Cytokin.pdf

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1.1. D~c tinh chung cua cac cytokin Cytokin la cac polypeptid duce san xufrt khi eo kich thich cua vi sinh vat hay cac khang nguyen khac nham trung gian va di~u hoa cac phan irng mi~n dich v~ viem (Hinh ). M~c du cytokin eo cfru true khac nhau nhung chung eo nhieu tinh chat chung. - Cytokin duce bai ti€t voi hrong nho va tu han che. - Cac phan ling cua cytokin tlnrong da huong va trung l~p (Hinh 2). - Cytokin nay thirong anh hirong d€n sinh t6ng h<JPva tac dong cua cytokin khac. ,-Mi'7'· b,-djdI----::b,;.m-oInh----,1

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Hinh 1. Cac chirc nang cua cytokin trong suc d~ khang cua eo th~ chii

(A) Trong miin dich bdm sinh, cac cytokin duac san xudt bai dai thuc bao va td bao NK va lam trung gian cho dap ung viem chong lai vi sinh vdt. (B) Trong miin dich thu duac, cytokin kich thich sir tang sinh va biet hoa lympho bao da tidp xuc khang nguyen va hoat hoa CClc

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- Tac dong cua cytokin eo th~ mang tinh cue bQ hoac h~ thong, - Cytokin b~t dAu tac dong cua minh nho g~n vao thu th~ d~c hieu cua minh tren mang t~ bao dich,

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.. - Nhirng tin hieu ben ngoai eo th~ di~u hoa str bQc IQ cua thu th~ cytokin vi th~ di~u hoa luon ea dap ling cua cytokin. - Tac dQng cua da s6 cytokin tren t~ bao la tao ra bi~n d6i bieu hien gen, lam xuc1thien cac chirc nang moi va doi khi gay tang sinh t~ bao dich.

Hinh 2. Cac tinh chit cua cytokin Day la cac vi du v~ cac tinn chat cua cytokin: tinh tdc a(mg da huong: mt5tcytokin co thi cho tdc dung len nhi~u d bao khdc nhau, tinh tac at5ng trung lij.p: nhi~u cytokin co thi co cung tac dung tren mt5t loai ti bao, tinh hiep luc: hai hay nhieu cytokin tao tac dung manh hen mt5t loai, VG tinh a6i khang: mot cytokin co tld uc chi tdc a(jng cua m(jt cytokin khac.

1.2. Chtrc niing cua cytokin Cytokin eo 3 chirc nang chinh: 1. Lam ch~t trung gian va di~u hoa mi~n dich barn sinh: day la cac cytokin duce san xuat boi thirc bao don nhan. Vi~c san xuc1tcac cytokin nay

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duce kich thich boi cac san pham cua vi khuan nhu lipopolysaccharid (LPS) hoac cua v:irus nhu ~NA chu6i kep va chung hoat dQng nhu la mQt bQ ph~ . cua h~ mien dich barn sinh. Ciing eo khi cac cytokin nay diroc san xuat do kich thich cua te bao T d~c hieu khang nguyen, luc nay chung hoat dQng voi tu each la mQt bQ phan cua h~ mi~n dich thu duce. Tac dQng cua nhom cytokin nay la tren te bao nQi mo va cac ID~i bach cau de tao ra phan irng viem som. T~ bao NK ciing san xuAt mQt sB cytokin, 2. Lam chAt trung gian va di~u hoa mi~n dich thu duce: day la cac cytokin duce san xuAt boi chu yeu la te bao lymph6 T nh~m chong lai khang nguyen la. MQt sB cytokin eo tac dung chu yeu la di~u hoa su tnrong thanh va biet hoa cua cac quan the Iympho bao khac nhau do do chung dong vai tro quan trong trong giai doan hoat hoa cua dap irng phu thuoc te bao T. MQt sB cytokin khac eo xuAt xir nr te bao T lai quan trong trong giai dean hieu qua vi chung eo clnrc nang di~u hoa cac loai te bao hieu qua nhu thirc bao, te bao trung tinh, ai toan, ... 3. Lam chAt kich thich tao mau: cac cytokin nay dO' cac te bao dem, bach cfru va met vai te bao khac cua my xirong san xuat, Chung eo the kich thich su phat trien va biet hoa cua bach cdu non, Tom lai, cac cytokin cua h~ rrii~n dich barn sinh va thu duce thirong do nhieu loai te bao khac nhau san xuAt va tac dQng -len nhieu loai te bao dich khac nhau. Tuy nhien, str phan biet nay khong eo tinh tuyet dBi vi mot cytokin.co th~ duce san xuAt ea trong dap irng barn sinh l~n thu duce, va cac cytokin khac nhau eo th~ tao ra mQt sB tac dung giong nhau.

