bo v cc t bo lympho non ang phn chia. + Vng v, ngoi lin bo l cc t bo lympho B trng thnh v mt s tng bo (plasmocyte). ng vt c v, khng c ti Fabricius nhng thay vo l c nhng m t bo to mu trong gan phi hoc trong ty xng ca ng vt trng thnh, chnh cc t no ny s pht trin thnh cc t bo lympho B. Vy ty xng l t chc tng ng vi ti Fabricius v mt chc nng. 1.2.2. Chc nng Nu ct b ti Fabricius phi g trc ngy th 17 th thy: g khng c kh nng p ng to khng th, trong mu khng c cc globulin min dch, vng c tr dnh cho t bo lympho B trong cc t chc lympho th cp tha tht, khng c cc nang lympho v khng thy xut hin cc trung tm mm. Nh vy r rng ti Fabricius v ty xng l ni bit ha v trng thnh ca dng t bo lympho B l cc t bo c tim nng sinh khng th, chu trch nhim chnh trong p ng min dch dch th. 2. T chc lympho th cp Lch, hch bch huyt, t chc lympho nim mc,... cu thnh t chc lympho th cp. Ni sinh sng ca cc t bo lympho trng thnh n t cc t chc lympho s cp v l ni gp g vi cc i thc bo. Chnh trong nhng t chc lympho th cp ny m cc p ng min dch c thc hin. 2.1. Hch bch huyt

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Hch bch huyt ngi thng c hnh ht u, pha lm gi l rn hch ni cc mch mu n v i. Nu b dc mt hch bch huyt ta thy hch c bao bc bi mt bao collagen c cc nhnh n su vo nhu m hch v c th phn bit lm 3 vng: - Vng v: L vng t bo lympho B cn gi l vng khng ph thuc tuyn c. y cc t bo lympho b tr st nhau to ra cc nang lympho s cp. Khi c khng nguyn kch thch, cc nang s cp pht trin rng xut hin cc nang th cp. - Vng cn v: L vng t bo lympho T cn gi l vng ph thuc tuyn c. Nu mt ni no trn da b khng nguyn xm nhp th s c s tng sinh ca cc t bo lympho T ti vng cn v ny, ngc li khi ct b tuyn c hoc khi tuyn c b teo th vng cn v cha rt t t bo. - Vng ty: C nhiu xoang bch mch, t chc lin kt v mt t lympho xm nhp t vng cn v vo. Hch bch huyt l mt t chc lympho th cp, c trch nhim thanh lc khng nguyn khi chng xm nhp vo c th bng ng bch huyt (ch yu qua da). Do vy, hch thng nm ti ni phn nhnh ca cc b mch bch huyt. 2.2. Lch Lch khng ch l mt t chc lympho th cp m cn l c quan to mu trong thi k bo thai v c lc trng thnh mt s ng vt . Lch cng c bao bc bi mt bao collagen v khi ct dc thy 2 vng: - Vng ty : L ni ph hy cc hng cu gi - Vng ty trng: L ni tp trung cc t bo lympho gm 2 vng nh: + Vng tp trung t bo lympho T l vng chung quanh tiu ng mch lch, cn gi la vng ph thuc tuyn c ca lch. + Vng tp trung t bo lympho B to thnh cc nang lympho l vng cng trong ty trng nhng khng bao quanh ng mch, cn gi l vng khng ph thuc tuyn c ca lch. Khi c khng nguyn kch thch, cc nang lympho s cp s pht trin thnh cc nang th cp cha cc t bo lympho di dng hot ng tng t nh cc nang th cp trong hch bch huyt. Ngoi chc nng ca lch i vi h to mu, v phng din min dch hc c th xem lch nh mt mng lc ln x l cc khng nguyn xm nhp c th bng ng mu. 2.3. Cc t chc lympho lin kt vi nim mc (MALT) Cc t chc lympho th cp khng c nang bao bc cn gi l t chc lympho lin kt vi nim mc (MALT = Mucosa-associated lymphoid tissu) v n nm di vng nim mc ca nhiu c quan v t chc khc nhau. Mt trong nhng t chc lympho lin kt nim mc quan trng l hch hnh nhn nm quanh vng hu (gm tuyn hnh nhn khu ci, li, vm v hu) hnh thnh vng Waldeyer.

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y l ni cha nhiu t chc lympho di dng cc nang lympho th cp. ng tiu ha, t chc lympho lin kt nim mc chia lm 2 loi. loi tp trung v loi phn tn: + Cc mng Peyer l ni tp trung cc t bo lympho to thnh cc nang vi s lng t 200 n 300 mng, cc mng ny nm v pha b t do ca rut. + Cc t bo lympho loi phn tn th ri dc theo nim mc ng tiu ha k c rut tha. Dc theo nim mc ph qun v nim mc ng tit niu sinh dc cng c nhiu t chc lympho nim mc tng t. Thnh phn t bo t chc lympho nim mc gm c t bo lympho B v T nhng cc t bo lympho B sn xut khng th IgA tit l chim a s (IgA tit l mt khng th c kh nng i qua lp nim mc v gip nim mc chng vi s xm nhp ca cc vi sinh vt). Vy c th ni rng t chc lympho nim mc c vai tr rt quan trng trong cc p ng min dch ti ch.

S 2.1. Lin h gia t chc v t bo lympho 3. Lin h gia t bo v t chc lympho 3.1. S di chuyn ca t bo lympho Cc t bo non dng lympho xut pht t t bo mm ca ty xng s theo ng mu n t chc lympho s cp tng ng, ti y chng c hun luyn thnh cc t bo lympho B hoc T trng thnh nhng cha tip xc vi khng nguyn nn gi l cc t bo cn trinh (virgin cells). Cc t bo li c chuyn vn bng ng mu n cc t chc lympho th cp c hoc khng c nang bao bc m y chng c thi gian sng t vi tun cho n vi nm. Mi ngy c khong 109 t bo lympho ri khi cc t chc lympho s cp n t chc lympho th cp v s vo ng v tr nht nh dnh cho chng thc hin chc nng ca mnh khi c khng nguyn xm nhp. 3.2. S ti tun hon ca cc t bo lympho Cc t bo lympho sau khi n cc t chc lympho s cp khng c nh ti ch m lun lun c s ti tun hon. Mt s t bo sau khi n lch, bch huyt, t chc lympho nim mc,... thc hin chc nng ca n ri cht i. Mt s khc th li tip tc ra i bng ng bch huyt, tr li mu ri quay

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tr li hch hoc lch,... v c nh th to thnh mt nhm cc t bo tun hon nhiu nm trong c th. Mi gi c khong 1-2% tng lng t bo lympho lu thng trn cc con ng ni trn, s lu thng ny l cn thit gip cho t bo tr v ng ni c ng ca mnh v gip cho chng c iu kin tip xc vi cc khng nguyn xm nhp. V mi t bo lympho ch c hiu cho mt loi khng nguyn cho nn nu khng c s lu thng lin tc ny th cc lymphos kh tm gp c khng nguyn tng ng mt cch kp thi.

S 2.2. Nhim v ca cc t bo lympho trong t chc lympho II. Cc t bo tham gia p ng min dch 1. Ngun gc

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Hnh 2.1. S bit ho cc dng t bo t t bo mm Tt c cc t bo ca h min dch u pht xut t cc t bo mm vn nng ti ty xng. Cc t bo ny bit ha thnh 2 dng t bo chnh: - Dng lympho: Cc t bo mm chung ca dng lympho bit ha tip thnh cc t bo tin B hoc tin T, theo th t cc tin t bo ny s ri ty xng n t chc lympho s cp. Ngoi ra cn c mt qun th lympho th 3 gi l lympho nuls c nhng tnh cht rt khc vi 2 qun th lympho trn m ngun gc cha c xc nh mt cch r rng. - Dng ty: Cc t bo mm chung ca dng ty s bit ha tip thnh cc bch cu n nhn, cc bch cu ht v tiu cu ... 2. Cc t bo dng lympho 2.1. T bo lympho B 2.1.1. Bit ha Cc t bo mm dng lympho bit ha thnh cc t bo tin B khi u bng s tng hp chui nng muy) trong bo tng nhng cha c chui nh. Tip theo l s tng hpchui nh m phn ln ( thuc typ kapa), chui nng v chui nh ghp li thnh phn t Ig trong bo tng gi l CIg ( (cytoplasma immunoglobulin). Cc CIg ca t bo tin B sau c biu l ln b mt t bo gi l SIg (surface immunoglobulin). cc t bo lympho B trng thnh u c SIg thuc lp IgM hoc phi hp gia lp IgM v IgD

Hnh 2.2 S bit ho ca t bo lympho B 2.1.2. Du n Cc t bo lympho B chim khong 5-15% t bo lympho ca mu. Trong qu trnh bit ha, chng biu l mt s du n b mt (surface marker), du n c tnh cht kinh in l SIg m a s l IgM

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n phn c u k nc ca chui nng gip cho vic neo phn t vo mng t bo. y l th th ch yu m t bo lympho B dng nhn bit khng nguyn. Ngoi ra cc t bo lympho B cn c cc du n khc nh MHCII, cc th th dnh cho b th (CR2, CD21), cng nh cc du n khc: CD19, CD20, CD22,... 2.1.3. Hot ha Khi mt khng nguyn i vo c th chng s chm trn vi mt lng khng l cc t bo lympho B c mang cc khng th b mt khc nhau. Mi mt khng th c v tr nhn bit khng nguyn v khng nguyn th ch kt hp vi khng th no ph hp vi n nht. Cc t bo lympho B khi kt hp c vi khng nguyn s nhn c mt tn hiu khi ng tip tc bit ha thnh tng bo, l cc t bo c tim nng sinh khng th. Do cc t bo lympho B c chng trnh ha ch sn xut mt loi khng th c hiu no m thi cho nn cc khng th va mi c tng hp bi tng bo s hon ton tng ng vi khng th gc ban u. Nh vy khng nguyn chn khng th nhn bit mnh mt cch c hiu qu. S hot ha t bo lympho B cn ph thuc vo bn cht ca khng nguyn: - Khng nguyn khng ph thuc tuyn c typ I nng cao c th hot ha trc tip mt t l ng k lympho B. - Khng nguyn khng ph thuc tuyn c typ II c cu trc lp li khng b ging ha c th to ra lin kt cho (cross linking) hot ha t bo lympho B. - Khng nguyn ph thuc tuyn c th s hot ha t bo lympho B cn thit phi c s hp tc ca t bo lympho T h tr (Th) thng qua cc cytokin.

Hnh 2. 3. Hot ho theo c ch chn lc khng nguyn ca lympho B

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2.2. T bo lympho T 2.2.1. Bit ha Hnh 2.4. Bit ho ca t bo lympho T 2.2.2. Du n Cc t bo lympho T chim khong 65% t bo lympho ca mu. Cc t bo lympho T trng thnh u c kh nng nhn bit khng nguyn nh vo TCR (T cells receptor), ti th th nhn bit khng nguyn ny c s phi hp vi phn t CD3 cho php hot ha t bo saukhi nhn bit khng nguyn. Nhng qun th t bo lympho T khc nhau cng mang nhng du n c hiu ring. V d: t bo lympho Th c CD4, Tc c CD8,... Cn c vo nhng du n ny m ngi ta c th nhn din c chng nh cc khng th n clon tng ng . 2.2.3. Hot ha

Hnh 2.5 . Hot ho t bo lympho T Nh vy, s hot ha t bo lympho T ngh (TG) cn hi 2 tn hiu: Tn hiu 1: Gm 1 phc hp bc 3 TCR+KN( x l) + MHC tng ng . Tn hiu 2 : L Interleukin 1 (IL1) do t bo trnh din khng nguyn tit ra. 2.3. T bo lympho nuls Ngoi cc t bo lympho ni trn, cn c mt s t bo lympho khc chim khong 15- 25% t bo lympho ca mu v c vai tr quan trng trong phn ng gy c t bo. 2.3.1.T bo NK v LAK: c kh nng git cht cc t bo ung th gi l cc t bo dit t nhin hay t bo NK (Natural killer cells); t bo dit hot ha bi lymphokin (LAK=Lymphokin activated killer cells).

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2.3.2. T bo K: c kh nng git cc t bo c bao ph bi cc khng th gi l cc t bo dit (killer cells) hay t bo gy c qua trung gian khng th (ADCC: Antibody dependent cellular cytotoxic cells). T bo lympho nuls c vai tr ti quan trng trong vic bo v khng c hiu chng vi rut v chng cc t bo ung th m khng cn phi c cc th th nhn bit khng nguyn, cng khng b gii hn bi MHC nh cc t bo lympho Tc. 3. Cc t bo dng bch cu n nhn 3.1. Cc i thc bo ca h li ni m Cc tin t bo n nhn sinh ra cc t bo n nhn, t bo ny mn ng mu di tr n nhiu c quan v t chc khc nhau v ti , chng bit ha thnh cc i thc bo ca t chc ni chng c ng. Cc i thc bo ny hnh thnh nn mng li gi chung l h li ni m (RES = reticuloendothelial system) c tc dng bo v c th loi b cc khng nguyn khi chng xm nhp vo mu v t chc. Ty theo t chc c ng v ty theo tng giai on bit ha m cc i thc bo ny c nhng tn gi khc nhau.

