10. Liebman A . M . (1995): Classification and Clinical manifestation of Hemopoietic stem cell disorders. In Williams Hematology, New York, 1995, 229 - 2 3 8 .
11. RIbeIro, R.C., Eduado R. (2006): Management of APL in developing countries: Epidemiology, challenges, opportunities for international colaboration. Hematology, 1 62 - 1 68.
12. Steven L. S., Frankel S.R., Douer D.
(2001): United states multieentrer study of AS2O3 in relapse acute promyelocytic leukemia. J. Clin.
Oncology, 19: 3852 - 3 8 5 0
13. Vongknl J., Wang L., Xia L., Chen G., Miller W . H . (2001): Combined effect of ATRA and AS2O3 in acute promyelocytic leukemia cells in vitro and in vivo. Blood, 97: 264 - 269.
14. Zheng P.Z., Wang K.K., Zhang W . V.
( 2 0 0 5 ) : Systemic analysis of T r a n s c r i p t i o n and proteome in retionic a c i d e / arsenic trioside induced cell - d i f f e r e n t i a t i o n / apoptosis of APL. Proe. N a t l . A c a d . Sei. USA, 102:
7653 - 7 6 5 8 .
VAI TRO TOLL-LIKE RECEPTOR TRONG DAP L/NG MI§N DICH The role of Toll - like receptor in immune response
Pham Dang Khoa TrUdng Dai hoc Y Ha Ndi
Bio vg tfnh toan ven eua cd the la mdt thude tinh eua tat e l mpi loai sinh vaL tfl loai g i l n don (sinh vat ddn bao) dg'n loai eao cap (dpng vat cd vd va ecn ngfldi). Dap flng m i l n djeh la mot phflpng thdc quan trpng gidp mpi loai sinh vat b i o ve dflpe tinh toan ven eua ed t h i , thdng qua viec loai bd eae yg'u td la (khang nguyen) da xam nhap.
D i p dng m i l n djeh dflpc phan bigt 2 dang:
- Dap flng m i l n djeh khdng dae hieu (hay dap flng m i l n djeh bam sinh, d i p flng m i l n dich tU nhign) la d i p dng m i l n dich mang tfnh s i n cd, tfnh di truyin va khdng e i n q u i trinh m i n d m . Dap flng nay xuat hign trflde trong bae thang tig'n hoa eua sinh gidi.
- D i p dng m i l n djch dac hieu (bao gdm m i l n djch djch the v l m i l n djeh te bao) la k i t q u i eua qua trlnh m i n d m .
Trong sud't mdt thdi gian dai, d i p dng mien djch dac hieu dflpc tap trung nghien cflu n h i l u va
thu dflpc nhflng hieu big't phong phd, dang ke.
Trai lai, d i p flng m i l n dich khdng dac hieu ft dupe quan tam nghien cflu va sfl hieu big't chi dflng lai d chdc nang eua 4 hang rao: vat li, hoa hpe, tg' bao va eo dja. Tfl khi phat hien hg thdng Toll-like receptor, sfl h i l u big't v l tam quan trpng cua mien djch khdng dac higu cd nhflng bflde t i l n to Idn, gidp ehdng ta hieu rd hdn ve cd e h i nhan bie't k h i n g nguyen eua m i l n dich khdng dac hieu.
1. Dai cOdng ve Toll-like receptor
Nhflng nghien eflu v l he thdng de khang eua vat ehu d loai rudi giam (Drosophila) da cung cap nhflng hieu b i l t d i u tign v l ed che' nhan bie't khang nguygn cua m i l n djeh khdng dae hieu. 6 loai rudi gia'm, mpt hp Toll receptor ddng vai trd quan trpng trong eupc ehie'n da'u chdng lai sfl xam nhap cua eae y l u t d gay benh. Sau dp, d e receptor tfldng tfl nhfl Toll receptor d rudi giam da dflpc nhan bie't d dpng vat ed vu va chung dUde
gpi la Toll-like receptor (TLR). TLR la mpt hp ldn (ngay nay da big't ehdng it nhat gdm 10 thanh vien), cd chflc nang: (1) nhan big't eac ca'u thanh cua ye'u t d gay benh; (II) hoat boa m i l n dich khdng dac hieu; (III) kg't ndi m i l n dich khdng dae hieu va m i l n djch dac hieu.