1.3. Thl! thi Vtl tin hiju cytokin Tilt ea cac thu the cytokin d~u eo mot hoac nhieu protein xuyen mang va phan n~m ben ngoai te bao la phan g~n voi phan tir cytokin de tao ra luong tin hieu truyen vao, ben ~ro~g te bao. Cac thu the cytDk}n duce phan loai dua tren tinh tirong d6n~ ve eau true cua cac domain gan ket cytokin ben ngoai te bao. Co 5 ho thu the cytokin (Hinh 3A). 1. Th\1 th~ cytokin typ I: con duce goi la thu the tao mau, clnra mot hoac nhiSu ban sao cua m<)tdomain eo 2 c~p phan Ur cB dinh cystein va mot trinh tu can mang tryptophan-serin-X-!ryptop~an-serin (WSXWS), tro~g do X la mot acid amip batky. LO,}ithu the nay tiep nhan cac c¥tokin c~ eau tao cuon thanh 4 chuoi xoan c. Nhfrng thu the nay eo cac chuoi lien ket ligand d~c biet va mot hoac nhieu chu6i truyen tin hieu eo cAu true giong nhau khi tiep nhan cac cytokin khac nhau (Hinh 3B). 2. Thu th~ cytokin typ 11: loai nay ciing giong typ I vi eo 2 domain ngoai bao mang phan nr cB dinh cystein, nhung typ 11 khong eo trinh tu c~n mang WSXWS. Th\1 th~ IO,}inay eo mot chu6i polypeptid lien ket ligand va met chu6i truyen tin hieu.

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3. MQt 86 thu th~ cytokin eo cac domain Ig ngoai bao va duce xep vao sieu ho Ig. Nhom thu the nay lien ket voi nhtrng cytokin khac nhau va truyen tin hieu theo nhirng eo ch€ khac nhau. 4. Thu th~ TNF thuoc ve mQt ho thu th~ (trong do eo nhieu thu th~ khong phai cua cytokin) eo mang cac domain ngoai bao clnra nhieu phan tU c6 dinh cystein. Khi lien k€t voi ligand, cac thu th~ nay hoat hoa mQt 86 protein nQi bao d~ tao nen hien nrong chet l~p trinh (apoptosis) hoac kich thich bieu hien gen, hoac ea hai. C6c "" ••••••• qtoIda Thv H'l.in ~~I(hernop>ietin)

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B. Cac thu thJ cytokin duce cdu tao bai cac chuJi lien kit ligand ilij.c hi?u cytokin (thuang la chuJi

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5. Thu thS bay vong xoan xuyen mang hay con goi la, thu th~ hinh rftn boi vi cac domain xuyen mang cua chqng eo hinh dang giong con ran chay qua chay ve hai ben mango Trong h~ mien dich, thu the loai nay lam trung gian cho cac phan irng nhanh va thoang qua cua met h~ cytokin eo ten la chemokin

2. Cac cytokin trung gian vi di~u hoa mi~n djch bArn sinh 2.1. TNF (tumor necrosis factor) '" TNF la chat trung gian chinh cua phan irng viem cap chong vi khuan gram am va ,mQt ~o vi sinh v~t khac. TNF dQng thoi cling la chat chiu trach nhiem ve nhieu bien clnrng toan than cua nhiem trung nang. TNF lan, dau tien diroc tim thay trong huyet thanh dong v~t,xu ly voi noi 9QCto vi khuan (LPS) va eo me dung gay ra SlJ hoai tUcua cac khoi u trong eo the khi hien dien voi hrong loo.