S 2.3. Bit ha ca i thc bo Ngoi chc nng thc bo, m bo v tiu ha cc vt l, cc i thc bo ny cn tit mt s cht nh: cc enzym tiu protein, cc sn phm tham gia vo s khng nh C2 , C3 , C4, C5, interferon, interleukin 1, ... 3.2. Cc i thc bo trnh din khng nguyn Ngoi chc nng bo v s cp trn, mt loi t bo thuc dng bch cu n nhn cn ng vai tr cha kha trong vic khi ng cc p ng min dch c hiu. C th, chng hp ph khng nguyn, ct khng nguyn thnh nhng mnh nh trong bo tng ri trnh din n ln mng t bo cng vi MHC cc t bo lympho bo nhn din v hot ha lm thnh pha m mn cho p ng min dch c hiu. Cc t bo trnh din khng nguyn thy nhiu da, hch bch huyt, lch v tuyn c. T bo c trng cho loi ny l cc t bo Langerhans da lm nhim v bt gi, x l khng nguyn ri di

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chuyn vo vng v ca hch lympho gn nht trnh din khng nguyn cho cc t bo lympho T ti . Cc t bo dng bch tuc (interdigitating cell) gp nhng nang th cp ca t bo lympho B trong hch v lch cng l cc t bo trnh din khng nguyn. Nhng t bo trn cng thy tp trung nhiu ti vng ty ca tuyn c v bn thn chng c mang rt nhiu khng nguyn t thn. 4. Cc t bo dng bch cu ht c sn xut trong ty xng di dng nguyn ty bo vi tc khong 8 triu t bo mi pht v c i sng ngn ngi ch 2-3 ngy, chim 60-70% tng s bch cu trong mu. 4.1. Cc bch cu ht trung tnh Chim trn 90% bch cu ht trong mu. Trn b mt ca n c cc th th dnh cho mnh FC ca IgG v th th dnh cho C3 , nh cc receptor ny m bch cu ht trung tnh ( v i thc bo) d bm bt gi cc vi khun c gn vi khng th v b th (hin tng opsonin ha) do kh nng thc bo ca chng c nng cao v c hiu qu hn. Di nh hng ca cc yu t ha hng ng (chemotaxis factor), bch cu ht trung tnh b thu ht n v lm nhim v tiu thc bo, gii phng men tiu protid ng thi tit cc yu t hp dn thm cc bch cu khc lm cho phn ng vim ti ch c tng cng. Do vy bch cu ht trung tnh c vai tr rt quan trng trong phn ng vim cp do vi khun gy ra. Ngoi ra, bch cu trung tnh cn hin din ti cc vim khng do vi khun m do cc phc hp min dch. Nhiu bnh l do phc hp min dch xy ra bi s t tp qu mc ca bch cu ht trung tnh. Bch cu ht trung tnh cng p ng vi cc lymphokin nh yu t c ch di tn bch cu (MIF: Migration inhibition factor), yu t c ch s bm dnh bch cu,...cc yu t ny do cc lympho bo tit ra mc ch km gi bch cu ti ch xy ra phn ng vim. 4.2. Bch cu ht i kim v t bo mast Bch cu ht i kim tun hon trong mu ngoi vi vi s lng rt nh di 0,2% cn t bo mast th ch thy trong cc t chc m khng thy trong mu ngoi vi. Hai loi t bo ny c im ging nhau l trn b mt ca chng u c th th dnh cho mnh Fc ca IgE v trong bo tng ca chng c nhiu ht cha cc cht hot mch nh: histamin, serotonin, cht phn ng chm trong phn v (SRSA: Slow reactive substance of anaphylaxis),... Khi c d nguyn bm ln cc v tr kt hp khng nguyn ca IgE s kch thch gy hin tng v ht gii phng cc cht hot mch. Cc cht ny tc ng ln cc t bo c trn gy co tht v tc ng ln thnh mch mu lm tng tnh thm ... v l nguyn nhn ca cc tnh trng d ng, phn v. 4.3. Bch cu ht i toanCh c rt t trong mu ngoi vi khong 2-5% v cng nh bch cu ht trung tnh chng c kh nng tiu thc bo v tiu dit vi sinh vt nhng chc nng chnh ca chng l tp trung ti ni xy ra phn ng d ng.

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Trong bo tng ca bch cu ht i toan c nhiu ht cha cc men v cc cht c tc dng trung ha bt cc sn phm c gii phng ra do hin tng v ht t bo mast v bch cu i kim. Nh vy, bch cu ht i toan c tc dng iu ha s hot ha ca t bo mast v bch cu i kim. 5. Tiu cu Ngoi vai tr quan trng trong phn ng cm mu, tiu cu cn tham gia vo p ng min dch nht l trong phn ng vim. Tiu cu c hnh thnh t cc tiu cu m trong ty xng v trn b mt c cc th th dnh cho Fc ca IgG v IgE, cc th th dnh cho b th. Khi lp t bo ni m ca mch mu no b tn thng hoc khi c yu t hot ha tiu cu (PAF= Platelet activating factor) th ngay lp tc tiu cu s tp trung n v ngng vn tiu cu ng thi gii phng cc yu t lm tng tnh thm thnh mch, hot ha b th thu ht bch cu n ni tn thng to phn ng chng hu hiu hn.

Chng 3 KHNG TH V B TH
I. nh ngha khng th Khng th dch th bn cht l mt loi glycoprotein do khng nguyn kch thch to ra v c th kt hp mt cch c hiu vi khng nguyn y. Khng th cn c gi l globulin min dch (immunoglobulin), vit tt l lg, v khi chy in di min dch th khng th nm vng globulin.

Hnh 3.1. in di protit huyt tng

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II. S to thnh khng th dch th 1. Mi quan h khng nguyn chn lc mt lympho B to khng th Hin nay ngi ta tha nhn rng c th c sn khun to khng th trc khi tip xc vi khng nguyn, khun ny chnh l khng th b mt c sn lympho B. Mi t bo lympho B c chng trnh ha sn xut mt loi khng th khc nhau. Khi tip xc vi khng nguyn, t bo lympho B no c khng th b mt khi vi cu trc ca quyt nh khng nguyn th mi chuyn thnh tng bo sn xut khng th dch th, khng th dch th ny c cu trc ging nh khng th b mt ca t bo lympho B . Da trn cu trc, loi v trnh t cc axit amin ca cc quyt nh khng nguyn, c lng c khong 107-109 loi quyt nh khng nguyn khc nhau trong thin nhin. Nh vy cng c khong 107-109 loi t bo lympho B tng ng trong c th. 2. Mi t bo lympho B khi tip xc vi quyt nh khng nguyn th tng sinh v bit ha thnh nhiu tng bo Sau khi tip xc ln u vi khng nguyn, t bo lympho B tng sinh nhiu t ri chuyn thnh tng bo sn xut khng th. Khong vi ngy sau khi tip xc vi khng nguyn, khng th xut hin trong mu v t nng cao nht vo khong tun l th hai. l p ng tin pht. Do vy trn lm sng cc xt nghim tm khng th c hiu thng c thc hin vo khong sau mt tun khi pht bnh, lc m hiu gi khng th cao c th cho kt qu dng tnh.

Hnh 3.2. Mi quyt nh khng nguyn chn lc mt t bo lympho B to khng th

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Hnh 3.3. T bo lympho B tng sinh v bit ha thnh nhiu tng bo 3. p ng nh Trong qu trnh tng sinh v bit ha ca lympho B, mt s t bo con chu ca chng khng chuyn thnh tng bo, vn dng lympho B gi l lympho B nh. Cc lympho B nh ny c i sng di, khi gp li khng nguyn ln th hai s sn xut khng th nhanh v nhiu hn. l p ng th pht. p ng th pht l mt c s tim chng nhc li: trong a s cc trng hp sau p ng tin pht nng khng th gim dn theo thi gian, s tim chng nhc li c tc dng to ra mt p ng min dch mnh v ko di hn. 4. Khng th n dng Khng th n dng l khng th c to ra t mt dng tng bo bit ha t lympho B ban u sau khi c kch thch bi mt quyt nh khng nguyn. Khng th n dng do quyt nh khng nguyn no kch thch th ch kt hp c hiu vi quyt nh khng nguyn y m thi. Do c th tip xc vi nhiu loi khng nguyn, mi khng nguyn li c nhiu quyt nh khng nguyn khc nhau, nn khng th trong huyt thanh bao gm nhiu loi khng th n dng khc nhau.

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Hnh 3.4. p ng tin pht v th pht Cc kit test chn on min dch hin nay da vo cc khng th n dng nn c nhy cm v tnh c hiu cao. Phng php to khng th n dng l mt tin b quan trng trong min dch hc, c ng dng trong nhiu lnh vc nghin cu khoa hc v chn on lm sng (xem phn tham kho: Phng php to khng th n dng). III. Cu trc ca khng th dch th 1. Cu trc tng qut Khng th l mt phn t i xng, cu to bi 2 chui nng v 2 chui nh ging nhau i mt. 1.1.. Chui nh L (light: nh) Mi chui nh l mt chui polypeptid cu to bi khong 214 axit amin, c nh s th t t u NH2 n u COOH v c chia thnh hai vng: - Vng hng nh C (constant: hng nh): nm sau, c loi v trnh t axxit amin khng thay i. - Vng thay i V (variable: thay i): nm pha trc, c loi v trnh t axit amin thay i ty theo tng loi khng th. c bit, trong vng V c mt vng m loi v trnh t axit amin rt hay thay i gi l vng siu bin. Mi loi khng th n dng c mt vng siu bin khc nhau. C hai loi chui nh khc nhau: chui kappa v chui lamda. Trong phn t khng th hai chui nh ging nhau (hai chui kappa hoc hai chui lamda). 1.2. Chui nng H (heavy: nng) Chui nng c cu to tng t chui nh: chui polypeptid gm khong 440 axit amin, c nh s th t t u NH2 n u COOH v c chia thnh ba hoc bn vng ty theo tng chui nng: cc vng C gm CH1, CH2, CH3 (v CH4), vng V v vng siu bin. Mi loi khng th n dng c mt vng siu bin khc nhau. C 5 loi chui nng khc nhau: chui gamma, chui alpha, chui muy, chui delta v chui epsilon. Trong phn t khng th hai chui nng ging nhau. 1.3. S lin kt gia cc chui Hai chui nng ni vi nhau bng cc cu ni disulfua (S - S), s cu ni disulfua thay i ty tng chui. Chui nh ni vi chui nng cng bng cc cu ni disulfua. Trn chui nng, gia CH1 v CH2 l vng bn l. Nh vng bn l ny m phn t khng th c th khp li hoc m ra 0-180 lm cho phn t khng th d dng gn vi cc quyt nh khng nguyn tng ng. 1.4. Cc mnh ca khng th Cc men tiu m nh papain, pepsin c th ct phn t khng th ra thnh cc mnh. Papain ct phn t khng th ngay trc vng bn l cho ra 2 mnh Fab v 1 mnh Fc. Pepsin ct phn t khng th sau cng bn l cho ra 1 mnh F (ab) 2 v mt mnh Fc.

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F (fragment: mnh), ab (antigen binding: gn khng nguyn), c (cristallisable: kt tinh c) 1.5. V tr kt hp khng nguyn, ha tr khng th Hai vng siu bin ca chui nng v chui nh ca phn t khng th to thnh v tr kt hp vi quyt nh khng nguyn tng ng. Mi phn t khng th nguyn vn c hai v tr kt hp, gi l ha tr hai. Mnh Fab c mt ha tr, mnh F(ab) 2 c ha tr hai. Do phn t khng th c ha tr hai, khng nguyn c nhiu quyt nh khng nguyn, nn phn ng gia khng nguyn v khng th c th to thnh mng li Marrack. 1.6. Cc lp khng th - Tn ca cc lp: Khng th dch th c chia thnh nm lp: IgG, IgA, IgM, IgD v IgE. Tn ca lp da theo tn ca chui nng. Bng 3.1. Tn cc chui nng v chui nh ca cc lp Ig

Cc lp cn c chia thnh di lp: IgG: IgG1, IgG2, IgG3, IgG4 trong cc chui nng ln lt l gamma 1, gamma 2, gamma 3, gamma 4. IgA: IgA1, IgA2 ty theo chui nng l alpha 1 v alpha 2. - c im v cu trc ca cc lp: IgG dng monome n phn t, trng lng l 150000 (chui nh kappa hoc lamda l 25000, chui nng gamma l 50000). IgA c 2 dng: dng monome n phn t, trng lng l 160000, dng dime nh phn thng c trong dch tit gi l IgA tit (slgA, secretoire: tit). Igm thng dng ng phn trng lng l 900000. IgD dng n phn t trng lng 175000. IgE dng n phn t trng lng l 190000. Cc immunoglobulin khc nhau v chui nng: v t l % gluxit v c bit l khc nhau on Fc lin quan n chc nng ca tng immunoglobulin. 2. Cu trc chi tit

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Ni dung phn ny ch cp ti cc CDR (CDR: Complementarity Determining Region) ca vng siu bin. Vng siu bin ca chui nng cng nh chui nh c cu trc khng gian c bit, gip cho khng th kt hp c hiu vi khng nguyn. Ti , mi chui polypeptit un khc thnh nhng vng cung tham gia vo v tr kt hp vi quyt nh khng nguyn gi l cc CDR. Trn chui nh, CDR 1 gm cc axit amin c s th t t 28 n 31, CDR 2 t 55 n 65, CDR 3 t 90 n 95. Trn chui nng, CDR 1 gm cc axit amin c s th t t 30 - 33, CDR 2 t 51 n 68, CDR 3 t 102 n 107. Ba CDR ca chui nh cng vi ba CDR ca chui nng to thnh mt cu trc khng gian nh l mt kha, m cha kha chnh l quyt nh khng nguyn. Vng lm gia cc CDR gi l paratop, quyt nh khng nguyn gi l epitop.

Hnh 3. 5. Chui nh ca immunoglobulin

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3. Tnh cht ca cc lp khng th Bng 3.2. Tnh cht ca cc lp khng th

IV. c im v chc nng ca khng th 1. c im ca khng th 1.1. Tnh khng th

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Tnh khng th l kh nng kt hp c hiu vi khng nguyn tng ng, c hiu c ngha l khng th do khng nguyn no kch thch to ra th ch kt hp vi khng nguyn y m thi. Tnh khng th l c im quan trng nht ca khng th. Tuy nhin i khi xy ra phn ng cho gia khng th v khng nguyn khng tng ng do khng nguyn ny c cu trc gn ging vi khng nguyn kch thch to ra n. Phn ng cho cho hnh nh dng tnh gi trong phn ng min dch. V tr gn vi khng nguyn nm on Fab, gia cc CDR ca mi cp chui nng v chui nh. Nh vy mi phn t khng th nguyn vn c hai v tr gn vi khng nguyn, gi l c ha tr hai. Khng th dng dime c ha tr 4, khng th dng pentame c ha tr 10. Nh khng th c ha tr hai tr ln m kt hp khng nguyn-khng th c th to ra c mng li Marrack. on F(ab)2 cng c ha tr hai nn c th c s dng thay th phn t khng th nguyn vn trong mt s phn ng min dch khi cn trnh nhng tc dng ring ca on Fc. 1.2. Tnh khng nguyn - Tnh khng nguyn ca phn t khng th l kh nng kch thch c th khc to ra khng th khng li chnh n. L do l phn t khng th bn cht l mt loi protit c trng lng phn t ln, tiu chun l mt khng nguyn i vi c th khc. Khng th khng li khng th c gi l anti-lg. - Phn bit 3 nhm khng nguyn trn phn t khng th: + Nhm khng nguyn isotyp: Cc quyt nh khng nguyn isotyp ging nhau mi c th trong cng mt loi v nm trn vng hng nh ca chui nng v chui nh.Cc lp di khng th IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM, IgD v IgE c cc quyt nh khng nguyn isotyp khc nhau. + Nhm khng nguyn allotyp: Cc quyt nh khng nguyn allotyp ging nhau mts c th trong cng mt loi v nm ri rc trn vng hng nh ca chui nng v chui nh. + Nhm khng nguyn idiotyp: Cc quyt nh khng nguyn idiotyp c trng cho tng c th v nm trn vng thay i ca chui nng v chui nh. Mi quyt inh khng idiotyp c gi l idiotop, tp cc idiotop gi l idiotyp. 2. Chc nng ca khng th 2.1. Chc nng do vng hng nh Fc m nhim - C nh b th: Phn t khng th thuc cc lp v di lp IgM, IgG1, IgG2, IgG3 sau khi kt hp vi khng nguyn th s tng tc gia cc on Fc ca chng lm bc l v tr c nh b th trn CH2, nh thnh phn C1q ca b th n bm vo, dn n hot ha b th theo con ng c in (xem phn B th).