v l mat ca'u true, TLR la nhflng protein xuyen mang typ I, ehdng dupe nhdm vdi nhau thanh mpt hp gen gid'ng nhau dfla trgn tfnh tflpng tfl v l trinh tfl chudi cua ehung. Ta't e l chdng deu eho thay cd nhflng dae d i e m ca'u trdc dae biet. Mpt
TLR va cac phdi td cua chung
TLR TLR1
Nguon gdc phoi tO
so' doan lap lai giau leucine (LRR: leucine-rlch repeat) cd mat tai domain ngoai tg' bao eua phan tfl, chung tao ngn d e rau bam dinh eua cae phan tfl b l mat te' bao k h i c nhau. TLR xuygn qua mang bao tUdng va phan trong te bao cua chung rat gid'ng domain trong bao tUdng eua IL-1 receptor (IL-IR) va d e phan tfl cd lign quan; tuy vay, ta't e l d c thanh vien trong hp IL-1 R d i u cd mpt p h i n ngoai tg' bao dac trflng, tai dd 3 domain gid'ng IgG tao thanh mdt d i tui gan phd'i tfl (ligand-binding pocket).
Cac phdi tO Vi khuan Gram dUPng Modulin, lipopeptid TLR2 Vi khuan Gram dUdng
Pseudomonas aeruginosa Staphylococcus
Myeobacteriae, Mycoplasmae Listeria
Nam men
Trypanosoma cruzel Spirochetae
Lipoprotein, peptidoglyCan, lipoteichoic acid
Mannuronie acid polymer Modulin
Lipoprotein, lipopeptid, lipoarabinomannan
Vi khuan bi gig't bang nhigt Zymosan
Protein neo GPI LPS
TLR3 Virus dsRNA
TLR4 Vi khuan Gram am Vi khuan Gram dUdng
Thflc vat
Virus hpp b i d hd hap Vat chu
LPS
Lipoteichoid acid, mannuronie acid polymer
Taxol F protein
Hsp60, Hsp70, Fibronectin EDA domain
TLR5 Vi khuan Gram am Vi khuan Gram dUdng
Flagellin
TLR6 Vi khuan Gram dfldng Modulin, soluble tuberculosis factor (STF), Borrelia burgdorferi outer suface protein A
lipoprotein (OspA-L) TLR7
TLR8
Hdp chat khang virus nhd Hdp chat khang virus nhd
TLR9 Vi khuan CpG-DNA khong metyl boa
6 loai rudi gil^m, phd'i tfl ndi sinh dac higu dd'i vdi Toll receptor la protein Spaetzle. Nhflng cho den nay, khdng mdt protein nao tfldng tfl nhfl Spaetzle dfldc phat hien d ddng vat ed xfldng sdng. Ngfldi ta eho rang TLR d ngfldi la d e receptor "md edi" (orphan receptor), ehdng chi ed d e phdi tfl "cd hpi" (opportunistic ligand), dd la mpt sd khang nguygn cua vi khuan hay mdt so' protein npi sinh.
Profltin-hk© molecule Iprotozoa) \
'"'* r,I>
dsRMA (virus)
'/ •/ / / /
ssRMA (virus!
/
^
isRNA(virus)
Diacyl
lipopeptides (bacteria)
CpG DNA {bacteria, virus)
Zymosan (fungi)/
Triacyl lipopeptidesibatteria) Flagellin (bacteria)
LPS (bacleria)
Cac thanh vien trong ho TLR d ngfldi va cac phdi tfl tfldng dng
2. TLR va dap u'ng mien djch khong dac hieu 2.1. TLR4 can thiit di nhan biet lipopolysaccharide
Lipopolysaceharide [LPS) la mpt eau thanh chfnh cua mang ngoai vi khuan Gram am, gay sd'e npi dpc to', cd vai trd khdi dpng mdt loat kich thich dap flng m i l n djch, nhfl tao IL-12 (interleukin-12) va NO (nitric oxid). Hai gidng chudt, C3H/HeJ va C57BL10/SeCr, dUde b i l t la cd d i p dng tha'p vdi LPS. Hai nhdm nghign eflu dpc lap da phan tfch gen chju trach nhiem tinh d i p flng t h i p vdi LPS va da phat hign dfldc nhflng dot b i l n tai gen Tlr4 d nhflng gidng nay. d gid'ng chudt C3H/HeJ, mpt dot b i l n d i l m d vung bao
tfldng cua TLR4 da d i n d i n mdt thay ddi amino acid tfl proline thanh histidine. Sfl thay ddi amino acid ddn nay dflpc tha'y 11 lam cho tin higu qua trung gian TLR4 bj thig'u hut. Gidng chudt d i p flng thap vdi LPS thfl hai, C57BL10/ScCr, dflde thay la bj dot b i l n null (hign tflpng xda gen) tai gen Tlr4.