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2.1.1: Nguim g6c, thl} thi , , , Nguon san xuat TNF chu yeu hi thirc bao don nhan.juy nhien mQt so te bao khac nhir Iympho T, NK, duong bao puI!,g eo the tiet r~ chat nay. Kich thich manh nhat doi voi dai thirc bao de clan den san xuat TNF la LPS. Ngoai ra, mQt luong IOn cytokin nay con duce san xu~t boi cac vi khuan gram, am. Cac interferon y do te bao T va NK san xuat cling eo tac dung khuyech dai sinh tong hQP TNF cua dai thuc bao da duce LPS kich thich. Co 2 loai thu the cua TNF, loai eo trong hrong phan tU 55 kD eo ten l~ THF-RI va loai cQ trong hrong phan tU 75 kD eo t~n la TNF-RII. Cac thu the nay eo mat tren hau het cac loai te bao trong eo the. 2.1.2. Hoat tinh sinh hoc - Chirc n5ng sinh Jy chfnh c~a TNF la kich thich t~p trung, h~ bao trung tinh va te bao mono den noi nhiem trung va hoat hoa nhirng te bao nay de tieu diet vi khuan (Hinh 4). TNF lam bQCIQcac phan nr k€t dinh tren t~ bao nQ,imo lam dinh lai t€ bao bach eau, trung tinh va mono tai day. Hai phan tU ket dinh quan trong 6 day la selectin va ligand, danh cho integrin bach cau., , TNF kich thich te bao noi mo va dai thirc bao tiet ra chemokin nham tang cuong ai hrc cua integrin bach cAu d6i v6i ligand cua chung v,a tao nen str ,t~p trung bach eau, TNF con kich thich thirc bao don nhan tiet IL-I la chat eo tac dung rat giong TNF. " Ngoai, vaitro trong viem, TNF con khoi dQng cai chet l~p trinh doi voi mot so te bao. - ·Trong nhiem trung tram trong, TNF duce san xu~t ~ai luong IOnva g~y nen nhirng trieu chirng lam sang toan than cling voi cac ton thuong giai phau benh. N eu su kich thich san xuat TNF du jnanh thi no eo the gay ra san xuat thir~ TNF va hrong nay se tran vao mau de den gay ra cac tac dong 6 xa vi tri nhiern trung nhir mot hooc-mon v~y. Cac tac dong toan than cua TNF bao gom: + TNF tac dQng len vung dum d6i dS gay ra s6t, do do nguoi ta goi no la ch~t gay s6t noi sinh (dS phan biet voi LPS la ch~t gay s6t ngoai sinh). S6t xay ra do TNF (va ea IL-I ) duce thirc hien qua trung gian cua sinh t6ng hQPprostaglandin. Do vay, cac chat khang prostaglandin eo thS giam s6t do TNF va IL-l. + TNF tac dong len t~ bao gan lam tang t6ng hQP protein huyet thanh. Nhtrng protein huyet nrong do gan san xuat diroi tac dong cua TNF, IL-I va IL-6 tao nen dap irng pha cdp cua phan irng viem. + Su san xuat TNF keo dai gay ra tieu hao t€ bao eo va ma va cuoi cling dfin d€n suy kiet. + Khi mot hrong loo TNF duce san xuat thi kha nang eo eo tim va eo tron thanh mach bi ire ch€ gay ra 1\1thuyet ap va d6i khi ea s6c.

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Hinh 4. Cac hoat tinh sinh hoc cua TNF

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trung binh, TNF lam trung gian cac tac a(jng toan thdn cua phan tmg viem. Va vOi n6ng a(j cao, TNF gay ra cac bat thutmg benh Iy cua s6c nhiim trung.

+ TNF gay ra huyet kh6i nQi mach do tS bao nQi mo m~t tinh chat chong dong binh thirong. TNF kich thich t€ bao nQi mo bQc IQy€u t6 mo la mot ch~t heat hoa dong mau manh. Kha nang cua ch~t nay trong viec hoai tu u nhir ten goi cua no la k€t qua cua huyet khoi trong cac rnach mau cua u. + LUQ11gTNF 1611 hru thong trong mau con eo th~ gay ra r6i loan chuyen hoa, cu th~ la ha duong huyet do tang tieu thu duong nhung gan khong bit lai duce. Co mQt bi~ chirng nang cua nhiem trung gram am la s6c nhiem trung (con goi la s6c nQi dQc t6). Benh canh s6c bao g6m truy tim rnach, dong mau noi mach rai rac va r6i loan chuyen hoa. HQi chimg nay chinh la do TNF va mot s6 cytokin khac nhu IL-12, INF -y va IL-l duce san xu~t ra nhieu dum tac dong cua LPS vi khuan, Do nong dQ TNF huyet thanh eo th~ du bao duce benh canh s6c nay. Cac ch~t d6i khang TNF eo th~ ngan ngira tU vong trong mo hinh tlurc nghiem nhung tren lam sang thi khong, ma 1y do eo le ngoai TNF cac cytokin ciing eo tac dQng nhir TNF va manh khong kern.

