抗原免疫原及其識別

1、INSTITUTE FOR IMMUNOBIOLOGYDepartment of ImmunologyShanghai Medical College of Fudan University洪曉武 021-獲得性免疫獲得性免疫(Acquired Immunity)適應(yīng)性免疫適應(yīng)性免疫(Adaptive Immunity)特異性免疫特異性免疫(Specific Immunity)固有免疫固有免疫(Innate Immunity)先天免疫先天免疫(Native Immunity)非特異性免疫非特異性免疫(Nonspecific Immunity)種系發(fā)育，進(jìn)化形成種系發(fā)育，進(jìn)化形成 生來具備，應(yīng)答

2、迅速生來具備，應(yīng)答迅速 非特異性抗感染免疫非特異性抗感染免疫 也參與特異性免疫也參與特異性免疫固有免疫應(yīng)答固有免疫應(yīng)答 適應(yīng)性免疫應(yīng)答適應(yīng)性免疫應(yīng)答長期進(jìn)化中逐漸形成長期進(jìn)化中逐漸形成 抗原激發(fā)抗原激發(fā)種系共有，可遺傳種系共有，可遺傳 個(gè)體特有，不可遺傳個(gè)體特有，不可遺傳無免疫記憶、作用時(shí)間短無免疫記憶、作用時(shí)間短 有免疫記憶、作用時(shí)間長有免疫記憶、作用時(shí)間長粘膜和上皮細(xì)胞、吞噬細(xì)胞、粘膜和上皮細(xì)胞、吞噬細(xì)胞、NK T細(xì)胞、細(xì)胞、B細(xì)胞、細(xì)胞、APC gdgdT細(xì)胞、細(xì)胞、B1 B細(xì)胞細(xì)胞不針對特定抗原（反應(yīng)廣泛）不針對特定抗原（反應(yīng)廣泛） 針對特定抗原（反應(yīng)特異性）針對特定抗原（反應(yīng)特異性）

3、作用迅速、范圍廣泛作用迅速、范圍廣泛 抗原識別、增殖分化、效應(yīng)階段抗原識別、增殖分化、效應(yīng)階段 免疫（免疫（ImmunityImmunity）固有免疫（固有免疫（Innate immunityInnate immunity）適應(yīng)性免疫（適應(yīng)性免疫（Adaptive immunityAdaptive immunity）抗原抗原/ /免疫原的概念免疫原的概念免疫原（免疫原（ImmunogenImmunogen）-啟動(dòng)免疫應(yīng)答的物質(zhì)啟動(dòng)免疫應(yīng)答的物質(zhì)抗原（抗原（antigen, Agantigen, Ag）-啟動(dòng)適應(yīng)性免疫應(yīng)答的物質(zhì)啟動(dòng)適應(yīng)性免疫應(yīng)答的物質(zhì)固有免疫原（固有免疫原（InnagenInn

4、agen，IngIng）-啟動(dòng)固有免疫應(yīng)答的物質(zhì)啟動(dòng)固有免疫應(yīng)答的物質(zhì)PAMPPAMP、DAMPDAMP啟動(dòng)、激發(fā)以炎癥反應(yīng)為主啟動(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)固有免疫識別的效應(yīng)AgAg啟動(dòng)、激發(fā)以特異性啟動(dòng)、激發(fā)以特異性CTLCTL和和AbAb為主為主的免疫應(yīng)答，清除病原體和靶細(xì)胞的免疫應(yīng)答，清除病原體和靶細(xì)胞適應(yīng)性免疫識別的效應(yīng)適應(yīng)性免疫識別的效應(yīng) ImmunogenInnagen (INg)/Innate Molecular Pattern (IMP)Antigen (Ag)PAMPDAMPOthers?Immun

5、ogenicity Reactigenicity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抗原抗原/免疫原的概念免疫原的概念免疫原性（免疫原性（immunogenicity）抗原性（抗原性（antigenicity）免疫原性免疫原性(immunogenecity)(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)。antigenicityimmuogenicityimmuogenicityTTTAgAg免疫原的特點(diǎn)免疫原的特點(diǎn)固有免疫原固有免疫原抗抗 原原不限于特定

6、類別的成分或單一分子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)性分離免疫原性、免疫反應(yīng)性一致免疫原性、免疫反應(yīng)性一致啟動(dòng)、誘導(dǎo)適應(yīng)性免疫應(yīng)答啟動(dòng)、誘導(dǎo)適應(yīng)性免疫應(yīng)答以表位為識別基礎(chǔ)以表位為識別基礎(chǔ)就免疫應(yīng)答始動(dòng)因素而言就免疫應(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)?？乖漠愇镄钥乖漠愇镄钥乖禺愋钥乖禺愋愿拍?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

7、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)T T 細(xì)細(xì)胞胞抗抗原原受受體體及及其其識識別別抗抗原原的的特特點(diǎn)點(diǎn)l 只識別表達(dá)于細(xì)胞表面非己只識別表達(dá)于細(xì)胞表面非己MHC或與自身或與自身MHC分子結(jié)合分子結(jié)合 成復(fù)合物的多肽成復(fù)合物的多肽l 只識別氨基酸一級序列的多肽線性決定簇只識別氨基酸一級序列的多肽線性決定簇l TCR識別抗原肽受到自身識別抗原肽受到自身MHC的限制的限制 CD4+T只識別與只識別與MHC-II分子結(jié)合的肽段分子結(jié)合的肽段 CD8+T只識別與只識別與MHC-I分子結(jié)合的肽段分子結(jié)合的肽段只有只有A圖中圖中TCR可識別可識別APC所遞呈的抗