Du rang TLR4 da dflpe x l c minh la mpt receptor e i n thig't dd'i vdi sfl boat h o i cae te bao m i l n dich bdi LPS, nhUng mpt sd phan tfl k h i c cung dfldc tha'y la cd lign quan trong viec nhan bie't LPS, dd la G D I 4 va M D - 2 . C D M la mpt phan tfl neo glycosylphosphatidylinositol, bieu 16 chd y l u trgn dai thflc bao va bach c l u hat tmng
tinh, dflde mac nhan la d l g i n vao LPS da dfldc bit gid bdi prctein g i n LPS (LBP: LPS binding protein). MD-2 la mot phan tfl lien quan tfl nhien vdi phan ngoai te bao eua TLR4 va lam tang tinh dap flng vdi LPS.
2.2. TLR2 can thiet cho su nhan biet lipoprotein va peptidoglycan
Da ed mpt sd bang ehdng chp tha'y TLR2 ed khi nang nhan big't d c ca'u thanh tfl d e loai vi khuan gay bgnh k h i c nhau. Dd la lipoprotein tfl yeu td gay bgnh nhfl vi khuan Gram (-), vi khuan Gram (+), mycobacteria va spirochetes; pepti- doglycan va lipoteichoic acid tfl vi khuan Gram (-I-); lipoarabinomannan tfl mycobacteria va zymo- zan tfl nam. Phan tich chuot thig'u TLR2 da phat hien vai trd tign quyg't eua TLR2 trong viec nhan biet peptidoglycan v l lipoprotein.
Theo mdt sd tac gia, kha nang gan cua TLR2 vdi elc phdi td khac nhau la nhd kha nang tao heterodimer gifla nd vdi eae TLR k h I e , ehu y l u la TLR6vaTLR1.
Lipoprotein la nhflng protein chfla lipid, dfldc lien kit ddng hoa trj vdi nhflng cystein tai d i u tan NH2; chung hien dign trong mpt loat cac vi khuan, bao gdm e l c vi khuan Gram (-1-), Gram (-) va mycoplasma. Lipoprotein ed boat tfnh kfch thfch m i l n djeh la do cd nhflng tan cung NH2 dupe gan lipid. TLR2 lam trung gian eho dap flng vdi lipoprotein cd ngudn gd'c tfl M. tuberculosis, Borrelia burgdorfei, Treponema pallldium va Mycoplasma fermentans. Ngoai ra, TLR2 cdn lam trung gian eho d i p flng te' bao vdi mot loat eac vi khuan gay benh va d c san pham cua chdng. Dd la vach te b i o nam men, t o l n bp mycobacteria, lipoarabinomannan eua mycobacteria, toan bp vi khuan Gram (-n), peptidoglycan (PGN), glyeolipid cua Treponema va neo glyeophosphatidy I inositol cua Trypanosoma cruzi. Tuy vay dd'i vdi boat tinh cda TLR2, tinh dac hieu phdi td (ligand specificity) cung nhu k h i nang t r u y i n tin hieu dUpe quyg't
dinh bdi eae tfldng tac heterodimeric vdi cae TLR khae, nhu TLR6 v a T L R I .
2.3. TLR6 tham gia trong viec phan biet cac lipoprotein
Ngfldi ta da phan tich vai trd cua TLR6 bdi sfl bieu Id hinh thai am tinh trpi tren ddng tg' bao dai thflc b i o RAW264 va da chflng minh rang TLR6 phd'i hdp vdi TLR2 de p h l t hien kieu m l u dae biet eua peptidoglycan hoac modulin tig't ra tfl Staphylococcus aureus. C I c t i c gia cung da chflng minh rang TLR6 lien ke't vdi TLR2. K h I o sat ehudt thie'u hut TLR6 da phat hien thi'y TLR6 lien quan ve mat chflc nang vdi TLR2 v l phan biet gifla e l c lipopeptide y i khuan. Trong nghign cflu nay, dai thflc bao thig'u hut TLR6 khdng bieu hign bat cfl mdt dap flng viem nao dd'i vdi d i - palmitoyl lipopeptide ed ngudn gdc tfl my- coplasma. Tuy vay, ddng tg' bao nay dap flng binh thfldng vdi tripalmitoyi lipopeptide tfl d e loai vi khuan k h i c . T r i i lai, dai thflc bao thig'u hut TLR2 cho tha'y khdng d i p flng vdi bat cfl loai lipopeptide nao. D i l u nay eung eho thay sfl tdn tai cua cae TLR k h I e ed lien quan ve chdc nang vdi TLR2 de nhan big't tripalmitoyi lipopeptide. Vi the mpt sd TLR dfldng nhfl ed lign quan vdi cac TLR khac de phan biet mpt d c h tinh te' sfl k h i c nhau trong e l c eau thanh cua vi khuan.
