抗原免疫原及其识别

1、INSTITUTE FOR IMMUNOBIOLOGYDepartment of ImmunologyShanghai Medical College of Fudan University洪晓武 021-获得性免疫获得性免疫(Acquired Immunity)适应性免疫适应性免疫(Adaptive Immunity)特异性免疫特异性免疫(Specific Immunity)固有免疫固有免疫(Innate Immunity)先天免疫先天免疫(Native Immunity)非特异性免疫非特异性免疫(Nonspecific Immunity)种系发育，进化形成种系发育，进化形成 生来具备，应答

2、迅速生来具备，应答迅速 非特异性抗感染免疫非特异性抗感染免疫 也参与特异性免疫也参与特异性免疫固有免疫应答固有免疫应答 适应性免疫应答适应性免疫应答长期进化中逐渐形成长期进化中逐渐形成 抗原激发抗原激发种系共有，可遗传种系共有，可遗传 个体特有，不可遗传个体特有，不可遗传无免疫记忆、作用时间短无免疫记忆、作用时间短 有免疫记忆、作用时间长有免疫记忆、作用时间长粘膜和上皮细胞、吞噬细胞、粘膜和上皮细胞、吞噬细胞、NK T细胞、细胞、B细胞、细胞、APC gdgdT细胞、细胞、B1 B细胞细胞不针对特定抗原（反应广泛）不针对特定抗原（反应广泛） 针对特定抗原（反应特异性）针对特定抗原（反应特异性）

3、作用迅速、范围广泛作用迅速、范围广泛 抗原识别、增殖分化、效应阶段抗原识别、增殖分化、效应阶段 免疫（免疫（ImmunityImmunity）固有免疫（固有免疫（Innate immunityInnate immunity）适应性免疫（适应性免疫（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）-启动免疫应答的物质启动免疫应答的物质抗原（抗原（antigen, Agantigen, Ag）-启动适应性免疫应答的物质启动适应性免疫应答的物质固有免疫原（固有免疫原（InnagenInn

4、agen，IngIng）-启动固有免疫应答的物质启动固有免疫应答的物质PAMPPAMP、DAMPDAMP启动、激发以炎症反应为主启动、激发以炎症反应为主的免疫应答，清除病原体和凋亡细胞的免疫应答，清除病原体和凋亡细胞固有免疫识别的效应固有免疫识别的效应AgAg启动、激发以特异性启动、激发以特异性CTLCTL和和AbAb为主为主的免疫应答，清除病原体和靶细胞的免疫应答，清除病原体和靶细胞适应性免疫识别的效应适应性免疫识别的效应 ImmunogenInnagen (INg)/Innate Molecular Pattern (IMP)Antigen (Ag)PAMPDAMPOthers?Immun

5、ogenicity Reactigenicity熊思东.道亦道,非故道-试论固有免疫中的抗原和免疫原的定义.现代免疫学, 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) 指抗原分子能够刺激机体产生免疫应答(产生特异性抗体及免疫效应细胞)的性质。antigenicityimmuogenicityimmuogenicityTTTAgAg免疫原的特点免疫原的特点固有免疫原固有免疫原抗抗 原原不限于特定

6、类别的成分或单一分子不限于特定类别的成分或单一分子启动、诱导固有免疫应答启动、诱导固有免疫应答免疫原性、免疫反应性分离免疫原性、免疫反应性分离免疫原性、免疫反应性一致免疫原性、免疫反应性一致启动、诱导适应性免疫应答启动、诱导适应性免疫应答以表位为识别基础以表位为识别基础就免疫应答始动因素而言就免疫应答始动因素而言 异物性是抗原免疫原性的本质。 非己就是异物，抗原来源与宿主的关系越远，异物越强,免疫原性也越强。抗原的异物性抗原的异物性抗原特异性抗原特异性概念-指某一抗原分子只能诱导相应淋巴细胞发生免 疫应答的专一性，以及只能与相应抗体或效应 细胞特异性结合的专一性。意义-是免疫学诊断与防治的理论

7、依据 (1)两对半：检测HBV (2)接种牛痘：消灭天花决定抗原特异性的物质基础T T 细细胞胞抗抗原原受受体体及及其其识识别别抗抗原原的的特特点点l 只识别表达于细胞表面非己只识别表达于细胞表面非己MHC或与自身或与自身MHC分子结合分子结合 成复合物的多肽成复合物的多肽l 只识别氨基酸一级序列的多肽线性决定簇只识别氨基酸一级序列的多肽线性决定簇l TCR识别抗原肽受到自身识别抗原肽受到自身MHC的限制的限制 CD4+T只识别与只识别与MHC-II分子结合的肽段分子结合的肽段 CD8+T只识别与只识别与MHC-I分子结合的肽段分子结合的肽段只有只有A图中图中TCR可识别可识别APC所递呈的抗

8、原，形成所递呈的抗原，形成TCR-抗抗原肽三分子复合体原肽三分子复合体,产生产生TH细胞活化的第一信号细胞活化的第一信号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固有免疫的分子识别固有免疫的分子识别一般概念一般概念PRRsPAMPs天然免疫分子识别的机制天然免疫分子识别的机制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分泌型受体分泌型受体MBLLBP sCD14 细胞表面受体细胞表面受体CD14TLR (PGRP（昆虫细胞）（昆虫细胞）巨噬细胞甘露糖受体巨噬细胞甘露糖受体巨噬细胞清道夫受体巨噬细胞清道夫受体细胞内受体细胞内受体NODs（ LRR domain （leucine-rich repeat）Cysteine rich domainTIR domain1921年年 Litt