2.2. Interleukin-I (IL-l)

., Chirc nang chinh cua IL-I, cling giong nhu TNF, la lam trung gian cho dap irng viem cua eo the chu chong lai nhiem trung cling nhu cac kich thich viem khac, IL-I hoat dQng cung voi TNF trong h~ mian dich bArn sinh.

2.2.1. NguJn gJc, thl} thi Nguon san xuAt chu y€u cua IL-l, cling giong nhu TNF, la thirc bao don nhan hoat hoa. Nhung khac voi TNF, IL-I con duce san xuAt boi mQt s6 t€ bao khac nhu t€ bao trung tinh, t€ bao bieu mo, t€ bao nQi moo Co hai dang IL-l goi la IL-I a va IL-I f}, ea hai deu g~ vao mot loai thu the t€ bao va eo hoat tinh sinh hoc nhu nhau. Ca hai deu duce san xuAt duoi dang mQt tien chAt 33 kD va mot manh c~t 17 kD. Dang hoat dQng cua IL-l f3 la manh c~t ttbng khi dang hoat dQng cua IL-I a la ea tien chAt lfrn manh c~t. Da s6 IL-I tim thAy trong tuAn hoan la IL-l f3. Co hai thu the mang cho IL-l duce goi la thu the typ I va thu the typ II. Ca hai deu thuoc sieu ho Ig. Th\1·the typ I eo tren hAu h€t t€ bao con thu the typ II duce thay chu y€u tren t€ bao B, tuy nhien cling eo the kich thich tao ra tren mot s6 t€ bao khac.

2.2.2. Hoat tinh sinh h{Jc Hoat tinh sinh hoc cua IL-I cling giong nhu cua TNF va phu thuoc vao s6 hrong duce san xuAt. Khi diroc ti€t voi nong dQ thap, IL-l tac dQng nhu mot chAt trung gian cua phan irng viem tai ch6. No tac dQng len t€ bao nQi mo de tang bQc IQcac phan tu be m~t k€t dinh bach cAu nhu ligand cua integrin. Khi duce ti€t voi hrong IOn, IL-l di vao mau va eo tac dung nhu nQi ti€t t6. Tac dung toan than cua IL-l giong voi TNF la gay s6t, kich thich gan san xuat cac protein huyet tuong pha cAp, va tao ra su suy kiet. SIJ giong nhau ve tac dong cua IL-l va TNF rAt dang ngac nhien. Tuy v~y chung cling eo nhfrng khac nhau nhu: IL-l khong trung gian qua trinh chet lap trinh (apoptosis) cua t€ bao ngay ea khi eo n6ng dQ cao va ban than no khong gay s6c nhiem trung. Tlnrc bao don nhan eo san xuat ra met ch~t uc ch€ tir nhien d6i voi IL-I. chh nay eo chung thu the voi IL-I hoat dQhg nhu mQt chAt ire ch€ nrong tranh voi IL-l do do no duce goi l~ chAt d6i ~an~ thu the IL-l (IL-l receptor antagonist, IL-lra). IL-Ira eo the la met chat dieu hoa nQi sinh cua IL-l. 2.3. Chemokin Chemokin la mQt ho g6m nhieu cytokin eo kha nang kich thich bach eau di chuyen va diSu hoa SIJ di chuyen cua chung nr mau d€n cac mo. Tu chernokin la viSt t~t cua chemotactic cytokin eo nghia la cytokin hoa hirong dQng. MQt s6 chemokin eo th~ duce san xuat boi nhieu loai tS bao khac nhau

dS d6i pho voi kich thich viem va thu hut bach cAu d~n ch6 viem. MQt s6 chemokin khac duce san xu~t boi nhieu mo khac nhau ngay ea khi khong eo viern va cling thu hut bach cAu (chu y~u la lympho) d~n moo

