抗原免疫原及其識別

INSTITUTEFORIMMUNOBIOLOGY抗原/免疫原及其識別(Antigen/Immunogenanditsrecognition)DepartmentofImmunologyShanghaiMedicalCollegeofFudanUniversity洪曉iaowuhong@獲得性免疫(AcquiredImmunity)適應(yīng)性免疫(AdaptiveImmunity)特異性免疫(SpecificImmunity)固有免疫(InnateImmunity)先天免疫(NativeImmunity)非特異性免疫(NonspecificImmunity)種系發(fā)育，進(jìn)化形成生來具備，應(yīng)答迅速非特異性抗感染免疫也參與特異性免疫固有免疫應(yīng)答和適應(yīng)性免疫應(yīng)答的比較固有免疫應(yīng)答 適應(yīng)性免疫應(yīng)答長期進(jìn)化中逐漸形成 抗原激發(fā)種系共有，可遺傳 個(gè)體特有，不可遺傳無免疫記憶、作用時(shí)間短 有免疫記憶、作用時(shí)間長粘膜和上皮細(xì)胞、吞噬細(xì)胞、NKT細(xì)胞、B細(xì)胞、APC gdT細(xì)胞、B－1B細(xì)胞不針對特定抗原（反應(yīng)廣泛） 針對特定抗原（反應(yīng)特異性）作用迅速、范圍廣泛 抗原識別、增殖分化、效應(yīng)階段

免疫（Immunity）固有免疫（Innateimmunity）適應(yīng)性免疫（Adaptiveimmunity）抗原/免疫原的概念免疫原（Immunogen）--啟動(dòng)免疫應(yīng)答的物質(zhì)抗原（antigen,Ag）--啟動(dòng)適應(yīng)性免疫應(yīng)答的物質(zhì)固有免疫原（Innagen，Ing）--啟動(dòng)固有免疫應(yīng)答的物質(zhì)

固有免疫識別的效應(yīng) 產(chǎn)生活性氧、活性氮、抗菌肽 細(xì)胞因子、粘附分子、急性期蛋白 共刺激分子（B7.1、B7.2)

PAMP、DAMP啟動(dòng)、激發(fā)以炎癥反應(yīng)為主的免疫應(yīng)答，清除病原體和凋亡細(xì)胞固有免疫識別的效應(yīng)Ag啟動(dòng)、激發(fā)以特異性CTL和Ab為主的免疫應(yīng)答，清除病原體和靶細(xì)胞產(chǎn)生致敏的淋巴T細(xì)胞和Ab適應(yīng)性免疫識別的效應(yīng)適應(yīng)性免疫識別的效應(yīng)

ImmunogenInnagen(INg)/InnateMolecularPattern(IMP)Antigen(Ag)PAMPDAMPOthers?ImmunogenicityReactigenicity熊思東.道亦道,非故道----試論固有免疫中的抗原和免疫原的定義.現(xiàn)代免疫學(xué),2007,27(6):441-443抗原/免疫原的概念抗原的特性免疫原性（immunogenicity）抗原性（antigenicity）AgTBT漿細(xì)胞致敏T細(xì)胞抗體免疫原性(immunogenecity)

指抗原分子能夠刺激機(jī)體產(chǎn)生免疫應(yīng)答(產(chǎn)生特異性抗體及免疫效應(yīng)細(xì)胞)的性質(zhì)。AgTBT漿細(xì)胞致敏T細(xì)胞抗原性

指抗原分子與免疫應(yīng)答產(chǎn)物(抗體或免疫效應(yīng)細(xì)胞)發(fā)生特異性結(jié)合的性質(zhì)?？乖?antigenicity)antigenicityimmuogenicityTTTAg免疫原的特點(diǎn)固有免疫原抗原不限于特定類別的成分或單一分子啟動(dòng)、誘導(dǎo)固有免疫應(yīng)答免疫原性、免疫反應(yīng)性分離免疫原性、免疫反應(yīng)性一致啟動(dòng)、誘導(dǎo)適應(yīng)性免疫應(yīng)答以表位為識別基礎(chǔ)就免疫應(yīng)答始動(dòng)因素而言

異物性是抗原免疫原性的本質(zhì)。非己就是異物，抗原來源與宿主的關(guān)系越遠(yuǎn)，異物越強(qiáng),免疫原性也越強(qiáng)。抗原的異物性抗原特異性概念--指某一抗原分子只能誘導(dǎo)相應(yīng)淋巴細(xì)胞發(fā)生免疫應(yīng)答的專一性，以及只能與相應(yīng)抗體或效應(yīng)細(xì)胞特異性結(jié)合的專一性。意義--是免疫學(xué)診斷與防治的理論依據(jù)

(1)兩對半：檢測HBV(2)接種牛痘：消滅天花決定抗原特異性的物質(zhì)基礎(chǔ)表位T細(xì)胞抗原受體及其識別抗原的特點(diǎn)MHC與peptides