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- Truyn qua rau thai: Do c im cu to ca on Fc ca phn t khng th thuc lp IgG, nht l di lp IgG1, IgG3, IgG4, khng th c th c truyn t m qua thai nhi, to p ng min dch th ng cho tr s sinh trong khong su thng u tin. - Gn trn b mt t bo: Cc phn t khng th thuc cc lp v di lp IgE, IgG1, IgG3, IgG4 c kh nng gn trn b mt cc t bo mast v bch cu i kim thng qua cc receptor i vi on Fc ca chng (FcR). Do vy khi c khng nguyn n kt hp vi\ khng th trn b mt cc t bo ny th s dn ti hai qu trnh: (1) qu trnh gii phng cc cht sinh hc c sn trong cc ht ca t bo nh histamin, serotonin; (2) qu trnh tng hp t phospholipit mng t bo to ra cc cht nh l PAF, leucotrien, prostaglandin, thromboxan gy qu mn nhanh (xem chng Ri lon min dch). - Gy hin tng opsonin ha (opsonisation): Cc i thc bo v bch cu a nhn trung tnh c receptor i vi on Fc ca cc khng th thuc lp IgG v IgM. Khi cc khng th ny kt hp vi cc khng nguyn vi khun, th cc on Fc ca chng thu ht cc FcR ca i thc bo v bch cu a nhn trung tnh, lm cho nhng t bo thc bo ny d tip cn vi khun hn. Cng theo c ch trn, cc t bo NK (natural killer: t bo git t nhin) nh c FcR i vi on Fc ca lp khng th IgG nn d tip cn v tiu dit t bo ch hn. Hin tng ny gi l hiu ng ADCC (antibody dependent cellular cytotoxicity: c t bo ph thuc khng th). 2.2. Chc nng do vng thay i V m nhim - Nhn din khng nguyn: Chc nng ny c trnh by trong phn tnh khng th. Thng qua phn ng kt hp c hiu vi khng nguyn tng ng m khng nguyn (1)trung ha khng nguyn ha tan nh t vi khun; (2) ngng kt thnh cc thnh phn hu hnh nh vi khun; (3) ngn cn vi khun bm vo mng nhy nim mc ng h hp v tiu ha (tc dng ca slgA). - Truyn tn hiu: S nhn din khng nguyn to tn hiu cho lympho B ti phn b cc khng th b mt m u cho qu trnh trnh din khng nguyn ca lympho B (xem phn Hp tc t bo). V. Khi nim v b th 1. Th nghim ca Buchner - Mu 1: Huyt thanh d c khng th khng vi khun t + Vi khun t. Kt qu: Vi khun t b ngng kt, ri b v. - Mu 2: Huyt thanh d c khng th khng vi khun t, c hm nng 56oC trong 30 pht + Vi khun t. Kt qu: Vi khun t b ngng kt, khng b v. - Nu cho thm huyt thanh bnh thng vo mu 2: Vi khun t b v. - Kt lun: Trong huyt thanh bnh thng c yu t tham gia lm v vi khun. Yu t ny mt tc dng khi b hm nng 56oC trong 30 pht. Buchner t tn yu t ny l b th v chng c vai tr b sung cho tc dng ca khng th. 2. Cc thnh phn ca b th

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- B th l nhng protein c bit, c sn trong huyt tng di dng cha hot ha, ch yu do gan sn xut. - B th gm c 9 thnh phn: C1,C2,C3,C4,C5,C6,C7,C8 v C9. Trong C1 gm 3 thnh phn khc nhau: C1q, C1r, C1s. - C khong 10 yu t tham gia iu ha s hot ha cc thnh phn ca b th: C1 INH, I, H, B, D, P, C4bp, DAF, CR1 v protein S. - B th v cc yu iu ha hp thnh h thng b th. VI. Qu trnh hot ho b th B th c hot ha theo hai con ng khc nhau: (1) Con ng c in i t C1 n C9 nhng theo th t sau: C1, C2, C3, C4, C6, C7, C8, C9 (2) Con ng tt i t C3, b qua C1, C4 v C2: C3, C5, C6, C8, C9 Gi l c in v con ng ny c pht hin trc, nhng v mt tin ha th n xut hin sau con ng tt. 1. Hot ha b th theo con ng c in 1.1. Yu t gy hot ha - Ch yu l phc hp khng nguyn-khng th, trong khng th thuc lp v di lp IgM, IgG1, IgG2, IgG3. - Cc yu t khc: mng vi rut ARN, mt s trc khun Gram m... 1.2. Bc nhn din Khi c kt hp khng nguyn-khng th th cc Fc tng tc vi nhau lm bc l v tr n nh b th trn vng CH2. Nh , thnh phn C1q n gn vo, C1q c gi l n v nhn din. 1.3. Bc hot ha men - S hot ha: Khi C1q c hot ha th tr thnh men gy hot ha C1r. Sau C1r hot ha li tr thnh men gy hot ha C1s. c tip tc theo s :

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S 3.1. Hot ho b th theo con ng tt Nhng c im ca giai on hot ha men: + Khi mt thnh phn b th c hot ha th tr thnh men ct protein hn ch, ct thnh phn b th tip theo ra lm hai mnh: mnh nh nm trong pha lng, mnh ln tr thnh men tip tc tham gia dy chuyn hot ha. + S hot ha c tnh khuch i, ngha l mt phn t b th c hot ha th s gy hot ha nhiu phn t ca thnh phn b th tip theo. + C4b2b c gi l C3 convertase (men chuyn C3) ca con ng c in. + C3b bm ln mng t bo ch, kt hp vi C3 convertase chuyn thnh men ct C5 gi l C5 convertase (men chuyn C5). 1.4. Bc hnh thnh phc hp tn cng mng Khi C5b c hnh thnh th cc thnh phn b th tip theo cng ln lt n bm ln mng t bo ch, hnh thnh phc hp tn cng mng MAC (Membrane Attack Complex), c thng tng l nh khong 100 mng t bo ch, lm cho t bo b trng nc ri v

S 3.2. Phc hp tn cng mng (MAC) 2. Hot ha b th theo con ng tt

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S hot ha b th theo con ng tt khng cn n s hin din ca khng th. y l c ch khng t nhin tham gia bo v c th, c bit quan trng khi c th cha c khng th c hiu. 2.1. Cc yu t gy hot ha - B mt nhiu loi vi khun Gram (-) v Gram (+). - Cc t bo b nhim virut, nm v k sinh trng. - Phc hp khng nguyn-khng th, trong khng th thuc lp IgA, (IgA1 v IgA2). 2.2. Vng hot ha thng trc Bnh thng trong c th lun lun c mt lng nh C3b c to ra, ri b bt hot ngay nu khng c yu t gy hot ha: 2.3. S khuch i C3b v hot ha men - Khi c yu t gy hot ha th C3b tng cng kt hp vi yu t B lm cho vng thng trc c khuch i. - Cc C3b bm vo C3bBb hnh thnh phc hp (C3b)n Bb. (C3b)n Bb l C5 convertase ca con ng tt.

C3bBb l C3 convertase ca con ng tt. S 3.3. Vng hot ho thng trc ca con ng tt 2.4. Bc hnh thnh phc hp tn cng mng Ging nh con ng c in.

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S 3.4. S hnh thnh phc hp tn cng mng ca con ng tt VII. iu ho hot ho b th 1. Qu trnh hot ha b th c kim sot bi cc protein iu ha 1.1. Cc yu t c ch hot ha - C1 INH (C1 inhibitor): bt hot C1. - I (inactivator): bt hot C3b khi c s h tr ca H v CR1. - H (beta-1 H globulin): cofactor ca I. - C4bp (C4 binding protein): gn vi C4b, cnh tranh vi C2. 1.2. Cc yu t tng cng hot hot ha - B: khuch i C3b. - D: khuch i C3bBb. - P (properdin): n nh C3bBb. 2. Qu trnh hot ha b th khng nhm tn cng t bo c th T bo c th c cc yu t tham gia hy cc thnh phn b th v trnh c s tn cng ca MAC. - CR1 (Complement receptor): c trn b mt cc t bo mu ngoi vi. Khi C3b n bm vo t bo th CR1 gn vi C3b to iu kin cho yu t I bt hot C3b. - DAF (decay accelerating factor): lm phn ly C4b2a, C3bBb. Nh cc c ch trn m s hot ha b th xy ra cng thch hp. Nu qu yu th c th d nhim trng ti i ti li (nh trong trng hp thiu C2), nu qu mnh th t bo c th b tn thng (nh trong trng hp thiu C1 INH)... VIII. Tc dng sinh hc ca b th 1. Chng nhim trng - MAC c tc dng c thng t bo ch gy v t bo. - i thc bo c CR1 (receptor ca C3b) v CR3 (receptor ca C3bi). Khi C3b v C3bi bm vo vi khun th gy hin tng opsonin ha i thc bo qua trung gian cc receptor ny, gip cho i thc bo d tip cn v tiu dit vi khun. 2. Tham gia phn ng vim C2a l anaphylatoxin yu. C3a v C5a l nhng anaphylatoxin mnh, chng gy gii phng histamin t t bo mast v bch cu i kim, dn n gin mch tng tnh thm. C5a cn c tc dng ha ng ng dng i vi bch cu n nhn v a nhn trung tnh. Do vy chng tng cng phn ng vim.

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Chng 4 KHNG NGUYN V KHNG NGUYN MHC

I. Khng nguyn 1. inh nghia 1.1. Khang nguyn hoan toan Khang nguyn (Antigen) la nhng cht co kha nng: - Kich thich c c th tao ra ap ng min dich, kha nng nay c goi la tinh sinh min dich cua khang nguyn (KN). - Kt hp c hiu vi khang th (KT) tng ng, kha nng nay goi la tinh c hiu cua khang nguyn. Khi vao c th khang nguyn kich thich tao khang th tng ng vi hai loai khang nguyn c goi la khang nguyn khng phu thuc tuyn c va khang nguyn phu thuc tuyn c. - Khang nguyn khng phu thuc tuyn c: la nhng khang nguyn kich thich trc tip t bao lympho B tao ra ap ng min dich ma khng cn s co mt cua t bao lympho T. - Khang nguyn phu thuc tuyn c: la nhng khang nguyn cn co s giup cua t bao lympho T h tr (Thelper, Th) mi kich thich c t bao lympho B tao ra ap ng min dich. 1.2. Khang nguyn khng hoan toan (ban khang nguyn = Hapten) Hapten la phn t nho (t nhin hay nhn tao) mt minh khng co kha nng gy ra ap ng min dich nhng vn c nhn bit bi cac san phm cua ap ng nay (nu co). Nh vy hapten co tinh c hiu nhng khng co tinh sinh min dich. Khi hapten gn vi mt protein tai thanh mt phc hp thi phc hp nay co tinh sinh min dich. iu o co nghia la nu chi a hapten vao c th thi khng co ap ng min dich c hiu xay ra, nhng nu a phc hp protein-hapten vao thi c th se ap ng bng cach san xut khang th chng lai ca protein ln hapten. Khang th chng hapten do phc hp kich thich tao ra co th phan ng ca vi hapten t do.Trong trng hp nay ta co th xem hapten nh la mt quyt inh khang nguyn c thm vao bn canh nhng quyt inh khang nguyn khac a co mt trn phn t protein. 2. Cac c tinh cua khang nguyn 2.1.Tinh sinh min dich cua khang nguyn Tinh sinh min dich cua mt khang nguyn phu thuc vao cac yu t sau : 2.1.1. Tinh la cua khang nguyn Mt khang nguyn co tinh sinh min dich cang cao khi s khac bit gia c th nhn va khang nguyn cang nhiu hay noi cach khac khang nguyn cang la vi c th nhn bao nhiu thi kha nng kich thich tao khang th cang manh by nhiu.