2.3.1. Cau tao; nguJn g6c, thy thi T~t ea cac chemokin d~u la nhfrng polypeptid eo trong hrong phan nr 812 kD va clnra 2 cAu di-sulfua ben trong. Ngiroi ta da xac dinh diroc khoang 50 chemokin va nrong lai eo thS phat hien them. Chemokin diroc chia thanh nhieu ho dua tren s6 hrong phan nr cystein eo dAu t~n cung N. Hai ho chu yeu la ho chemokin CC eo cac phan nr cystein t~n cung nam canh nhau va ho CXC eo cac phan tU cystein t~n cung nam each nhau boi mQt acid amino Khi eo phan irng viem thi chemokin CXC tac dQng chu y~u len t~ bao trung tinh, con CC thi tac dQng len t~ bao mono, lympho va ai toan. Chemokin con eo ho C tire chi eo mot phan cystein hoac ho CX3C tire eo 2 phan nr Cystein each nhau boi 3 acid amino r V~ nguon gee, ca~ chemokin lien quan d~n phan irng viem duce san xuat boi te bao bach eau khi eo cac kich thich den tir ben ngoai. Con cac chemokin di~u hoa S,! hru thong t~ bao qua cac mo thi duce san xu~t boi nhirng t~ bao khac nhau trong cac me nay. Nguoi ta da xac dinh duoc 11 loai thu thS danh cho chemokin CC va duce d~t ten nr CCRl d~n CCRl1, 6 thu thS danh cho CXC duoc d~t ten nr CXC 1 d~n CXC6 va day chua phai la het, Th\1 thS cua chemokin duce thS hien tren t~ bao bach cAu, d?c biet tren t~ bao T nguoi ta th§y eo dt nhieu thu thS chemokin. T§t ea thu thS chemokin eo chung mot c§u true d?c trung la bao gom nhtrng domain eo c§u tao 7 vong xoan a xuyen mango Co mot s6 thu thS chemokin nhu CCR5 va CXCR4 eo tac dong nhu nhirng d6ng thu thS d6i voi HIV. MQt s6 lympho bao T hoat hoa eo thS ti~t ra nhimg chemokin lien k~t voi CCR5 va canh tranh cling voi virus qua do phong b~ nhiem trung HIV.

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2.3.2. Hoa: tinh sinh h{Jc Chemokin duce phat hien la nho vao chirc nang hoa hirong dong cua chung nhung that ra chung con eo nhieu clnrc nang quan trong khac trong h~ mien dich cling nhu cac h~ thong khac. - Chemokin t~p trung cac loai tS bao cua eo thS chu d~n vi tri nhi€m trung. Chemokin hien dien tren t~ bao nQi mo tac dQng len cac bach cAu di qu~ lam ch? cac integrin ~~ch cAu tan~ ai hrc k~t g~n voi ligand cua chun,g. Dieu nay rat quan trong de gill' bach eau lai nQi mo cua maD mach vung ton thuong. Ngoai ra, chemokin con kich thich S,! di chuyen cua bach cAu d~n noi eo t6n thirong tren eo sa dQ chenh nong dQ cua chemokin tai noi t6n tlnrong va cac noi khac. Cac chemokin khac nhau kich thich cac t~ bao khac nhau nho th~ ma kiem soat duce thanh phan cua cac t~ bao tai 6 viem. Vi du,

chemokin IL-8 huy dQng chu y~u t~ bao trung tinh, con chemokin eotaxin t~p trung t~ bao ai toan. - Chemokin di€u hoa su hru thong cua t~ bao lympho va cac bach cAukhac trong cac mo lympho ngoai bien. Day la mQt phat hi~n mm trong mien dich hoc. Cac chemokin eo kha nang thuc dAy cac t~ bao hieu qua da diroc hoat hoa va t~ bao T nho di chuyen d~n cac mo khong phai thuoc h~ lympho bao g6m ea da va niern mac. Su chon hra nhfrng t~ bao khac nhau d~ dua d~n cac mo khac nhau phu thuoc vao s6 hrong va thu th~ tren t~ bao cua tirng 10C;li chemokin.

2.4. Interferon (IFN) typ I Interferon typ I la nhirng chat lam trung gian dap irng som cua mien dich barn sinh chong lai cac nhiern trung virus.

2.4.1. cau tao, nguJn g8c

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IFN typ I g6m eo 2 nhom protein eo ten la IFN-a va IFN-~. IFN-a la mQtho _g6m eo 20 polypeptid eo cau true lien quan voi nhau va m6i polypeptid duce ma hoa boi mot gen rieng. IFN-a duce san xuat chu y~u boi cac tlurc bao don nhan va doi khi con duce goi la interferon bach eau, IFN-~ la mot protein duce san xuat boi nhieu 10C;li t~ bao nhir nguyen bao soi va vi th~ ma doi khi no con duce goi la interferon nguyen bao soi. Kich thich hieu qua nhat d6i voi su tong hQ'Pinterferon la nhi~m trung virus, nhat la cac virus RNA chu6i kep do virus tao ra trong qua trinh nhan len cua chung trong t~ bao chu. Trong phong thi nghiem, viec san xuat IFN typ I duce kich thich boi cac RNA chu6i kep nhan tao eo tin hieu dt giong voi nhiem trung virus. TS bao T duce khang nguyen heat hoa cling kich thich thirc bao don nhan t6ng hQ'PIFN typ 1. Mac dAu IFN-a va IFN-~ khac nhau v€ cau tao nhung chung lai g~n vao cung mot thu th~ va tao ra dap irng sinh hoc giong nhau.