2.4. TLR9 can thiet cho stf nhan biit CpG DNA vi khuan
CpG la d e doan ngan DNA d dd t i n suit chudi CG eao hdn nhflng ndi k h i c , gpi la CpG vl C va G dfl-dc ndi vdi nhau bdi c l u ndi phosphodiester.
Ngoai d c ca'u thanh gay benh cua vach tg' bao, DNA cua vi khuan dfldc bie't la cp boat tinh kfch thfch d c te' bao mign dich. Hoat tfnh kieh thfeh mign dich cua DNA vi khuan dflpc qui cho sfl hign dign eua eac motif CpG khdng metyl hoa.
Motif CpG d DNA genome eua dpng vat ed xfldng sd'ng dflpc thay vdi t i n suit thap va metyl h o i
cao, do dd d i n den khdng cd hoat tfnh kfch thich m i l n djch. C I c oligodeoxynucleotide tdng hdp (ODN) chda d e motif CpG khdng metyl h o i eung boat h o i d c tg' bao_ m i l n djch. Khi dung CpG DNA gay ra dap flng m i l n djeh kieu T h i cd t i e dung b i o vg ehdng lai mpt sd benh nhigm khuan va bgnh m i l n dich d md hinh dpng vat. Vi vay, CpG DNA gid day dupe dfl d o l n trflde la mpt ta chat ed t i c dung lam sang ddi vdi mpt loat vaccin ehdng d e bgnh nhigm khuan, ung thfl va dj dng.
Sfl lign quan cua TLR9 trong viec nhan big't CpG DNA da dUde chflng minh qua gidng ehupt thie'u hut TLR9. Dap flng t l b l p ' ddi vdi CpG DNA, bao gdm tang sinh tg' bao B, s i n xuat eac cytokin vigm tfl dai thflc bao, q u i trinh chin eua t l bao dendritic, d i u bj buy d ehudt thig'u TLR9.
Viec CpG DNA e l m flng sfl hoat hoa cua d c phan td tfn higu npi bao, bao gdm NF-KB, JNK va IRAK, cung bi tdn thfldng d chudt t h i l u TLR9. Vi vay, ehupt thig'u TLR9 ed d l k h i n g vdi hpi ehdng sdc d i n dg'n chg't gay ra do DNA.
2.5. TLR5 nhan biit flagellin
Flagellin la mpt protein ed khd'i Ifldng 55-kD dang mdndmer thu dflpc td flagella cda vi khuan, dang polymer trdng gid'ng nhU nhflng d i dudi them vao, keo dai tfl mang ngoai eua vi khuan Gram (-), chdng cd t i e dung day vi khuan trong mdi trUdng nUdc. Flagellin cung la mpt yg'u t d t i l n vigm cd higu Iflc. Vi khuan dupc flagella h o i , flagellin tinh c h i va mdi trfldng nudi cay vi khuan dupe flagella h o i d l dang d m dng sfl thoai h o i IKBd, sfl hoat hoa NF-KB va sfl bieu Id viec tdng hdp nitric oxid trong t l bao bieu md ngudi va dai thflc bao ehupt dupe chuyen dang. TLR5 nhan big't flagellin vi khuan tfl d hai loai vi khuan Gram (+) .va Gram (-).
C P c h i kfch thfeh m i l n djeh cua flagellin dflpc cho la nhd hoat boa IRAK (IL-IR- associated kinase) phu thudc vao tin hieu M y D 8 8 (myeloid differentiation factor 88) va sfl boat h o i NF-KB.
Flagellin eua VK Gram (+) va Gram (-) cd the dflpc xem nh-fl PAMP (pathogen-associated molecular pattern) boat dpng thdng qua TLR5.