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Vi du: Albumin cua ga hay chim co tinh sinh min dich cao hn albumin bo khi cung a vao c th loai d. Tuy nhin cn lu y rng cac khang nguyn protein cua c th nay cung co th kich thich mt c th khac cung loai san xut khang th nu khang nguyn protein u la i vi protein cua c th nhn. Hn na trong mt s trng hp bnh ly thi thanh phn cua chinh c th cung co th gy ra ap ng tao khang th chng lai no, ngi ta goi nhng thanh phn nay la t khang nguyn. 2.1.2. Cu tao hoa hoc cua khang nguyn Cac khang nguyn thuc loai protein va polysaccarid co tinh sinh min dich cao khi dung di dang hoa tan va ca khi chung nm trong mt cu truc phc hp, vi du vo vi khun. Cac khang nguyn la lipid, steroid va axit nucleic co tinh sinh min dich yu hoc khng co tinh sinh min dich. Khang nguyn cang phc tap v ca cu tao ln kich thc thi chung cang co th kich thich mt ap ng min dich manh. Vi du: cac khang nguyn hu hinh (vi khun, vi rut ,cac t bao). Cac phn t protein ln (hemoxyamin) cung co tinh khang nguyn manh. Trn cu truc cua khang nguyn co nhng vi tri chiu trach nhim chinh trong vic kich thich tao khang th va kt hp vi khang th khi xay ra phan ng kt hp khang nguynkhang th . Nhng vi tr i n ay c goi la nhng q uyt inh khang ngu yn (determinant antigen) hay epitop. Khang nguyn cang phc tap cang co nhiu epitop, do o tinh sinh min dich cang cao. Ngoai thanh phn hoa hoc ra, cu truc lp th va kha nng tich in cua cac phn t khang nguyn cung co anh hng n tinh sinh min dich. Co le s tich in co vai tro trong vic chon loc cac t bao lympho co thu th c hiu tng ng. Con cu truc lp th co anh hng n mc chuyn hoa cua khang nguyn trong c th nhn (khi bi chuyn hoa cac khang nguyn se l thm cac quyt inh khang nguyn). 2.1.3. Cach gy min dich va liu khang nguyn Hu ht cac khang nguyn hu hinh (vi khun, hng cu, vi rut hoc cac polymer ln) khi a vao c th nhn bng ng tinh mach hoc tim bp vi liu khac nhau u co th d dang kich thich tao khang th. Trong khi o, nhiu khang nguyn la protein hoa tan phai co mt quy trinh gy min dich thich hp hoc phai cn mt cht h tr mi gy c ap ng tt. Cht h tr o c goi la ta cht, loai thng c dung la ta cht Freund gm hn dich vi khun lao cht trn trong nc va du. Mt s nghin cu cho thy ta cht co tac dung lam tng chc nng cua ai thc bao va t bao lympho T h tr. 2.1.4. Kha nng ap ng cua c th y la mt yu t quan trong : cung mt khang nguyn nhng cac c th khac nhau co nhng ap ng nhiu mc khac nhau. Vi th Landsteiner a phn bit hai khai nim: tinh khang nguyn va tinh sinh min dich, trong o:

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Tinh sinh min dich = Tinh khang nguyn + Kha nng ap ng cua c th nhn 2.2. Tinh c hiu cua khang nguyn Tinh c hiu cua mt ap ng min dich la do: - Mi khang nguyn co mt cu truc c hiu ring. - Kha nng nhn bit mt cach c hiu cua cac t bao lympho do co thu th cho tng loai khang nguyn. Tinh c hiu cua khang nguyn khng phai do toan b cu truc cua ca phn t khang nguyn quyt inh ma do nhng quyt inh khang nguyn (epitop ) quyt inh. Epitop co hai chc nng: - Kich thich c th tao ra ap ng min dich c hiu vi khang nguyn o. - Lam vi tri khang th hoc t bao lympho T mn cam co th gn vao mt cach c hiu. Mt khang nguyn protein phc tap co th co nhiu quyt inh khang nguyn khac nhau do o ma no co th kich thich tao ra nhiu loai khang th khac nhau cung mt luc. Tuy theo khang nguyn co th phan ng cung luc vi mt hoc nhiu khang huyt thanh cha khang th do no tao ra ma ngi ta goi la khang nguyn n gia hay khang nguyn a gia . (Trong cac phan ng huyt thanh hoc chi co cac khang nguyn a gia mi co kha nng tao ra mang li kt tua hoc ngng kt vi cac khang th tng ng ). Phan ng cheo (Cross - reaction): Tinh c hiu cua khang nguyn rt cao tuy vy trong thc t hai khang nguyn khac nhau co th co phan ng cheo vi nhau. Nguyn nhn cua phan ng cheo la do trn hai khang nguyn nay co hai epitop ging nhau hoc it nht la tng t nhau Phan ng cheo d xay ra vi cac khang nguyn polysaccharid va cung xay ra vi cac khang nguyn protein (vi du: albumin trng ga va albumin trng vit ). Trong thc nghim chung ta co th loai tr phan ng cheo bng phng phap hp thu. Vi du: ta bit khang huyt thanh khang A thng cho phan ng cheo vi khang nguyn B nn khi lam phan ng tim khang nguyn A thi kt qua d sai lac do tim nhm ca B. Nh vy trc khi tim A ta cho u khang huyt thanh khang A vi khang nguyn B, nhng phn t nao cho phan ng cheo se tao phc hp vi B. Sau o loai bo phc hp nay bng ly tm ta se co khang huyt thanh khang A tinh khit khng con phan ng cheo vi B. 2.3.Cac c tinh khac Ngoai hai c tinh chinh k trn, khang nguyn con co th co mt vai c tinh phu. Nhng c tinh phu nay khng thng xuyn nhng cung mang lai nhng thay i v cht lng va s lng trong ap ng min dich. 2.3.1. Tinh gy di ng Mt s khang nguyn d gy san xut IgE hn do o tao ra di ng tc khc. Vi du nh: phn hoa, noc cua mt s su bo...ap ng min dich chuyn thng t IgM sang IgE.

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Tinh cht nay phu thuc vao c ia cua ca th nhn. 2.3.2. Tinh gy dung nap Mt s khang nguyn co kha nng gy mn cam i vi loai vt nay nhng khng gy c mt s loai vt khac. o la tinh trang dung nap tuy thuc vao liu lng, cach a khang th vao c th va tuy thuc ca vao c ia. 2.3.3. Tinh ta cht Ta cht cho phep lam tng cng ap ng min dich i vi khang nguyn. Ban thn mt s khang nguyn co thm tinh cht o. 2.3.4. Tinh gy phn bao Ngoai ap ng min dich c hiu, khang nguyn co th gy thm tinh trang tng globulin gamma mau chung do kich thich s phn bao cua t bao lympho B. 3. Mt s khang nguyn quan trong 3.1. Khang nguyn nhom mau 3.1.1. Khang nguyn nhom mau h ABO H nay bao gm bn nhom mau khac nhau A, B, AB, O. Ky hiu nhom mau biu thi khang nguyn b mt hng cu. C th nhom mau A co khang nguyn A trn b mt hng cu. Nhom B co khang nguyn B , nhom AB co ca khang nguyn A va khang nguyn B, Nhom O khng co ca khang nguyn A va khang nguyn B trn hng cu . Ngoai ra do c th co trang thai dung nap vi khang nguyn cua ban thn nn trong huyt thanh khng co khang th chng lai khang nguyn co trn b mt hng cu cua no, nhng i vi khang nguyn thuc nhom khac thi no lai co khang th chng lai nghia la: - c th nhom A co khang th chng B - c th nhom B co khang th chng A - c th nhom AB khng co khang th chng A,B - c th nhom O co khang th chng A, B. Cac khang th nay xut hin t nhin trong huyt thanh. Cac khang nguyn thuc h ABO do mt locus gen kim soat vi 3 allel A, B, va O, trong o A va B tri hn O. Dung enzym ct cac ose ra khoi phn polysaccharid trong khang nguyn thi tinh c hiu cua khang nguyn bi thay i do o tinh c hiu cua cac khang nguyn nhom mau trong h ABO c quyt inh bi s co mt cua mt s gc ose trong phn polysaccharid. Cac khang nguyn nay u co chung mt loi sphingolipid-polysaccharid, nu gn thm gc fucose thi xut hin cht H. Cht H co trn b mt hng cu cua hu ht cac c th va la nn xut hin khang nguyn A va B.

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Nu tai vi tri galactose cui cung cua cht H: - gn thm gc n- acetyl galactosamin thi xut hin khang nguyn A - gn thm gc galactose thi xut hin khang nguyn B. Nh vy tham gia vao s hinh thanh cac khang nguyn nhom mau ABO co hai h gen: h gen Hh i vi cht H va h gen ABO hoat ng c lp vi nhau. ai a s trong chung ta co gen H nhng cung co ngi khng co (c th ng hp t hh), nhng ngi nay du co gen cua h ABO nhng khng co khang nguyn A hoc khang nguyn B nn c ghi nhn thuc nhom mau O. Khi chuyn mau O tht s vao (tc co cht H) thi co th gy tai bin chuyn mau. Nhom mau c bit nay goi la nhom O Bombay . 3.1.2.. Khang nguyn h nhom mau Rh Nm 1930 Landsteiner va Wiener goi nhng ngi co hng cu ngng kt vi huyt thanh tho khang hng cu cua khi Rhesus la ngi Rh+ va nhng ngi con lai la Rh-. Nhng sau nay ngi ta nhn thy cac khang nguyn trong h Rh khng chi n gian nh vy. H Rh co nhiu khang nguyn phn ln co tinh phan ng cheo va co tinh sinh min dich yu, chi co khang nguyn D la co tinh sinh min dich manh. Khi trn hng cu co khang nguyn D thi c th o c goi la Rh+ ma khng cn y n cac khang nguyn khac trong h Rh. Khang th chng D khng xut hin t nhin trong mau nh cac khang th h ABO. Vi khang nguyn Rh phn b tha tht trn b mt hng cu nn kho tao ra mang li ngng kt, mun xac inh nhom mau Rh ngi ta phai dung th nghim Coombs gian tip 3.2. Khang nguyn vi sinh vt Khang nguyn vi sinh vt la loai khang nguyn rt phc tap gm co khang nguyn vo, khang nguyn thn, khang nguyn lng, khang nguyn ngoai t bao (c t, enzym). - Khang nguyn vo: khang nguyn vo cua ph cu thng c nghin cu nhieu nht. Khang nguyn nay thuc loai polysaccharid, co ti 80 typ huyt thanh. - Khang nguyn thn: cac vi khun rut non, lp ngoai cua vach vi khun co mt lipopolysaccharid. Phn lipid co tinh c va phn polysaccharid co tinh khang nguyn, o chinh la khang nguyn thn (con goi la khang nguyn O). Salmonella co hn 60 khang nguyn O khac nhau. Khang nguyn O cu tao gm hai phn: phn nhn c ban va phn cac chui ngang, phn nay gm nhng tiu n vi oligosaccharid sp xp lp i lp lai. Chinh cac chui ngang quyt inh tinh c hiu cua mi nhom Salmonella. - Khang nguyn lng (con goi la khang nguyn H) ban cht la protein, quyt inh tinh c hiu cua mi typ Salmonella. Co trn 1000 typ huyt thanh Salmonella khac nhau. - Cac khang nguyn ngoai t bao nh cac c t va enzym cung co ban cht la protein. Mt khang nguyn ngoai t bao cua lin cu la Streptolyzin O thng c dung trong chn oan huyt thanh. Cac vi khun bach hu, un van co ngoai c t gy bnh va cac vc xin phong cac bnh nay u la

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nhng c t c giai c (giai c t) Vi khun ta va mt s E. Coli co khang nguyn ngoai t bao la c t rut. Cac khang nguyn vi rut co th b mt hat virion hoc bn trong. Tuy theo tinh c hiu co th phn bit thanh khang nguyn nhom, khang nguyn typ, khang nguyn typ phu. + Khang nguyn nhom: vi du khang nguyn nucleoprotein la khang nguyn chung cho tt ca vi rut u + Khang nguyn typ: vi du trong bnh bai lit cho phep phn bit 3 typ vi rut bai lit khac nhau. + Khang nguyn typ phu: vi du vi rut cum ngoai phn bit 3 typ A, B, C con inh cac typ phu. Cac typ phu cua A va B la kt qua cua nhng bin i cua khang nguyn b mt. 5.3. Khang nguyn polypeptid tng hp Khang nguyn nay la cac polyme cua cac gc axit amin lin kt vi nhau bng cac lin kt peptid. Homopolyme: polymer chi gm mt loai axit amin. Copolyme: polymer gm hai hoc nhiu loai axit amin. Polyme khi: polyme gm nhiu oan peptid nho co th t nht inh lin kt vi nhau. Khang nguyn polypeptid tng hp c dung nghin cu anh hng cua kich thc, hinh dang lp th , thanh phn hoa hoc... n tinh sinh min dich cua khang nguyn. II . Phc hp ho hp t chc chnh (MHC) 1. ai cng 1.1. Phat hin khang nguyn hoa hp t chc Chung ta bit rng khi ghep mt c quan hay mt b phn (manh da) t mt c th nay sang mt c th khac, nu hai c th co b gen hoan toan phu hp ( vi du : sinh i cung trng hoc cac c th ng vt trong cung dong thun chung) thi manh ghep se tn tai c va phat trin binh thng trn c th nhn. Nu hai c th co b gen khac nhau thi manh ghep la vt la i vi c th nhn va c th nhn se sinh ra ap ng min dich loai bo manh ghep. o la phan ng thai ghep. V sau George va cng s a kham pha ra mt nhom khang nguyn chut, ma khi nhom khang nguyn nay ging nhau gia con cho va con nhn thi manh ghep co thi gian sng lu hn. Nhom khang nguyn nay c goi la khang nguyn hoa hp t chc 1.2. Gii thiu s lc v gen Ngi ta thy rng phu trach ma hoa cac khang nguyn hoa hp t chc la mt vung c bit cua genom va c goi la phc hp hoa hp t chc chinh (Major Histocompatibility Complex = MHC). chut nht no mang tn la vung H2 va nm trn nhim sc th 17. Nhng h thng tng ng vi phc hp hoa hp t chc chinh chut a c phat hin trn tt ca cac ng vt co vu khac. ngi phc hp hoa hp t chc chinh la cum gen HLA (Human Leucocyte Antigen) nm trn canh ngn cua nhim sc th s 6 (ngi ta goi la HLA vi phat hin u tin trn b mt bach cu). Vung nay chim khoang 3.800 kb va c chia nho thanh lp I, lp II va lp III. Cac gen HLA co 3 c im ni bt: tinh a dang, tinh ng tri va tinh lin kt cht che.