8、原，形成所遞呈的抗原，形成TCR-抗抗原肽三分子復(fù)合體原肽三分子復(fù)合體,產(chǎn)生產(chǎn)生TH細(xì)胞活化的第一信號細(xì)胞活化的第一信號Primary activation of nave T cells requires two independent signals signal 1:specific but weakinteraction betweenMHC:peptide complex and TCR/CD4 or TCR/CD8 signal 2 (co-stimulator), interactions between: B7 and CD28 (required) adhesion mole

9、cules (optional, increase contact)O = C - C H2 - C H2 AntigenC H2 - O HCH2 - CH2 - NH3+C - C H2 - C H2=O-OCH2 CH2 - CH2CH2CH2 - CH2CH2CH2 - CH2 - CH2CH2CH2 - CH2CH2CH2-C=O-O+ H3 N - C H2 Ionic bond van der Waals interactions Hydrophobic interactionsHydrogen bondIonic bondAntibodyResting B cellCrossl

10、inked B cellAntigenB-cellmembraneIg-/CytoplasmITAMFynBlkLckITAM sequenceSrc SykKinases固有免疫的分子識別固有免疫的分子識別一般概念一般概念PRRsPAMPs天然免疫分子識別的機(jī)制天然免疫分子識別的機(jī)制bacteriumsig1(stimulation)1959, original SNS model: lymphocytes are activated by recognition of foreign things.Sir FM Burnet(1899-1985) Cohn M, Mitchison NA,

11、 Paul WE et al. Reflections on the clonal-selection theory. Nat Rev Immunol. 2007, 7:823-30. Burnets original modeleach lymphocyte expresss mutiple copies of a single surface receptor specific for a foreign entity.signaling through this surface receptor initiates the immune response.the self-reactiv

12、e lymphocytes are deleted early in life1969 Bretscher & CohnB cells die when they see antigen(signal one) unless rescued by help(signal two)sig1sig1(stimulation)Two signal modelCostimulationSig2(co-stimulation)1975 Lafferty & CunninghamT helper cells die when they see antigen unless rescued

13、by co-stimulation(signal two) from APCs.bacteriumPRRs1989 JanewayAPCs do not co-stimulate unless activated via PRRs(receptors for evolutionarily distant infectious non-self) PRRs-PAMPsThe Infectious-Nonself Model )APCs are activated by danger/alarm signals from injured cells, such as those exposed t

14、o pathogens, toxins, mechanical damage, and so forthThe Danger modelPolly Matzinger1994 Polly Matzinger APCs are activated by endogenous cellular alarm signals from distressed or injured cellsDistressed cellNormal cellSteinman RM, Cohn ZA.Identification of a novel cell type in peripheral lymphoid or

15、gans of mice. I. Morphology, quantitation, tissue distribution. J Exp Med. 1973 May 1;137(5):1142-62.Steinman RM, Cohn ZA.Identification of a novel cell type in peripheral lymphoid organs of mice. II. Functional properties in vitro.J Exp Med. 1974 Feb 1;139(2):380-97. Steinman RM, Lustig DS, Cohn ZA

16、. Identification of a novel cell type in peripheral lymphoid organs of mice. 3. Functional properties in vivo.J Exp Med. 1974 Jun 1;139(6):1431-45. Steinman RM, Adams JC, Cohn ZA.Identification of a novel cell type in peripheral lymphoid organs of mice. IV. Identification and distribution in mouse s

17、pleen.J Exp Med. 1975 Apr 1;141(4):804-20.Steinman RM, Kaplan G, Witmer MD, Cohn ZA.Identification of a novel cell type in peripheral lymphoid organs of mice. V. Purification of spleen dendritic cells, new surface markers, and maintenance in vitro.J Exp Med. 1979 Jan 1;149(1):1-16.http:/www.rockefel

18、/research/abstract.php?id=150Ralph M Steinman. Dendritic cells: versatile controllers of the immune system.Nature Medicine, 2007,13, 1155 - 1159 Ralph M SteinmanCohn ZA and Ralph M SteinmanCohn ZA and Ralph M SteinmanMichel Nussenzweig,Kayo Inaba and Wesley van Voorhis/files/0801profile.pdf分泌型受體分泌型受體MBLLBP sCD14 細(xì)胞表面受體細(xì)胞表面受體CD14TLR (PGRP（昆蟲細(xì)胞）（昆蟲細(xì)胞）巨噬細(xì)胞甘露糖受體巨噬細(xì)胞甘露糖受體巨噬細(xì)胞清道夫受體巨噬細(xì)胞清道夫受體細(xì)胞內(nèi)受體細(xì)胞內(nèi)受體NODs（ LRR domain （leucine-rich repeat）Cysteine rich domainTIR domain1921年年 Littl