2.6. TLR3 nhan biet dsRNA
Sfl t l i sao eua virus trong cae te' bao bj n h i l m d i n dg'n vige tao ra d c dsRNA va d m flng interferon typ I. dsRNA cd the dflde xem nhfl la PAMP vi nd khdng phai la mpt thanh p h i n eau tao cua te' bao vat ehu. NgUdi ta tha'y d ehupt thig'u hut TLR3 cd giam d i p flng vdi y l u td' thay the' RNA virus, poly{l:C) (polyinosinic- polycytidylie acid). Dieu nay chflng td TLR3 cd lien quan trong viec nhan bie't dsRNA. dsRNA virus gan vao TLR3 bieu Id tren be mat tg' bao ed the dfldc b i t ngudn tfl d c tg' bao bj p h i hu'y' bdi d c virus gay benh. TLR3 nhan b i l t dsRNA, do dd d m dng viec tao ra interferon, mot yg'u to quan trpng trong ed ehe' tieu digt virus. Lam sao de mpt virus khdng gay benh eho tg' bao, khdng d n trd e l m flng interferon bdi dsRNA v l ed tfldng t i e vdi he thd'ng TLR la chu de cua nhflng nghign cdu hien nay.
3. Cac con dUdng tin bleu thong qua TLR
3.1. Con dtfdngphu thuoc MyDBB
Con dfldng tfn hieu thdng qua hp TLR cd tinh tfldng ddng eac vdi ecn dfldng cua hp IL-1 receptor (IL-IR). Ca TLR va IL-IR d i u tflpng t i c vdi mpt protein tig'p ndi M y D 8 8 trong d e domain TIR eua chdng. Khi boat hda, M y D 8 8 gan kinase lign kg't IL-IR (IRAK: IL-1 receptor associated kinase) vao receptor. IRAK dfldc boat hoa bdi sfl phosphoryl hoa va sau dd lien kg't vdi TRAK6, d i n dg'n sfl boat h o i cua hai con dudng tin higu rigng bigt, JNK va NF-KB. Chuot thig'u hut MyD88 khdng thay cd bat ky mpt d i p flng nao vdi d c cytokin thupe hp I L - 1 , d i l u nay da chflng minh r i n g M y D 8 8 la mdt adaptor can thie't trong eon dfldng tin higu qua trung gian I L - 1 . Mpt vai trd quan trpng khae cfla M y D 8 8 trong eon dUdng tin
hieu qua trung gian TLR eung da dUdc tha'y d chudt thie'u hut M y D 8 8 . Chuot thie'u hut M y D 8 8 cho thay khong cd dap flng viem vdi LPS, bao gom viec tao ra eae hoa cha't trung gian trong viem bdi dai thflc bao, sfl tang sinh tg' bao B va sdc npi dpc td. C I c dap dng tg' bao vdi pepti- doglycan va lipoprotein bj buy d ehupt thie'u hut MyD88. Hdn nfla, d e te b i c tfl ehupt thie'u hut MyD88 khdng tha'y cd dap dng n I o vdi CpG DNA. Cudi cung, ehupt thig'u hut M y D 8 8 cd sfl d l khang vdi hpi chflng sdc gay ra bdi flagellin.
Nhflng n h i n xet trgn da chflng minh M y D 8 8 la can thie't cho dap dng viem gay ra bdi tat c l cac thanh vign cfla hp TLR. Thflc vay, ehupt thig'u hut MyD88 cd tfnh nhay d m eao ddi vdi n h i l m Staphylocoeus aureus. Mpt d i l u thu vi la ehudt thieu hut MyD88 dUde nudi trong dieu kign khdng CO cac yg'u td g l y benh dae biet thi rat khoe manh. Tuy vay, khi dflpc nudi trong d i l u kien thong thudng cd sfl hien dign eua mpt sd yg'u t d gay benh, thi nhieu ehudt thie'u hut M y D 8 8 non se bi cac bgnh nhigm khuan nhu I p xe va bj chet trifdc khi cai sfla. Dieu nay eho tha'y sfl boat hoa miln djch tU nhign phu thupe M y D 8 8 la rat quan trpng cho vige ngan ngfla d c benh n h i l m khuan, ngay c l khi globulin m i l n dich dUde eung cap dlydu tfl me.