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Mc du MHC ln u tin c phat hin nh vai tro cua no trong thai ghep, ngay nay ngi ta bit rng cac protein san phm cua oan gen nay a tham gia vao nhiu cng oan trong nhn din min dich bao gm tng tac gia cac t bao lympho khac nhau cung nh gia cac lympho bao vi cac t bao trinh din khang nguyn. 1.3. Phn lp khang nguyn va phn b trn t bao cua khang nguyn hoa hp t chc Cac protein cua MHC gm co ba lp khac nhau ve ca cu truc ln chc nng: - Lp I co HLA- A tng ng vi H- 2K chut nht HLA- B tng ng H- 2D chut nht HLA- C tng ng H- 2L chut nht Cac HLA lp I co mt trn tt ca cac t bao co nhn . Chung c biu l mt cach phong phu trn t bao dong lympho, it hn gan, phi va thn, rt it nao, c xng. S lng phn t HLA lp I thay i tuy theo tinh trang bit hoa hay tinh trang hoat hoa cua cac t bao. - Lp II co HLA- DR tng ng vi H- 2I chut HLA- DP HLA- DQ Cac HLA lp II co trn t bao B, mt s t bao T, ai thc bao, t bao mono, t bao biu m do o lp II lin quan n ap ng min dich nhiu nht. IFNg va TNFa lam tng xut hin cac phn t nay. - Lp III co C2, C4, Bf- Lp III la cac gen nm gia lp I va lp II,o la cac gen cua b th khng lin quan gi n tinh cht hoa hp t chc. 2. Cu truc cua khang nguyn MHC Khang nguyn MHC thng dc tim thy trn mang t bao (vi la phn t tham gia vao tng tac t bao) chung la nhng phn t glycoprotein cm vao mang t bao do o nghin cu c chung ngi ta thng phai tach ri chung khoi mang bng hai cach: + Dung cac cht ty giai phong chung khoi mang. + Dung enzym papain ct phn MHC nm thoi ra khoi b day cua mang. 2.1. MHC lp I Cu truc cua MHC lp I gm hai chui polypeptid ring bit lin kt khng ng hoa tri vi nhau. Chui a gn vi ng co trong lng phn t khoang 44.000 Da, gm 345 axit amin va mt chui khng co ng la b2 microglobulin, co trong lng phn t 12.000 (gen phu trach oan peptid nay khng nm trong h gen hoa hp t chc chinh). Chui a gm co 3 linh vc nm ngoai t bao a1, a2 va a3; co mt phn xuyn mang khoang 26 axit amin va mt phn bn trong nguyn sinh cht. b2 Microglobulin co trong lng phn t 11,5kD, vi 99 axit amin. No c ma bi mt gen ngoai h thng HLA, khng tham gia vao b mt khang nguyn cua phn t HLA nhng no cn cho qua trinh

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th hin cua lp I. Nu thiu bm sinh b2 microglobulin thi quyt inh khang nguyn cua lp I khng th hin c. 2.2. MHC lp II Cu truc cua MHC lp II gm hai chui polypeptid khac nhau a va b lin kt vi nhau bi lc ni khng ng hoa tri. Ca hai chui u cm vao mang t bao va u mang cac n vi ng. Chui b co trong lng phn t khoang 30 kDa, co 2 linh vc ngoai t bao b1 va b2. Chui a co trong lng phn t khoang 32 kDa, cung co 2 linh vc ngoai t bao a1, a2; mt phn xuyn mang va mt phn nm bn trong nguyn sinh cht. Khi khao sat ring tng chui peptid a va b ngi ta thy rng a s cac bin th chi xay ra chui b. 3. Chc nng cua khang nguyn MHC Cac t bao lympho T nhn din c khang nguyn la nh co mi lin quan vi cac phn t MHC trn b mt cac t bao khac hay noi cach khac vic trinh din khang nguyn cho t bao lympho T phu thuc cht che vao MHC. 3.1. Chc nng cua MHC lp I Cac phn t MHC lp I trinh din khang nguyn trn b mt t bao ich cho t bao T CD8 trong cac phan ng min dich. Cac protein la (t bao ung th, vi rut nhim vao trong t bao...) bi thoai hoa trong nguyn sinh cht cua t bao di tac ng cua cac enzym tiu am (proteasom), tao thanh nhng oan peptid khoang 9 a.a. Chung se c chuyn n mang li ni nguyn sinh kt hp vi linh vc a1, a2 cua MHC lp I va cung vi phn t nay trinh din trn b mt cua cac t bao nhim.

MHC lp I Hinh 4.1. Cu truc phc hp hoa hp t chc

MHC lp II

Cac thu th cua t bao T (TCR) trn TCD8 se nhn din phc hp khang nguyn- MHC lp I. Qua trinh nhn din nay tao ra tin hiu u tin hoat hoa cac t bao. Ngoai ra phn t CD8 va cac cp

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phn t bam dinh khac trn hai t bao nay se hoan tt mi tng tac va kt qua la t bao T CD8 se c hoat hoa, tit ra cht perforin gy ly giai t bao nhim. 3.2. Chc nng cua MHC lp II Cac phn t MHC lp II trinh din khang nguyn trn b mt t bao trinh din khang nguyn (APC = Antigen Presentating Cell ) cho t bao lympho h tr T CD4. Vi khun, protein ngoai lai... c cac t bao n nhn/ai thc bao, t bao lympho B, t bao tua thu tom va x ly thanh cac peptid khang nguyn co t 9- 24 axit amin. Tip o nhng peptid khang nguyn nay lin kt vi phn t MHC lp II va toan b phc hp c biu l trn b mt cac t bao trinh din khang nguyn. T bao lympho T h tr ( T CD4) se nhn din khang nguyn thng qua thu th t bao lympho T. Qua trinh nhn din nay tao ra tin hiu u tin hoat hoa cac t bao. Ngoai ra phn t CD4 va cac cp phn t bam dinh trn ca hai t bao (CD2-LAF3 va LAF1-ICAM1) se hoan tt mi tng tac. Cui cung t bao T CD4 hoat hoa, san xut cac cytokin t kich hoat va kich hoat cac t bao hiu ng min dich khac thc hin chc nng tiu dit khang nguyn cua minh. Nh vy, khang nguyn MHC vi hai lp chinh: lp I (HLA-A, HLA-B, HLA-C) va lp II (HLA-DP, HLA-DQ, HLA-DR ) co chc nng trinh din khang nguyn, tao mi tng tac gia cac t bao a quan xuyn toan b h min dich. Nu thiu mt vai gen cua h MHC se lam giam kha nng chng cua c th va bnh nhn se cht vi suy giam min dich. Mt s nghin cu cho thy rng: co mi lin quan gia HLA vi mt vai bnh t min. Vi du : bnh vim t sng x cng vi HLA-B27; bnh ai ng phu thuc insulin vi HLA- DR3, HLA-DR4. o chinh la c im di truyn cua phc hp hoa hp t chc chinh.

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Chng 5 P NG TO KHNG TH V MIN DCH TRUNG GIAN T BO

p ng min dch ch yu gm hai phng thc l min dch dch th trung gian vi khng th l cc globulin min dch v min dch t bo trung gian vi nhim v ca cc t bo lympho T. Nhng t bo lympho trng thnh ch bit ha tip tc khi n gp c khng nguyn, khi chng s tip tc tng sinh thnh mt s ln t bo lympho c hiu khng nguyn vi mc ch loi b chnh khng nguyn gy nn p ng . T bo lympho T c th trc tip git cht t bo nhim hoc hot ha i thc bo i thc bo tiu dit cc vi sinh vt gy bnh trong ti ni bo. Mt khc t bo lympho T cn c vai tr quan trng trong vic kch thch t bo lympho B bit ha thnh tng bo sn xut khng th chng li hu ht cc khng nguyn; ngoi ra p ng ny c vai tr quan trng chng li cc tc nhn gy bnh ni bo. I. p ng to khng th p ng min dch dch th c thc hin qua trung gian khng th l cc globulin min dch (immunoglobuline) gi tt l Ig, c sn xut t t bo lympho B. Tt c cc immunglobulin c tng hp t mt clon t bo B ring bit th c tnh c hiu khng nguyn nh nhau, nhng ty thuc giai on chn m c th c mt isotype immunglobulin khc nhau. Nhng Ig ny th hin nh l cu trc nhn bit khng nguyn ca t bo lympho B nhng ng thi n cng th hin nh l nhng phn t hiu lc c bn. 1. Cc giai on bit ha ca t bo lympho B Ngi ta phn bit s chn khng ph thuc khng nguyn trong ty xng v gan thi k bo thai v s chn ph thuc khng nguyn c quan lympho ngoi bin (cc nang nguyn pht v th pht ca hch lympho, mng Peyer, v.v ... ) 1.1. Khi cha gp khng nguyn - T bo mm to mu (hematopoietic stem cell) pht trin thnh tin t bo B (pre B cell), c gan bo thai v ty xng ngi. Tin t bo B ch tng hp nhng chui nng typ m (muy), nhng cha tng hp c nhng chui nh v c th chnh v vy m cha c kh nng nhn dng khng nguyn (cha c cc th th (cht tip nhn). - Tip theo l giai on pht trin thnh t bo lympho non (immature B lymphocyte), vn cn nm trong t chc lympho bo thai v ty xng ngi, c IgM trn b mt ( chui nh k - kappa hoc l - lamda) nhng tip xc vi khng nguyn hnh nh vn cn dn n mt s dung th.

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- Tip theo t bo lympho B cha chn bit ha thnh t bo lympho B chn (mature B lymphocyte) v cng trnh din IgD ln b mt t bo bn cnh IgM v c cng tnh c hiu khng nguyn (c cng vng V do cng s dng b gen V.D.J ). Nu giai on ny n khng gp khng nguyn th n cng sm b hy v thi gian bn hy khong t 3 - 4 ngy. Mi t bo lympho B c khong 105 phn t IgM v IgD trn mng t bo. N hot ng nh nhng cht tip nhn (receptor) khng nguyn c hiu v ng vai tr quan trng i vi s kch thch cm ng khng nguyn ca t bo lympho B. Song song vi s bc l IgM, IgD ln mng t bo th nhng cht tip nhn i vi mnh Fc ca IgG, i vi mnh b th, lymphokin, vi rut Epstein Barr v.v ... cng c bc l. 1.2. Khi gp khng nguyn T bo lympho B chn c th c kch thch qua s lin kt ca khng nguyn ln IgM b mt hoc IgD vi s phi hp t bo lympho T h tr v nhng t bo c kch thch ny s tng sinh thnh mt clon t t bo lympho B vi hai con ng sau: - Hu ht pht trin thnh mt clon tng bo sn xut khng th c vai tr quyt nh trong p ng min dch dch th. - Mt s t t bo lympho B c kch thch khc chuyn thnh t bo lympho B nh c i sng lu (c th sng n 6 nm). Nhng t bo lympho ny c vai tr quan trng trong p ng min dch th pht. 2. S sp xp cc gen m cho khng th trn t bo mm S tng hp cc vng thay i ca chui nng v chui nh v tr kt hp khng nguyn din ra qua s phi hp ca nhng gene Immunglobulin ca t bo lympho trong khi pht trin t t bo mm n t bo B chn.Nhng gene cn cho s sn xut khng th c khu tr trn 3 nhim sc th khc nhau: - Gene tng hp chui nng (H) nm trn nhim sc th s 14. - Gene tng hp chui nh (L) typ kappa nm trn nhim sc th s 2. - Gene tng hp chui nh (55 L) typ lamda nm trn nhim sc th s 22.

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Hnh 5.1. S tng hp ca chui nh khng th (Vng thay i ca chui L c m ha bi hai on gen) Vng thay i ca chui nh L s c m qua 2 on DNA tch bit, hai on ny tp trung trong t bo B qua s sp xp DNA. on u tin m 95 hoc 96 axit amin u tin ca chui nh v c coi l on V (Variable). on DNA th 2 m khong 12-14 axit amin cui cng ca vng thay i v c tn l on gen J (Joining). Vng thay i ca chui nng c kha trong 3 on gene ri. B sung vo nhng on V v J c mt on gene th 3 m cc axit amin gia nhng on Vh v Jh, on b sung ny gi l on gen D (diversity ) . C nhiu gene cho cc on thay i . i vi chui L kappa th c khong 250 on Vk v 4 on Jk hot ng. i vi chui nng th ln hn nhiu nhng cha xc nh c chc chn , c tnh khong t 200 - 1000 on Vh, khong 12-15 i vi Dh v 4-6 i vi Jh. Mi gene V lun c chui L (leader ) i trc. i vi phn hng nh ca Immunglobulin cua mi lp hoc lp ph th c mt gene hng nh C (constant). S hnh thnh mt gene hot ng chu trch nhim cho s tng hp mt khng th c hiu din ra qua s ti phi gene nh H.1 v H.2.

Hnh 5.2. S tng hp ca chui nng khng th (Vng thay i ca chui H c m ha bi ba on gen)

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S ti phi hp ngu nhin ca nhng on V vi 15 on Dh v 4 - 6 on Jh cho ta mt kh nng phi hp theo tnh ton l khong 109 n 1011 - Locus chui nng trn nhim sc th 14: 5 - L1 - Vh1 - // - Ln - VHn - // - Dh1 - // - DHn - J 1, 2, 3 , 4 ,5 ,6 - Cm - Cd - Cg3 - Cg1 - Ce2 - Ca1 - Cg2 - Cg4 - Ce1 - Ca2 - 3 (trong c khong 200 -1000 gen m cho Vh, 15 gen cho D v 4 gen J) - Locus chui nh typ kappa trn nhim sc th 2: S ti phi hp gen chui L tng ng vi s ti phi hp chui H, bt u bng s sp xp locus chui kappa qua s ti phi hp ca mt trong nhiu on gen V vi 1 trong 5 on gen J . 5 - L1 - Vk1 - // - Ln - Vkn - // - Jk1 ,2 , 3 , 4 ,5 - Ck - 3 - Locus chui nh typ lamda trn nhim sc th s 22 : 5 - L1 - Vl1 - // - Ln - Vln - // - Jl1 Cl1 - Jl2 Cl2 - Jl3 Cl3 - Jl4 Cl4 - Jl5 Cl5 - Jl6 Cl6 - 3 ( Trong khong 200 gen m cho vng V lamda ) 3. S ti sp xp cc gien qua cc giai on bit ha ca t bo lympho B - Locus chui nng trn nhim sc th 14: 5 - L1 - Vh1 - // - Ln - VHn - // - Dh1 - // - DHn - J 1, 2, 3 , 4 ,5 ,6 - Cm - Cd - Cg3 - Cg1 - Ce2 - Ca1 - Cg2 - Cg4 - Ce1 - Ca2 - 3 (trong c khong 200 -1000 gen m cho Vh, 15 gen cho D v 4 gen J) - Locus chui nh typ kappa trn nhim sc th 2: S ti phi hp gen chui L tng ng vi s ti phi hp chui H, bt u bng s sp xp locus chui kappa qua s ti phi hp ca mt trong nhiu on gen V vi 1 trong 5 on gen J . 5 - L1 - Vk1 - // - Ln - Vkn - // - Jk1 ,2 , 3 , 4 ,5 - Ck - 3 - Locus chui nh typ lamda trn nhim sc th s 22 : 5 - L1 - Vl1 - // - Ln - Vln - // - Jl1 Cl1 - Jl2 Cl2 - Jl3 Cl3 - Jl4 Cl4 - Jl5 Cl5 - Jl6 Cl6 - 3 ( Trong khong 200 gen m cho vng V lamda ) 3. S ti sp xp cc gien qua cc giai on bit ha ca t bo lympho B S 5.1. S ti sp xp cc gien qua cc giai on bit ha ca t bo lympho B 1. S sp xp gien t bo mm : 5 - L - V - D - J - CH - 3 ( NST s 14 t b ) 5 - L - V - D - J - CH - 3 ( NST s 14 t m ) 2. S sp xp gien t bo tin B sm : 5 - L- V - DJ - CH - 3 5 - L - V - DJ - CH - 3 ( Sp xp DJ trn c 2 NST ) 3. S sp xp gien t bo tin B mun : 5 - L - VDJ - CH - 3 5 - L - V - DJ - CH - 3 S ti t hp VDJ nhim sc th th nht s c ch s ti t hp trong nhim sc th th hai; l s loi tr alen. Nu s ti t hp VDJ trn nhim sc th th nht khng thnh th s tip tc ti t hp trn nhim sc th th hai. Nu nhim sc th th hai cng khng thnh th t bo s b hy trong giai