2.4.2. Hoqt tinh sinb h(Jc HOC;lt tinh cua IFN typ I la bao v~ eo th~ chong lai nhiem trung virus va thuc dAy dap irng mi~n dich tS bao chong lai cac vi sinh v~t noi bao. (Hinh 5). - IFN typ I lIC chS su nhan Ien cua virus. IFN kich thich tS bao san xuat ra nhieu 10C;li enzym nhu 2'5'synthetase oligoadenylate eo tac dung ngan can sao chep cua virus DNA hoac RNA va lIC chS sir nhan len cua chung. Tac dung chong virus cua IFN typ I vira mang tinh tu than (autocrine) tire la lIC chS duce sir nhan len cua virus trong ban than minh vira eo tac dQng k~ c~n (paracrine) nghia la eo tac dung bao v~ cac tS bao chira nhi~m ben canh. - IFN typ I eo tac dung gia tang str boc IQ cua phan nr MHC lap I. TS bao T CD8+ eo kha nang nhan dien khang nguyen la lien kSt voi MHC lap I,

va IFN typ I thuc d~y su nhan dien d6i voi plnrc hop g6m lap I va khang nguyen virus tren t€ bao nhiem, qua do t€ bao gay dQC de dang nhan ra t€ bao chira virus va tieu diet chung. - IFN typ I kich thich su phat trien cua t€ bao Th 16 ngtroi, Hieu img nay eo duce la nho IFN typ I da thuc d~y S\l' boc IQ cac thu the chirc nang cua t€ bao T d6i voi cytokin khoi dQng Th1 la IL-12. IFN typ I con eo kha nang gia tang hoat tinh ly giai t€ ban cua t€ ban NK. R'bOO ~m virus

I I JI ~. ~ IFNtypI

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Hinh 5. Hoat tinh sinh hQc cua interferon typ I IFN typ I (IFN-a va IFN-fJ) duac san xudt boi cac ti bao nhiim virus va dai thuc bao. IFN typ 1 lrc ch~ nhiim trung virus VIZ thuc ddy hoat tinh chong lai t~ bao dii nhiim virus.

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- Trong phong thi nghiem, IFN typ I ire ch€ su tang sinh cua nhieu loai t€ bao, kS ea lympho. Co ch€ ire ch€ tang sinh nay cua IFN typ I v~n chira duoc fO.

Tom lai, chirc nang chu y€u cua IFN typ I la ire ch€ va loai bo nhiem trung virus. Trong lam sang nguoi ta da dung IFN-a nhu mot thuoc chong virus dS di~u tri mQt s6 thS viem gan. Con IFN-P thi duce dung dS di~u tri da xo hoa (multiple sclerosis), nhung eo che tac dong thi chua duce ro l~m. Ngoai ra, trong dap irng mi€n dich barn sinh con eo met s6 cytokin khac tham gia nhu IL-lO, IL-6, IL-5, IL-I5, IL-I8, IL-I9, IL-20, IL-21, IL-

22, lL-23, lL-24 nhung eo ch~ tac dQng cua chung chira hoan toan diroc sang to nen chung toi chira eo di~u kien d~ trinh bay. 3. Cac cytokin trung gian vI. di~u hoa mi~n djch thu dtrf}'C Day la nhtrng cytokin lam trung gian cho su tang sinh va biet hoa cua lyrnpho bao sau khi nhan dien khang.nguyen trong giai doan hoat hoa; d6ng thoi chung cling trung gian cho S\l hoat boa cua nhtrng t~ bao hi~u qua duce chuyen mon hoa trong giai doan hieu qua cua da,pirng mien dich thu dtroc. Viec san xu~t cytokin la mot trong nhirng dap img chinh cua t~ bao lympho T d6i voi khang nguyen. Nhieu loai vi sinh v~t va khang nguyen khi ti~p xuc voi eo th~ thi khoi dQng t~ bao T giup do CD4+ d€ chuyen chung thanh cac ti€u quAnth€ t~ bao hieu qua khac nhau do la Th 1 va Th2. Cac ti€u quAn th€ nay san xu~t cac loai cytokin khac nhau va thirc hien nhtmg clnrc nang khac nhau. Trong phAn nay chung toi chl d~ c~p d~n 2 cytokin chu y~u la lL-2 va interferon-y (IFN-y).