3.2. Con dtfdng khong phu thuoc MyD88
Mae du vai trd quan trpng eua eon dfldng phu thupe MyD88 trong d i p flng v i g m da dfldc chL'fng minh rd rang d ehupt thie'u hut M y D 8 8 , nhUng mpt nhan xet khae cung da dflde ndi tdi.
0 dai thflc bao tfl ehupt thie'u hut M y D 8 8 , ngfldi ta khdng tha'y sfl boat hoa JNK va NF-KB e l m u'ng bdi lipoprotein va CpG D N A , dieu dd phu hdp vdi khdng cd dap dng v i g m vdi c l hai eau thanh vi khuan nay. Tuy vay, sfl boat hoa JNK va NF-KB e l m flng bdi LPS v i n dflpc tha'y d dai thUc bao tfl ehupt thig'u hut M y D 8 8 d mfle tflpng
dfldng vdi te' bao binh thfldng, mac du cd cham hdn. Ta't nhien, sfl boat hoa JNK va NF-KB d m flng bdi LPS khdng dflpc tha'y d dai thflc bao tfl chudt thig'u hut TLR4. Nhflng nhan xet tren cho tha'y sfl tdn tai eua con dfldng khdng phu thudc M y D 8 8 trong tin higu qua trung gian TLR4 va da lam nay sinh mot so' va'n d l : tai sao lai can eon dudng khdng phu thupe M y D 8 8 ; Con dUdng nay cd vai trd gi. Vi sao eon dUdng nay lai dae hieu vdi tin hieu LPS Con dfldng nay dfla v I o nhflng phan tfl nao? Nhflng nghien eflu gan day da dfla ra dfldc mdt so' eau t r i Idi.
Sfl trfldng thanh eua te bao DC d m flng bdi LPS, dflde x l c djnh bdi sfl bieu Id eua cae phan tfl ddng kfch thich va sfl tang cfldng hoat tfnh allo- stimulatory cua t l bao T, dflpc thay la binh thudng d ehudt thig'u hut M y D 8 8 , nhUng khdng thay d ehupt thig'u hut TLR4. D i l u nay eho tha'y sfl trfldng thanh cda t l bao DC e l m dng bdi LPS dfla vao eon dfldng khdng phu thupe M y D 8 8 . Phan tfch cac gen e l m flng LPS d dai thflc bao ehupt thig'u hut MyD88 da nhan big't dflde eac gen d i l u hoa IFN, nhfl e l c gen ma h o i eho IP-10 va GARG16.
Sfl kfch thfch LPS cua dai thflc bao ehupt thie'u hut MyD88 da eho thay dan dg'n sfl boat hoa IRF-3.
Nhfl v l y , gid day chdc nang sinh hpe cua eon dudng khdng phu thupe MyD88 dang d i n trd ngn rd rang hdn.
4. Ket luan
Sfl p h l t hign ra d e TLR da eho ehdng ta mot d i u mdi quan trpng trong ed ehg' mign dich khdng dac hieu la van de trong sud't mpt thdi gian dai edn ehUa dUpc lam s i n g td. NhU chdng tdi da md t l , vai trd cd tinh bat budc cua d c TLR trong vige nhan bie't d e eau thanh vi khuan da va dang dupe k h l m p h i nhanh chdng. D i l u nay cd ich cho viec ly g i i i cd ehe cua mign djeh khdng dac higu va sfl kg't ndi gifla mien dich khdng dae hieu va m i l n dich dac higu.
TAI LIEU THAM KHAO
1. Muzio M., Mantovani A. (2000). Toll-like receptor. Microbes and Infection 2000, 2, 251 - 255.
2. Means T.K., Golenbock D.T., Fenton M.J.
(2000). The biology of Toll-like receptors.
Cytokine & Growth Factor Reviews 2000, 1 1 , 219-232".
3. Kalsho T., Akira S. (2000). Critical roles of Toll-like receptors in host defense. Critical Reviews in Immunology 2000, 20, 393 - 405.
4. Akira S., Takeda K., Kalsho T. (2001).
Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Publishing Group 2 0 0 1 , http://immunol.nature.com
5. Takeda K., Akira S. (2001). Roles of Toll-like receptors in innate immune responses. Genes to Ce//s 2 0 0 1 , 6, 7 3 3 - 7 4 2 .
6. Werling D., JungI T.W. (2003). Toll-like receptors linking innate and adative immune response. Veterinary Immunology and Immunopathology 2003, 9 1 , 1 - 12.