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on ny. Nu c th ARN thng tin s mang V.D.J.C muy tng hp chui muy, do trong bo tng c chui muy. 4. S sp xp gien t bo tin lympho B n t bo lympho B non 5 - L - VJ - Ck- 3 ( locus chui L kappa trn NST th nht b nhim sc th th hai) 5 - L - V - J - Ck - 3 (locus chui L kappa trn NST th hai) S ti t hp VJ trong nhim sc th th nht s c ch s ti t hp trong nhim sc th th hai, l s loi tr isotyp chui nh. ARN thng tin s mang V.J.Ck tng hp chui nh kappa, do trn b mt t bo lympho B non c IgM vi chui H l muy v chui L l kappa. Nu s ti t hp VJ trong NST th nht ca b NST s hai khng thnh th s c ti sp xp trn nhim sc th th hai; nu s ti t hp VJ trong nhim sc th th hai cng khng thnh th locus chui nh lamda nhim sc th s 22 li ti sp xp theo mt cch tng t. Nu t hp thnh cng th s c IgM b mt chui nng muy v chui nh lamda. Nu mi ti t hp ln lt khng thnh th t bo s b hy. 5. S sp xp gene t bo lympho B trng thnh Trn b mt t bo lympho B trng thnh c IgM b mt v c IgD. Nu khng gp khng nguyn th t bo s b hy. Nu gp khng nguyn th t bo s tng sinh v bit ha thnh nhiu tng bo sn xut khng th. i vi p ng nguyn pht b gen VDJ s c sao chp vi mt gene m nn khng th c to thnh l IgM. S chuyn i sang mt lp globulin khc din ra trong vng S (switch), ti y gene muy s b tht lc do chuyn i v c thay gene gamma 3 tng hp IgG3. Tip theo li c s chuyn i lp, l s thay i chui m, chui delta bng gamma, alpha v epsilon vv... Lu cc gene m cho vng C khc nhau nm theo th t pha sau VDJ (pha 3), u tin l Cm nn gii thch ti sao trong p ng tin pht lp khng th ch yu IgM. Cc lp khng th ny c cng tnh c hiu khng nguyn v c cng vng V (do cng s dng b gene VDJ )

Hnh 5.3. S chuyn i ca cc lp Ig trong p ng min dch (S chuyn i lp Ig trong p ng min dch nu vng VDJ kt hp vi gen m th RNA s sn xut IgM. trong qu trnh chn lin quan n t bo Th c l hot ho c ch t bin vng VDJ, gen C Cg3- c thay vo gen m.. Gen m v gen d b mt v s sao m sn xut IgG3)

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S chuyn i t Immunglobulin mng sang Immumglobulin tit: S chuyn i din ra nu cc t bo lympho B hot ha thnh tng bo. Nhng Immumglobulin tit th nh hn Immumglobulin thm xuyn mng v n khng c nhng axit amin b sung phn tn cng C cui chui nng cm phn t ny ln mng t bo do chng tit vo mu S sp xp cc gien trn t bo lympho B trng thnh : Nh ni nhng gien J cn cho chui nh , nhng gien D v J cn cho chui nng ; mi gien V th lun c chui L i trc, do : Chui nng : - L- VDJ - // - C Chui nh : - L - VJ - // - C 6. Tnh a dng ca khng th Hu nh mi mt cht u c th gy mt p ng to khng th v p ng ny cng a dng trn mt khng nguyn v bao gm nhiu phn t khng th khc nhau. Tp hp ton b cc c hiu khng th trong mt c th ngi ta gi l danh mc khng th. Thng n bao gm khong 1011 cc phn t khc nhau. Qu trnh ti phi hp thn c th gn mi on gene V vi mi on gene J hoc DJ. Do phn ln tnh a dng khng th xut hin l qua s tuyn chn cc phi hp khc nhau t nhiu on gen, t mi lnh vc V s c to nn.

Hnh 5.4. S ti t hp ngu nhin ca cc gene to nn tnh a dng ca khng th S lng cc vng thay i khc nhau c th c c l ty thuc vo s lng cc on gien ca mi typ .

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- i vi chui L typ kappa: C khong 250 on Vk v 4 oan Jk hot ng. Nh vy tng s kh nng phi hp l 250 . 4 = 1000 - i vi chui nng th kh hn v con s chnh xc ca on VH th cha r, phng on t 200 1000. S lin kt ngu nhin ca nhng on V vi 15 on Dh v 4 on Jh s cho mt con s phi hp c th c t 200 . 15 . 4 = 12 000 in 1000. 15 . 4 = 60.000 . Nu ly tr trung bnh l khong 400 on Vh th s kh nng phi hp l 400 . 15 . 4 = 24.000 nh gi tnh a dng c th c c qua s phi hp ca nhng chui nng v nh: Chui H . L = V. D. J . V . J = 400 . 15 . 4 . 250 . 4 = 2,4 . 107 Tuy nhin khng phi tt c mi ti sp xp u lun lun t c,nn theo tnh ton con s ny thng nh hn. Nhng thc t do t bin thn trong t bo lympho B khi tip xc vi khng nguyn m s lng khng th cng thm phong ph v a dng hn nhiu. 7. S hp tc gia t bo lympho T v t bo lympho B 7.1. i vi khng nguyn ph thuc t bo lympho T i vi khng nguyn ph thuc t bo lympho T th s kch thch t bo lympho B cn c s h tr ca t bo lympho T. Qua s hot ha ng thi ca t bo lympho T nhng cytokin s c gii phng. Mt s cytokin hot ng nh l yu t hot ha v / hoc tng trng i vi s chn ca t bo B nu s tip xc gia t bo lympho B v t bo lympho T c bo m nh vo phn t CD40 ca t bo lympho B vi cht gn CD40 ca t bo lympho T h tr. bit ha thnh tng bo sn xut khng th c hiu t bo lympho B phi nhn c 2 tn hiu ng thi: + S lin kt ca khng nguyn ln Immumglobulin b mt ca t bo lympho B (Tn hiu 1) + Th th ca t bo lympho Th nhn din phc hp khng nguyn- MHC lp II c vn chuyn ln mng t bo B, ng thi cht gn CD40 trn b mt t bo Th s gn ln CD40 trn t bo lympho B; qua cytokin mi c gii phng (IL4) v tc ng ln cht tip nhn ca cytokin trn t bo lympho B (Tn hiu 2) . 2 tn hiu t bo lympho B mi bit ha thnh tng bo sn xut khng th. Mt s cytokin khc c th gy chuyn i isotyp nh : IL2, IFN-g : Tc dng chuyn i IgM sang IgG1 , IgG3 IL4, IL13 : Tc dng chuyn i IgM sang IgE , IgD IL5, IL2 : Tc dng chuyn i IgM sang IgA v.v...

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Hnh 5. 5. C ch hp tc t bo lympho T v t bo lympho B 7.2. i vi khng nguyn khng ph thuc t bo T i vi khng nguyn khng ph thuc tuyn c th s h tr ca t bo lympho T l khng cn thit, t bo lympho B c th hot ha trc tip. Nhng khng nguyn ny thng l nhng khng nguyn c cu trc QKN lp li nhiu ln. V d: p ng min dch IgM chng lipopolysaccarid ca mng vi khun hoc khng nguyn nhm mu hay p ng IgG2 chng polysaccarid v ph cu vv... (c l c h tr t nhng cytokin khng phi t t bo lympho T) . II. p ng min dch qua trung gian t bo Min dch trung gian t bo thuc phm vi nhim v ca t bo lympho T. Sau khi t bo lympho T chm dt s pht trin ca mnh tuyn c, n i vo mu ri n c quan lympho ngoi bin. Sau n li quay vo mu tr li cho n khi gp khng nguyn. tham gia vo p ng min dch, cc t bo lympho T non phi c kch thch tng sinh v bit ha thnh nhng t bo c th tham gia vo vic loi b cc tc nhn gy bnh v lc ngi ta gi l t bo lympho T hiu lc. C ba dng hot ng ca t bo lympho T hiu lc: N pht hin cc khng nguyn bt ngun t cc yu t gy bnh khc nhau v c trnh din bi 2 loi phn t MHC khc nhau thng qua th th ca t bo lympho T (TCR ). Th th ca t bo T c tng hp cng tng t qu trnh hnh thnh phn ln khng th bi t bo lympho B. V l thuyt c khong 1015 cht tip nhn c hiu khng nguyn t bo c to thnh . Nhng khng nguyn ca cc tc nhn gy bnh pht trin trong bo tng (vi rut), cc protein ni bo v protein c hiu u ...(cn gi l protein ni sinh) th s c vn chuyn ln b mt t bo bi phn t MHC lp I v trnh din cho t bo TCD8 gy c n trc tip dit t bo nhim.

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Nhng khng nguyn ca nhng vi sinh vt gy bnh pht trin trong nhng ti ni bo v c vi khun tip nhn ngoi bo, c t ... cn gi l nhng protein ngoi sinh th s c vn chuyn ln b mt t bo bi phn t MHC lp II v trnh din cho t bo lympho TCD4. T t bo ny c th bit ha thnh 2 loi t bo lympho T hiu lc: - Bit ha thnh t bo lympho T gy vim ( cn gi l Th1); n s hot ha i thc bo nhim i thc bo c th tiu dit cc tc nhn gy bnh ni bo. - Bit ha thnh t bo lympho T h tr (cn c gi Th2); n s kch thch t bo lympho B sn xut khng th chng li tc nhn gy bnh (c t vi khun ) . Nhng t bo nh hng ln t bo lympho T hiu ng s c coi nh l t bo ch. p ng min dch trung gian t bo c vai tr quan trng trong vic loi b cc vi khun, vi rut sng trong t bo, cc t bo ung th v t bo ghp. 1. T bo lympho TCD4 v s khi ng p ng min dch. T bo lympho TCD4 khi ng c p ng min dch qua trung gian t bo ln min dch dch th : - Min dch trung gian t bo + T bo lympho TCD4 gy vim (Th1) c kh nng nhn din phc hp KN-MHC lp II trn i thc bo nhim hot ha i thc bo nhim, t i thc bo hot ha mi c th tiu dit tc nhn gy bnh. V d c ch khng vi vi khun lao, vi khun Hansen, Pneumocytis carinii... + T bo lympho TCD4 h tr (Th2) c kh nng nhn din phc hp KN-MHC lp II trn t bo trnh din khng nguyn ri tit ra cytokin (IL2, IL6, INFg) kch thch tin t bo T gy c thnh t bo T c hiu lc gy c (Tc).T t bo Tc mi c kh nng ly gii t bo ch. V d c ch khng vi vi rut cm , c t ... - Min dch dch th T bo lympho TCD4 h tr nhn din phc hp KN - MHC lp II trn t bo lympho B c hiu v hot ha t bo lympho B cho vic sn xut khng th chng tc nhn gy bnh. Bng cch tit cytokin, t bo lympho TCD4 s tp trung cc t bo hiu ng khng c hiu v kch thch chc nng hot ng ca chng bin cc t bo ny tr thnh cc yu t tham gia vo p ng min dch c hiu : + TNF- a v LT : hot ha bch cu a nhn trung tnh v t bo ni mc mch mu. + IL5 : hot ha bch cu i toan. + IFN-g :hot ha bch cu n nhn. + IL2 : hot ha t bo NK, t bo T v c t bo B 1.1 Qu mn mun v cc t bo hiu ng

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Qu mn mun l mt p ng min dch qua trung gian t bo trong t bo hiu ng quan trng nht l i thc bo. Kiu p ng ny l c ch khng i vi vi khun ni bo nh vi khun lao, Listeria monocytogen....Chng pht trin trong cc ti ni bo ca i thc bo do trnh c tc dng ca khng th v hiu lc c ca t bo Tc. Trong trng hp ny cc vi khun s b loi tr nu t bo T CD4 gy vim hot ha c i thc bo. V vy t bo T CD4 c th ng mt vai tr quan trng trong vic bo v chng li cc tc nhn gy bnh pht trin trong ti ni bo. S hot ha ai thc bo din ra qua du hiu lin kt mng ca t bo T CD4 gy vim v qua cytokin hot ha i thc bo do t bo Th1 tit ra (quan trng nht l IFN-g v c IFN-a).