3.1.IL-2 IL-2 la mQt y~u t6 phat tri€n d6i voi lympho T va chiu trach nhiem phat trien clon t~ bao T sau khi nhan dien khang nguyen .. Vi Iy do nay, lL-2 luc d~u eo ten la y~u t6 phat trien t~ bao T. IL-2 duce san xu~t ra chu y~u tac dong len chinh ban than t~ bao do.

3.1.1. Ngutm gJc, cau true, th{l thi IL-2 dtroc san xu~t phan Ion boi t~ bao T CD4+ va mQt it boi t~ bao T CD8+. Str hoat hoa t~ bao T boi khang nguyen va cac d6ng kich thich se tao ra S\I sao chep gen IL-2 cling nhir t6ng hop va ti~t cytokin nay. IL-2 duce san xuat trong thoi gian ngan voi s6 hrong it sau 6-8 gio duce heat hoa. 1L-2 duce ti~t ra la mot glycoprotein eo trong hrong 14-17 kD, cuon thanh met c~u true eo 4 vong xoan c. Str boc IQ thu th€ chirc nang cua lL-2 diroc thuc dAy boi kich thich khang nguyen, do do t~ bao T nao nh~n dien khang nguyen thi se tang sinh uu tien khi dap irng voi IL-2 duce san xu~t trong dap irng mien dich thu duoc, Thu th€ lL-2 (IL-2R) c~u tao boi 3 protein khong d6ng hoa tri eo ten la (1" 13, va y. Cac chu6i u va 13 tham gia vao lien k~t voi cytokin; cac chu6i 13 va y thi tham gia vao dfut truyen tin hieu; con ban than JL-2 g~ voi chu6i u -don thuan eo ai hrc r~t th~p va khong dftn d~n hieu qua sinh hoc nao ro rang.

3.1.2. Hotu tinh sinh h!,c Mac du hie dAu ngiroi ta phat hien ra lL-2 nhu la mQt y~u t6 phat trien t~ bao T, nhtrng that ra IL-2 eo nhi~u chirc nang trong dap irng mien dich thu duoc (Hinh 6).

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.. , - IL-2 do te b~o T tiet ra khi nhan dien khang nguyen chiu trach nhiem ve viec tang sinh te bao dac hieu khang nguyen. Khi tiep xuc voi IL-2, te bao T cho thdy eo tang vot ~6ng d<) cac cyelin d~n den .hoat hoa nhieu loai kinase. Cac kinase nay phosphoryl hoa v~ hoat hoa nhieu protein cua te bao de cac protein nay kich thich te bao chuyen tU dang G ,1 sang dang S cua chu I, ky phan bao. Ngoai ra, IL-2 con lam giam p27 la chat uc che doi voi hoat d<)ng cua cac phirc hop cyclin-kinase do, do thuc ddy qua trinh tang hop cyelin. IL-2 lam tang thoi gian song cua te bao bang each khoi d<)ng protein Bel-2 la chdt chong ki~u chet te bao tu nhien (apoptosis). Tac dung cua IL-2 chu y,€u la len chinh te bao tiet ra no, 'nhung ciing eo phAn nao lac d<)ng vao cac te bao ben canh.

Hinh 6. Hoat tinh sinh hec ciia IL-2 1L-2 kich thich SI! tang sinh viz bi~t hoa cua lymphti bao T viz B viz d bao NK. JL-2 ciing co chtrc

niing ire ch~ dap ung miJn dicb (vi du chong Iai tl! khdng nguyen) bimg each tao ra hien tuang ch~t ldp trinh cua t~ bao T qua trung gian cua Fas vizkich thich hoat tinh cua d bao T didu hoa.

- IL-2 tang cirong S\l tang sinh va biet hoa te bao. No kich thich su phat trien cua te bao NK va tao ra cai goi la giet te bao do lympho bao hoat hoa (Lymphokine-activated killer, LAK). IL-2 tac d<)ng len te bao B tren ea hai khia canh: kich thich phat trien va tang tang hop khang th~. - IL-2 tao ra cai chet l~p trinh cua te bao T duce khang nguyen hoat hoa. Str kich thich lap di l~p lai cua te bao T CD4+ voi sir hien dien cua IL-2 lam cho cac te bao nay nhay can: voi cai chet l~p ,trinh qua,con dirong Fas. Dieu thuvi la mot cytokin eo the vira kich thich te bao T song va tang sinh nhirng d6ng thoi ciing gay ra cai chet cho te bao. Hinh nhu neu met dap irng

••

mien dich eo xu hirong t6n tai lau dai va tS bao T tiSp xuc voi hrong IL-2 ngay cang tang thi eo kha., nang chSt theo kieu lap trinh va dful dSn cham dirt dap irng .",., nay. IL-2 con eo the kich thich phat trien te bao T dieu hoa de lam dirng dap irng.