只識別表達(dá)于細(xì)胞表面非己MHC或與自身MHC分子結(jié)合成復(fù)合物的多肽

只識別氨基酸一級序列的多肽線性決定簇TCR識別抗原肽受到自身MHC的限制——

CD4+T只識別與MHC-II分子結(jié)合的肽段

CD8+T只識別與MHC-I分子結(jié)合的肽段只有A圖中TCR可識別APC所遞呈的抗原，形成TCR-抗原肽三分子復(fù)合體,產(chǎn)生TH細(xì)胞活化的第一信號Primaryactivationofna?veTcellsrequirestwoindependentsignalssignal1:specificbutweakinteractionbetweenMHC:peptidecomplexandTCR/CD4orTCR/CD8signal2(co-stimulator),interactionsbetween:B7andCD28(required)adhesionmolecules(optional,increasecontact)O=C-CH2-CH2…AntigenCH2-OHCH2-CH2-NH3+C-CH2-CH2=O-OCH2CH2-CH2CH2CH2-CH2CH2CH2-CH2-CH2CH2CH2-CH2CH2CH2-C=O-O+H3N-CH2IonicbondvanderWaalsinteractionsHydrophobicinteractionsHydrogenbondIonicbondAntibodyRestingBcellCrosslinkedBcellAntigenB-cellmembraneIg-α/βCytoplasmITAMFynBlkLckITAMsequenceSrcSykKinases固有免疫的分子識別一般概念PRRs－PAMPs天然免疫分子識別的機(jī)制一般概念固有免疫機(jī)制存在對“異己”的分子識別分子識別可區(qū)分“有害”和“無害”物質(zhì)分子識別依賴多種受體和細(xì)胞膜分子分子識別并非針對某一特點(diǎn)的抗原

bacteriumsig1(stimulation)1959,originalSNSmodel:lymphocytesareactivatedbyrecognitionofforeignthings.BcellSirFMBurnet(1899-1985)

CohnM,MitchisonNA,PaulWEetal.Reflectionsontheclonal-selectiontheory.NatRevImmunol.2007,7:823-30.ClonalselectionTheSelf-NonselfModelBurnet’soriginalmodeleachlymphocyteexpresssmutiplecopiesofasinglesurfacereceptorspecificforaforeignentity.signalingthroughthissurfacereceptorinitiatestheimmuneresponse.theself-reactivelymphocytesaredeletedearlyinlife1969Bretscher&CohnBcellsdiewhentheyseeantigen(signalone)unlessrescuedbyhelp(signaltwo)sig1BcellTcellsig1(stimulation)TwosignalmodelCostimulationSig2(co-stimulation)1975Lafferty&CunninghamThelpercellsdiewhentheyseeantigenunlessrescuedbyco-stimulation(signaltwo)fromAPCs.bacteriumPRRs1989JanewayAPCsdonotco-stimulateunlessactivatedviaPRRs(receptorsforevolutionarilydistantinfectiousnon-self)PRRs-PAMPsC.A.Janeway,Jr.,M.D.TheInfectious-NonselfModel(1943-2003)APCsareactivatedbydanger/alarmsignalsfrominjuredcells,suchasthoseexposedtopathogens,toxins,mechanicaldamage,andsoforthTheDangermodelPollyMatzinger1994PollyMatzinger

APCsareactivatedbyendogenouscellularalarmsignalsfromdistressedorinjuredcellsDistressedcellNormalcellSteinmanRM,CohnZA.Identificationofanovelcelltypeinperipherallymphoidorgansofmice.I.Morphology,quantitation,tissuedistribution.

JExpMed.1973May1;137(5):1142-62.SteinmanRM,CohnZA.Identificationofanovelcelltypeinperipherallymphoidorgansofmice.II.Functionalpropertiesinvitro.JExpMed.1974Feb1;139(2):380-97.SteinmanRM,LustigDS,CohnZA.Identificationofanovelcelltypeinperipherallymphoidorgansofmice.3.Functionalpropertiesinvivo.JExpMed.1974Jun1;139(6):1431-45.SteinmanRM,AdamsJC,CohnZA.Identificationofanovelcelltypeinperipherallymphoidorgansofmice.IV.Identificationanddistributioninmousespleen.JExpMed.1975Apr1;141(4):804-20.SteinmanRM,KaplanG,WitmerMD,CohnZA.Identificationofanovelcelltypeinperipherallymphoidorgansofmice.V.Purificationofspleendendriticcells,newsurfacemarkers,andmaintenanceinvitro.JExpMed.1979Jan1;149(1):1-16.DC的發(fā)現(xiàn)/research/abstract.php?id=150RalphMSteinman.Dendriticcells:versatilecontrollersoftheimmunesystem.NatureMedicine,2007,13,1155-1159steinma@

RalphMSteinmanCohnZAandRalphMSteinmanCohnZAandRalphMSteinmanMichelNussenzweig,KayoInabaandWesleyvanVoorhis/files/0801profile.pdf固有免疫識別受體及其配體模式識別受體及其配體自身抗原識別受體及其配體

模式識別受體（Patternrecognitionreceptors,PRRs）分泌型受體MBLLBP

sCD14

細(xì)胞表面受體CD14TLR(Toll-likereceptors，TLRs)PGRP（昆蟲細(xì)胞）巨噬細(xì)胞甘露糖受體巨噬細(xì)胞清道夫受體細(xì)胞內(nèi)受體NODs（nucleotide-bindingoligomerizationdomain，NODs）Mannan-bindinglectinformsacomplexwithserineprote