Hnh 5.6. p ng min dch i vi VK ni bo c iu khin bi t bo TCD4 gy vim Cc cytokin c gii phng t t bo Th1 khi tip xc vi t bo trnh din khngnguyn: - IFN-g : hot ha i thc bo i thc bo tiu dit vi khun bn trong n . - LT (TNF-b ) : git cht cc i thc bo nhim mn gii phng cc vi khun bn trong n nhm li ko cc i thc bo mi n tiu dit . - IL-2 : tng sinh t bo T v s lng t bo hiu ng . - IL-3 + GM-CSF : gy bit ha i thc bo trong ty xng . - LT + MCF : gy xuyn mch i thc bo n vim . - MCF + MIF : tp trung i thc bo ti vim Mt khc khi i thc bo hot ha, n c th gy thng tn t chc ti ch; chnh v vy t bo ny phi c iu ha hot ha mt cch nghim ngt. T bo T CD4 gy vim (Th1) sn xut nhiu cytokin khc nhau khng nhng hot ha i thc bo nhim m cn git cht i thc bo gi gii phng cc vi khun cha bn trong no, nhm li cun i thc bo mi n vim. Nh vy t bo T

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CD4 gy vim ng vai tr quan trng trong vic kim tra v iu khin phn ng bo v ca tc ch i vi tc nhn gy bnh ni bo. Chnh s thiu ht chc nng ny ti bnh nhn AIDS m dn n s nhim khun ni bo trm trng v d lao, pneumocystis carinii...(do gim t bo Th1 nn khng hot ha c i thc bo; do gim kh nng khng ni bo). V d p ng qu mn mun: Khi tim protein tinh khit vi khun lao cho ngi nhim lao hoc chng lao. Khong 4 gi sau tim thy tp trung bch cu trung tnh; khong 12 gi sau thy thm nhim t bo T, bch cu n nhn, cc t bo ni mc mch mu co li v tng tnh thm, thot fibrinogen vo t chc, ni tim ph n v cm cng. Hin tng ny ch im mt phn ng qu mn mun, c th pht hin sau tim 24-48 gi. Phn ng ny c th truyn vay mn qua t bo T CD4. 2. Qu trnh x l khng nguyn, t bo trnh din khng nguyn v cc giai on nhn bit - hot ha. 2.1. Qu trnh x l khng nguyn. T bo T c th khng nhn din khng nguyn ha tan m protein phi c chuyn thnh dng c kh nng sinh min dch; iu ny din ra trong t bo trnh din khng nguyn. Sn phm cui cng ca mt qu trnh trnh din khng nguyn i vi t bo T CD4 l mt mnh peptit tng i ngn khong 10-20 a. amin c kh nng sinh min dch v lin kt ln protein MHC lp II trn mng t bo trnh din khng nguyn. S bin i mt khng nguyn t dng khng lin kt MHC thnh dng lin kt MHC s c coi l qu trnh x l khng nguyn. Qu trnh x l khng nguyn bao gm 4 giai on: - S nhp ni bo ca khng nguyn / t bo thc bo. S thc bo c th c mnh ln qua s lin kt ca phc hp khng nguyn khng th ln cht tip nhn mnh Fc ca thc bo n nhn hoc ca t bo B (FcR). - S phn ct khng nguyn bi enzym tiu protit trong cc ti ni bo (endosome). - S lin kt cc mnh peptit ln protein MHC lp II trong ti ni bo (endosome). - S vn chuyn phc hp peptit- MHC lp II ln mng t bo trnh din khng nguyn 2.2. T bo trnh din khng nguyn (APC) v cc giai on nhn bit, hot ha. -T bo trnh din khng nguyn l t bo c kh nng trnh din mnh peptit khng nguyn ln c 2 lp phn t MHC v chuyn giao mt tn hiu ng kch thch qua phn t B7. Ba typ t bo c th hot ng nh mt t bo trnh din khng nguyn c in l i thc bo, t bo bch tuc v t bo ympho B. Mi t bo c mt chc nng khc trong p ng min dch. T bo T ch c bit ha ri tng sinh khi n ng thi nhn c 2 tn hiu t cc t bo trnh din khng nguyn: - Tn hiu 1: Cht tip nhn ca t bo T nhn din phc hp khng nguyn-MHC trn t bo trnh din khng nguyn .

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- Tn hiu 2: L tn hiu ng kch thch qua phn t B7 trn t bo trnh din khng nguyn gn ln phn t CD28 ca t bo T. + i thc bo : Khi cha hot ha th khng hoc c rt t phn t MHC lp II v cng cha bc l phn t B7. S hnh thnh cc phn t ny s c to nn qua s tip nhn khng nguyn , ch yu l cc khng nguyn vi khun. + T bo bch tuc: N bc l nhiu phn t MHC lp I v c MHC lp II cng nh phn t ng kch thch B7. N trnh din cc peptit khng nguyn vi rt v c t t bo. Nhng peptit c trnh din ln MHC lp I th s c nhn bit bi t bo T CD8 t bo ny c th gy c trc tip hoc trnh din ln MHC lp II th s c nhn bit bi t bo T CD4 (n c th bit ha thnh Th1 v Th2). T bo Th2 s kch thch t bo lympho B sn xut khng th ngn cn s t nhp ca vi rt vo trong t bo Nh vy trong nhim vi rt, t bo bch tuc kch thch c t bo TCD8 ln t bo TCD4. + T bo lympho B: C kh nng nhn bit cc quyt nh cu trc ca protein v cacbonhydrat (khng nguyn ha tan) vi cht tip nhn mng IgM v IgD. Bn cnh chc nng to khng th, t bo lympho B cng c th ng vai tr ca mt t bo trnh din khng nguyn i vi t bo TCD4 qua MHC lp II v bc l c phn t B7 v d Staphylococcus aureus, Streptococcus pneumoniae, Clostridium tetani, Poliovirus, Pneumocystis carinii.... T bo B cng cn 2 tn hiu hot ha: - S lin kt ca khng nguyn ln IgM hoc IgD mng. - S hot ha qua cytokin hoc mt cu b th v d C3d. - S nhn din khng nguyn qua t bo T T bo CD4 v CD8 nhn din khng nguyn bng cht tip nhn khng nguyn ca t bo T qua s tuyn chn clon tng t t bo B. Tuy nhin c th n khng tip nhn khng nguyn ha tan t do m khng nguyn ch dng lin kt vi cu trc MHC c trnh din ln mng t bo trnh din khng nguyn hoc t bo ch ( s gii hn bi MHC)

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Hnh 5.7. Cc t bo lympho T hiu lc i vi cc tc nhn gy bnh khc nhau Tm li s quyt nh p ng min dch dch th hay min dch t bo l chnh hoc phi hp c hai, iu ny ph thuc vo s bit ha ca t bo TCD4 thnh t bo Th1 hoc Th2. S hot ha tuyn chn thnh TCD4 gy vim th p ng min dch trung gian t bo l chnh v ngc li thnh TCD4 h tr th p ng min dch dch th l chnh. Ngi ta nhn thy vai tr MHC v cytokin c to ra c nh hng n con dng bit ha ny. V d i vi vi khun Mycobacterium chng hn; vi khun xm nhp vo c th th pht trin trong cc ti i thc bo. Mt p ng c hiu lc ca tc ch l i hi phi hot ha c i thc bo qua TCD4 gy vim.

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+ Ti bnh hi lnh tnh th c (Tuberculoid leprosy): ch yu TCD4 gy vim c cm ng, ngi ta thy c mt t vi khun sng st , mt t khng th c to thnh v hu ht ngi bnh c sng st (Th1 tit IFN-g, IL-2, TNF-a) + Ti th hi c tnh: ch yu TCD4 h tr c cm ng nn p ng min dch li l dch th. Khng th khng hiu qu i vi cc vi khun ni bo , do vi khun hi pht trin khng b km ch .Th ny thng a n t vong (Th2 tit IL-4 v IL-10 ) II. S C T BO TRUNG GIAN QUA T BO T Tt c cc vi rt v mt s vi khun ch c pht trin trong bo tng ca t bo nhim v rt l mt loi k sinh phc tp, n khng c b my tng hp v chuyn ha ring. Do pht trin trong bo tng nn trnh c tc dng ca khng th, do n ch b tiu dit khi git cht t bo nhim. Trong trng hp ny t bo TCD8 gy c ng vai tr quan trng v n c th git cht mt cch c chn la cc t bo nhim ny. S bit ha t tin Tc thnh t bo Tc c th gy c trc tip cng i hi 2 tn hiu: + Tn hiu 1: Cht tip nhn t bo T nhn din phc hp KN-MHC lp I trn t bo trnh din khng nguyn hoc t bo ch . + Tn hiu 2: Cytokin do t bo TCD4 tit ra (IL-6, IL-2, IFN-g) khi n nhn din chnh khng nguyn y trn t bo trnh din khng nguyn. Trn sc vt thc nghim, nu loi b t bo TCD8 gy c th con vt s b nhim vi rt rt nng n.Tng t chut hay ngi nu thiu MHC lp I cng vy s b nhim trng vi rt rt nng (MHC lp I cn thit trnh din khng nguyn vi rt cho t bo TCD8) - Chc nng chnh ca t bo Tc Bng cch ly gii t bo ch, t bo Tc c kh nng git cht cc vi sinh vt pht trin trong bo tng m ch yu l vi rt v mt s vi khun (Toxophasma gondii,...). Mt khc n cng c kh nng git cht cc t bo ung th v cc t bo ghp. loi b cc t bo nhim hoc t bo l m khng hy hoi t bo lnh, t bo TCD8 ch git cht mt cch c chn la nhng t bo ch bc l khng nguyn c hiu m thi. T bo TCD8 gy c cng sn xut IFN-g v c TNF-a km hm s nhn ln ca vi rt,lm tng s bc cc phn t MHC lp I v hot ha i thc bo. - C ch ly gii ca t bo Tc. c th ly gii t bo ch, trc ht t bo Tc gn ln t bo ch thng qua cht tip nhn c hiu KN-MHC lp I. Sau gy hiu lc c trc tip bng cch gii phng 2 loi cytotoxin l fragmentine v perforin. Perforin s khoang nhng l thng qua mng t bo ch fragmentine (cn gi l Granzyme) c th i vo trong t bo v tiu dit t bo ch gi l s git cht t bo c chng trnh ha. C ch th 2 lin quan n cc cht c t bo hot ha enzym, c th l lymphotoxin hoc cht

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c cu trc tng t. N hot ha enzym phn ct phn t DNA ca t bo ch; v khi DNA b phn ct th t bo ch cng b phn ct v cht gi l hin tng Apoptose. III. T BO DIT T NHIN T bo dit t nhin l di nhm ca t bo lympho T c ngun gc ty xng.N c kh nng dit mt s t bo u hoc t bo nhim vi rt . Kh nng ny khng c hiu v khng b gii hn bi phn t MHC nn c gi l t bo dit t nhin. T bo NK c hot ha bi IL-2 v nht l IL-12 v t gii phng TNF-a, IFN-g. T bo NK c th th dnh cho mnh Fc ca phn t IgG nn c kh nng ly gii t bo ch thng qua hin tng ADCC (antibody dependent cellular cytotoxicity): u tin khng th c hiu gn ln t bo ung th hoc t bo nhim vi rt. Tip theo phc hp ny gn ln t bo NK thng qua th th dnh cho mnh Fc, do t bo NK c iu kin tip cn vi t bo ch v tiu dit t bo ch. Trong trng hp IL-2 c nng cao, t bo NK s bit ha thnh t bo LAK (Lymphokin Activated killer ) c kh nng dit t bo ung th rng ri.

Chng 6 IU HO P NG MIN DCH

Hot ng ca h thng min dch l hot ng ca cc t bo nhm phn bit ci ti v ci khng phi ti. Khng nguyn xm nhp vo c th kch thch s hot ha ca cc t bo lympho B v t bo lympho T v p ng min dch c khi ng; cc t bo tr nn tng sinh mnh m. Bng thc nghim, ngi ta nhn thy cc dng t bo B c th tip tc pht trin n mc v hn khi c c cc i kin thch hp trong nui cy. Nhng iu ny khng xy ra trong c th, tr khi c tn thng bnh l dng t bo min dch nh trong lon sn tng bo. Ngoi ra khi khng nguyn xm nhp vo c th, p ng min dch c huy ng ph hp vi bn cht ca khng nguyn nhm loi tr khng nguyn v bo v cho c th. iu ny c ngha l c s kim sot v iu ha p ng min dch trong c th. Cc t bo tham gia vo p ng min dch nn s tng tc v iu ha gia chng vi nhau cng nh trong h thng ni tit, cc phn t tham gia p ng thng tin ny c th ngay trn mng t bo gi l th th t bo, sIg v qua cc cht do t bo tit ra (cytokin, khng th, ha cht trung gian). I. Khng nguyn Mt khng nguyn khi vo c th c th c hai kh nng: - Kch thch c th p ng min dch (immunogen) - Khng gy p ng min dch gi l dung th min dch (tolerogen) 1. C ch dung th: c ch dung th l c ch gip cho c th khng chng li khng nguyn bn thn v cn gp trong nhng trng hp dung th i vi nhng khng nguyn t bn ngoi vo.

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1.1. Vai tr dung th khng nguyn: khng nguyn bn thn c dung th bi t bo lympho T v B; khng nguyn l l cht gy p ng min dch nhng cng c th gy dung th tu theo bn cht l ho, liu lng mn cm v ng vo ca chng. C ch dung th trong c hai trng hp trn ging nhau, dng t bo lympho b c ch vi khng nguyn gy dung th. Dung th hay gy p ng min dch th cng qua con ng tng tc vi th th nhn din khng nguyn TCR v BCR (sIg), kt qu ph thuc vo giai on pht trin ca dng t bo lympho cn non hay chn v bn cht khng nguyn. C ch chung ca dung th l (1) khng nguyn lm cht dng t bo c hiu, d xy ra mt giai on nht nh trong qu trnh bit ho dng (2) khng nguyn gy ra s tr (v cm) khng cn cm ng ca dng t bo. 1.2. C ch dung th ca t bo lympho T : duy tr s dung th vnh vin i vi khng nguyn bn thn bng c ch loi tr v v cm - Cc dng t bo lympho Tc v Th t phn ng vi khng nguyn bn thn thng b cht tuyn c giai on trng thnh bit ho do b loi tr vnh vin. Tuy nhin nu khng nguyn khng c mt tuyn c trong thi k ny th nhng dng t bo tng ng s khng b loi tr ; sau ny c dp c th gy bnh t min chng li cc khng nguyn trn. C ch v cm cho thy d khng nguyn c kt hp vi MHC lp II (i thc bo) cn thit c s kch thch ca cc yu t dch th nh IL-1 mi hot ho c t bo lympho Th. S v cm c th xy ra nu i thc bo khng to c tn hiu ny. S v cm ny c th xy ra t giai on bit ho tuyn c, khi tip xc vi khng nguyn bn thn. - C ch dung th ca t bo B xy ra vi 2 c ch trn. Vic loi tr dng t bo B xut hin khi n trng thnh v bit ho tu xng nu tip xc vi khng nguyn giai on non lc t bo B ch c sIgM nn d v cm. Ngoi ra tnh v cm cn c gy ra do tng tc gia khng nguyn v BCR do c ch v cm mc du c y sIg kt hp vi khng nguyn 2. Khng nguyn tham gia kim sot p ng min dch KN c nh hng n phng thc v cng ca p ng min dch. 2.1. Bn cht khng nguyn 2.1.1. Cu trc ho hc kch thch p ng min dch khc nhau. Khng nguyn polysacharid v lipid khng kch thch p ng min dch t bo. p ng min dch dch th i vi khng nguyn ny khng ph thuc t bo lympho T, ch yu khng th thuc lp IgM c i tnh thp, khng c phn ng th pht v t bn vng. Cc khng nguyn protein gy p ng min dch t bo ln dch th gp trong mt s nhim khun v a s vi rt, Ig ch yu thuc lp IgG d dng to ra p ng min dch tin pht v th pht. p ng c min dch nh ko di. Do cc trng hp nhim vi rt t nhin hay do chng nga c sc khng nhiu nm v c khi c i. Trng hp khng nguyn tc ng