3.2.lnterferon-r(IFN-rJ . IFN-y la cytokin chinh hoat hoa dai thuc pao va dong vai tro rAt quan trong trong mien dich barn sinh cling nhu mien dich thu duce. IFN-y con diroc goi la IFN mien dich hay IFN typ 11.No cling eo phdn nao chirc nang chong virus nhung chu yeu la met cytokin hieu qua cua dap irng mien dich.

3.2.1.

cs« true, ngu6n g8c, thl! thi

IFN-y la mot protein dimer do tS bao NK, tS bao Thl CD4+ va CD8+ san xuat. No la cytokin d~c ttyng cua Thl . TS bao NK san xuAt IFN-y khi eo kich thich cua mot thanh phan vi sinh v~t nao do hoac IL-2, ~ong tnrong hQ'Pnay IFN-y tac dQng nhu mot chat trung gian cua dap irng mien dich barn sinh. Trong dap irng mien dich thu duce, tS baoT san xuAt IFN-y trong khi nhan dien khang nguyen va dieu nay diroc thuc day boi IL-2 va IL-l8. Thu th€ cua IFN-y ban g6m hai chu6i polypeptid thuoc ho thu th€ cytokin typ 11. Trong hai chuoi nay thi mot chuoi eo chirc nang gan voi cytokin va chu6i kia thi truyen tin. hieu.

3.2.2. Hoqt tinh sinh hoc Chirc nang cua IFN - YrAt quan trong trong mien dich tS ban chong lai vi khuan nQi bao (Hinh 7). -lFN-y la cytokin hoat hoa dai thuc bao, no giup tS ban T va NK hoat hoa dai thirc ban d€ ~St cac vi sinh v,~tdffduce thirc bao. IFN-y tlnrc hien diSu nay nho kich thich S\l tong hQ'Pcac chat trung gian oxy phan irng va oxid nitric. - IFN-y kich thich su bQc IQ cua MHC lap I va lap 11va cac chat d6ng kich thich tren tS bao trinh dien khang nguyen. IFN - Y cling kich thich su san xuAt cua nhieu protein tham gia vao qua trinh xu ly khang nguyen nhu chat v~n chuyen (TAP), va hai thanh ph~n LMP - 2, LMP - 7 cua proteasotp va HLA - DM. Nhu v~y IFN - Y thuc day su trinh dien khang nguyen phoi hop voi MHC va khuyech dai su nhan dien trong dap irng mien dich. IFN-y cling la chat hoat hoa tS ban nQi mac thanh mach va tang cirong kha nang tac dong cua TNF tren tS ban nQi mach, tao ra kSt dinh tS ban lympho vao thanh mach va xuyen mach di dSn vi tri nhiem trung, - IFN-y kich thich sir biet hoa cua tS bao T CD4+ con nguyen ven thanh ti€u nhom Thl va ire chS su tang sinh cua tS bao Th2. Tac dQng cua IFN-y len Thl mot phan duce trung gian boi IL-l2. Ngoai ra, IFN-y kich thich sir san xuat ySu t6 san chep d~ tao ra bi~t hoa Thl.

- IFN-y tac qQng len t€ bao B g~chuyen mach cac ti~u lap IgG, nhdt la IgG2 chuot nhat va uc che chuyen mach sang cac isotyp phu thuoc IL-4 nhir IgE va IgG 1 a chuot. Nhu v~y, IFN-y cling tao ra dap irng khang th~ va tham gia vao qua trinh loai bo vi sinh v~t qua trung gian qua trinh tlnrc bao. - IFN-y ho~t hoa t€ baD trung tinh va kich thich ho~t tinh t€ bao NK.

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4. Cytokin kich thich tao man Bap img mi~n dich bdm sinh va thu duce t(;10ra nhieu cytokin tham gia vao qua trinh t(;10mau tire la tham gia t(;10nguon t€ bao cho dap irng mi~n dich, Tuy nhien, trong pham vi cua quyen sach nay chung t6i khong d~ c~p chi ti€t ma chi trinh bay tren sa d6 diroi day d~ dQc gia tham khao (Hinh 8).

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