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trc tip t bo lympho T m khng cn MHC lp II trnh din gi l siu khng nguyn nh c t rut ca lin cu khun v khng nguyn v nhn (nucleocapside) ca vi rut da. Ngi ta cng c th chia khng nguyn khng ph thuc t bo lympho T (khng ph thuc tuyn c) lm hai loi l khng nguyn TI-1 v khng nguyn TI-2, hot ho t bo B theo hai c ch khc nhau: Khng nguyn TI-1 c th trc tip hot ho t bo lympho B v dn n phn bo. nng cao, cc khng nguyn ny c th tng sinh v bit ho t bo lympho B m khng cn tnh c hiu, gi l hin tng hot ho a dng, khng nguyn ny cn c gi l yu t phn bo t bo B (v d LPS). Tuy nhin nng thp th cc khng nguyn ny ch gn vi cc th th c hiu c trn b mt t bo B v hot ho c hiu t bo B Bng 6.1. p ng min dch i vi cc loi khng nguyn

Khng nguyn TI2 khng ph thuc tuyn c nh cc polysaccharid v vi khun c cu trc lp li c kh nng hot ho t bo B bng con ng bn ngoi. Trong khi khng nguyn TI-1 c th hot ho c t bo B cha trng thnh v trng thnh th khng nguyn TI-2 ch c th hot ho t bo B trng thnh, iu ny gii thch ti sao tr em kh c th sn xut y khng th chng khng nguyn polysaccharid. Khng nguyn TI-2 hot ho rng ri t bo B nh lin kt cho vi cc th th b mt, tuy nhin nu mt lin kt qu nhiu c th lm cho t bo B tr nn v cm (anergy). 2.1.2. Liu lng khng nguyn: liu khng nguyn ln hay liu nh tim nhc li thng c kh nng c ch p ng min dch (hin tng dung th min dch). Gii thch trong nhim khun nng, bnh nhn khng p ng min dch. Nng khng th gim khi nng khng nguyn gim. Nu mt c ch ny, c th s trn ngp cc dng t bo lympho c hiu v cc sn phm ca chng (Ig, cytokin)

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2.1.3. ng vo khng nguyn: p ng min dch i vi khng nguyn thay i theo ng vo ca khng nguyn . Khng nguyn theo ng mu c khuynh hng gy sc phn v hoc gy dung th min dch, khng nguyn tim ng di da kch thch t chc lympho hch gn . 3. Tc dng iu ho ca khng th 3.1. iu ho m tnh ngc: Cc khng th c sn xut trong qu trnh p ng min dch c th c ch tr li p ng to khng th. Tim cc khng th c hiu vi mt loi khng nguyn no vo tnh mch trc hoc trong khi gy mn cm vi chnh khng nguyn th lng khng th sn xut s gim. Hin tng ny gi l c ch iu ho m tnh ngc nh vo: - Trung ho khng nguyn v loi tr khng nguyn bng c ch thc bo - Khng th phong b cc quyt nh khng nguyn ngn cn quyt nh khng nguyn tip xc vi sIg trn t bo lympho B khng cho hot ho t bo B. - Khng th gn vi th th Fc c trn t bo lympho B s c ch trc tip hot ho.S c ch xy ra khi ng thi c s tng tc gia khng nguyn vi mnh F(ab)2 v mnh FcIgG ho tan vi th th Fc chnh ngay trn t bo . Vy khng th c ch ngc s sn xut khng th l thng qua vai tr c ch chnh ca FcR trn t bo lympho B - Cc phc hp min dch: Phc hp min dch c th c ch s hot ho ca ca t bo lympho Th hay cm ng t bo lympho Ts. Cc phc hp min dch c th lm ri lon sn xut cytokin. i thc bo khi tip xc vi phc hp min dch, c th sn xut cht chng th th ca IL-1 (anti - IL-1R), cht ny cnh tranh vi IL-1 gn vi IL-1R gy c ch p ng min dch v gim sn xut IL-2. ng dng thc tin trong iu ho m tnh ngc khng th l d phng tan mu trong bt ng nhm mu Rhsus gia m v con. 3.2. Idiotyp v mng li idiotyp-anti idiotyp tham gia iu ho min dch C ch ny t cn bn vo gi thuyt mng li iu ho idiotyp v anti idiotyp ca Niels jerne, sau c gii Nobel nm 1974. Gi thuyt nu ln rng mt khng nguyn kch thch p ng t bo lympho c hiu ng thi gy ra hng lot p ng khc qua khng th anti idiotyp. Theo gi thuyt mng li, h min dch duy tr c trng thi n nh l do tng tc gia idiotyp v anti idiotyp. 3.2.1. Khng th anti idiotyp: tnh a dng ca phn t khng th cho php nhn din c v s cc quyt nh khng nguyn (epitope) nm trn phn t khng nguyn , c c kh nng ny l do s bin i cc k nhy cm ca vng siu bin trong vng thay i (vng V) ca F (ab), s bin i ny to nn nhng quyt nh khng nguyn mi. Cc t bo lympho nhn din cc khng nguyn khng nh l khng nguyn ca bn thn. Cc nghin cu thc nghim cho thy trong c th lun tn ti cc dng t bo lympho c kh nng nhn din b mt kt hp khng nguyn ca cc khng th (khng nguyn idiotyp) cng nh cc th th trn b mt ca cc t bo lympho khc. p ng c hiu i vi idiotyp to ra khng th anti idiotyp. Cc quyt nh khng nguyn to nn idiotyp gi l idiotop,

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phn vng V to nn din kt hp c hiu vi idiotop ,gi l paratop, mt s khc nm ngoi vng kt hp vi khng nguyn . i vi khng th anti idiotyp thu c c th phn lm hai loi (1) khng th chng cc idiotop bn trong paratop (2) chng li cc idiotop nm ngoi paratop. Nh vy ch c loi th nht l tc dng ln din kt hp ca khng nguyn s c ch phn ng min dch, nhng anti idiotyp khc th gn ln cc quyt nh khng nguyn nm ngoi vng kt hp khng thuc v tr c hiu khng nguyn , cc v tr ny c th xut hin cc Ig khc; do mng li idiotyp-anti idiotyp s iu ho min dch i vi a khng nguyn (c th xy ra vi cc th th b mt t bo lympho B v T). 3.2.2. C ch iu ho ca mng li idiotyp v anti idiotyp : thc nghim chng minh s dng khng nguyn gy mn cm cho sc vt th nht c khng th chng khng nguyn . Tinh khit khng th ny v nh s l KT1 (tc l Id1); Sau tim id1cho sc vt th hai c khng th th 2 (Id2); ngi ta li tinh khit Id2 mn cm cho sc vt th 3 v c tip tc nh th. Kt qu cho thy KT 2 (Id2) chnh l anti Id1, s nhn bit Id1 c trn KT1 nhng ng thi cng nhn bit c Id1 c mt trn KT3 (anti Id2 tc Id3). Tng t KT4 c tnh cht ging KT2.v.v. nhng ch phn nh KT3 (anti Id2) l kt hp vi khng nguyn u tin. Nh th mt Id c th c nhiu nhm quyt nh khc nhau ca khng nguyn c th khi ng cc t bo B c hiu khc nhau nn thng c mng idiotyp gy phn ng cho iu ho p ng min dch cho n khi nng khng nguyn hay khng th gim dn v tr v nh lc cha mn cm, ngha l dp tt p ng min dch III. Vai tr ca cc t bo trong iu ho p ng min dch 1. Vai tr ca t bo lympho Ts (suppresseur) T bo Ts l di nhm ca t bo lympho T, khc vi Th v Tc. T bo Ts c chc nng c ch giai on hot ho p ng min dch . Nm 1960 R. Gerhson v cs chng minh vai tr ca t bo Ts khi thc nghim trn chut; bng cch tim mt liu khng nguyn rt ln theo ng tnh mch th chut khng p ng min dch . Tip tc tim tr li liu khng nguyn bnh thng sinh min dch nhng chut cng khng p ng. Nu ly t bo lympho ca chut khng p ng ny tim cho chut ng gen th tnh trng tr ny cng xy ra d vi liu tim khng nguyn bnh thng . S c ch ny khng xy ra vi loi khng nguyn khc. Tnh trng khng p ng min dch c th chuyn t c th ny sang c th khc v c chng minh do di nhm t bo lympho Ts c hiu m trch. Vai tr t bo Ts quan trng trong nhng trng hp sau: - c ch p ng min dch i vi nhng t khng nguyn khng tip xc vi cc t bo lympho non trong qu trnh bit ho ti tuyn c.

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- C th c ch p ng min dch i vi khng nguyn ngoi lai qua c ch t bo lympho Th v trc tip vi t bo B do nhng chng minh vai tr khi ng ca t bo Th i vi t bo Ts. 2. Vai tr ca cc t bo h tr T bo lympho Th to thun cho p ng min dch ca t bo lympho B ch yu l thng qua cc cytokin, s h tr ny c hiu vi cc isotyp ca Ig v t bo Th c th th vi cc Fc ca cc lp ca Ig khc nhau. S h tr ca t bo Th trong p ng min dch l i vi khng nguyn ph thuc tuyn c. T bo Th c vai tr ca trong nhn bit quyt nh khng nguyn ca protein ti v t bo B nhn bit quyt nh khng nguyn ca hapten. Kh nng chng minh bng thc nghim nh sau: S dng khng nguyn tng hp bng cch gn hapten DNP (dinitrophenol) vi albumin b (AB), gy mn cm cho chut nhiu ln. Nu ti mn cm vi chnh DNP -AB th p ng th pht mnh; nu ln 2 tim DNP gn vi lng trng trng g (OA) ngha l thay i cht ti th khng xut hin p ng vi DNP-OA. Th nghim cho thy t bo Th nhn din nhm quyt nh khng nguyn ca protein ti v t bo B nhn din hapten. Ngoi ra Th cn tc ng vo t bo lympho tin Tc tr thnh t bo Tc hot ho thng qua cc cytokin. Cc t bo h tr khc nh i thc bo, t bo lympho B v t bo tua u cn thit cho p ng ph thuc tuyn c. i thc bo trnh din khng nguyn cho t bo lympho T bo gii hn bi phn t MHC, chng sn xut cc cytokin (ng kch thch) lm tng sinh v hot ho cc t bo T bo v B tng ng. IV. Tc dng iu ho min dch ca cc cytokin Bng 6.2. Chc nng iu ho ca cytokin

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Bn cnh tc dng iu ho ca khng nguyn, khng th, t bo lympho Ts, Th th cc cytokin do cc t bo hot ho tit ra c th tng cng hay c ch p ng min dch. Tc dng ca cytokin thng khng c hiu. Chc nng kch thch ca cytokin thng nhm khuch i p ng min dch nhm loi b khng nguyn . Cc cytokin thng c sn xut lin tip v nh hng ln nhau c v s lng v chc nng. V d vng kn khuch i p ung min dch ca cytokin l tng tc hai chiu ca t bo lympho T v i thc bo. T bo lympho Th1 tit IFN-g tng biu l MHC lp II trn i thc bo lm cho i thc bo hot ho mnh hn tr li tng cng cho t bo lympho Th1. i vi t bo lympho B th tc dng ca IL-4 lm tng biu l MHC lp II. T bo lympho Tc tit IFN-g, TNF-a, IL-2 tng biu l MHC lp I t bo ch nn tng cng tng tc gia t bo lympho Tc v t bo ch. Nh vy, i vi t bo lympho T tu theo s hot ng ca t bo lympho Th di nhm Th1 hay Th2 m hot ng min dch qua trung gian t bo c tng cng hay c ch. Ngoi ra, cn c cc cytokin c ch p ng min dch nh TGF-b do nhiu loi t bo tit ra k c t bo lympho T; prostaglandin E2 hot ho AMPv nn c ch tit IL-1; TNF-a ngn cn hot tnh IL-2 v gim bc l MHC ca t bo T. v.v. V. nh hng ca cc yu t di truyn v thn kinh - ni tit 1. Chng minh gen nh hng chc nng p ng min dch - Thc nghim chng minh c hn 10 cm gen lin quan n kh nng x l v trnh din khng nguyn ca i thc bo. - Gen p ng min dch gn lin vi gen Ig: gen m cho idiotyp ca khng th chng li hapten pazophenylarsonate gn vi gen m cho vng C ca Ig trn nhim sc th, do ngi ta sn xut c khng th c hiu idiotyp ny. Kh nng sn xut cc loi khng th khc nhau c th b gii hn nu s lng gen vng thay i (gen V) trn nhim sc th c hn: chut thiu gen Vdex th khng p ng vi dextran -Lin quan vi phc hp MHC: thc nghim vi cc khng nguyn n gin, ngi ta chng minh mi chng chut c kh nng p ng khc nhau i vi tng loi khng nguyn. p ng min dch lin quan gen Ir chut nht hay gen MHC lp II ngi v khng nguyn ch c trnh din vi t bo lympho T do MHC lp II . 2. Vai tr ca h thn kinh - ni tit 2.1. Tc ng ca ni tit trn t bo min dch : cc t bo min dch c nhiu th th i vi ni tit nh corticoid, insulin, GH, oestradiol, testosteron, acetylcholin, endorphin, enkephalin. Cc glucocorticoid, oestradiol, testosteron, progesteron c ch p ng min dch trong khi GH, thyroxin v insulin th ngc li. Thc nghim ct tuyn thng thn hay b stress u c lin quan bin i t

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bo min dch. Sau khi mn cm khng nguyn, giai on t khng th cao nht th nng glucocorticoid cao s c ch p ng min dch 2.2. Tc ng ca h min dch trn h thn kinh - ni tit IL-1 kch thch s tng hp glucocorticoid thng qua trc tuyn yn - thng thn; to cc ni tit ti ch nh prostaglandin; IL-1 v TNF-a gy st thng qua ri lon trung tm iu nhit. Ngoi ra mt s cytokin cn nh hng ln chc nng khc ca c th nh gy ra hi chng suy mn c th trong nhim khun nng ko di do IL-1 v TNF-a, tc ng ln tu xng kch thch to t bo mu.v.v. 2.3. Tc dng ca ch n, luyn tp .v.v. - Ch n y cht dinh dng s tng cng kh nng thc bo, p ng to khng th, kh nng dit khun ni bo. Thiu km trong ch n lm gim hot tnh sinh hc ca thymulin (hoc mon tuyn c) v lm gim p ng min dch t bo . - Tp luyn hoc lao ng nng s gy stress lm suy gim min dch v tng nhy cm vi nhim khun. - Tui gi thng gy gim p ng min dch t bo, nhng ngi c tui th cao thng c chc nng min dch tt. Nhng hiu bit v iu ho min dch khng phi ch c vai tr quan trng trong min dch hc c bn, nghin cu v hot ng sinh l ca h min dch m cn c ch trong vic thit k vc xin, cho vic iu tr cc bnh l min dch nh t min, suy gim p ng min dch v qu mn.

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