生命科学基础综合-自身免疫病-1110演示教学.ppt

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1、生命科学基础综合-自身免疫病-1110非我物质正免疫应答自我物质负免疫应答免疫耐受pathogenstumor自我物质非我物质正免疫应答自身免疫病AutoimmuneDisease,AID负免疫应答（自身耐受）免疫耐受机制障碍autoantibodyautoreactiveTcellsautoantigen/selfantigens自身抗原AutoimmuneDisease(AID)定义：自身耐受机制遭破坏，产生自身抗体和自身反应性淋巴细胞攻击并破坏自身的正常组织细胞，机体出现病理改变和相应临床表现条件：高水平的自身抗体和（或）自身反应性T细胞有明确的自身抗原（抗原局限或广泛分布）用患者血

2、清或淋巴细胞可使疾病被动转移可复制出相似的动物模型特点：易感性随着年龄增加而增加，女性高于男性遗传倾向性甲亢抗促甲状腺激素刺激激素受体（TSHreceptor）抗体Autoantibody-mediateddysfunction重症肌无力抗乙酰胆碱受体(AChR)抗体AutoreacitiveTcellandautoantibodymediateddamageRheumatoidArthritis类风湿性关节炎AutoantigensinRA变性IgG(anti-IgG:rheumatoidfactors)TypeI,IIcollagenHumanCartilageglycoprotein

3、39(HCgp-39)CitrullinatedfibrinogenHSPs……抗瓜氨酸化蛋白抗体Anticitrullinatedproteinantibodies(ACPA)：重要的RA诊断与预后指标NEnglJMed,1985.313:353–360Type1diabetesAutoreacitiveTcell-mediateddamageβ-cellantigensspecificCD8+/CD4+TcellAutoantigensintype1diabetesInsulin(Science,1983)GlutamicAcidDecarboxylase65(GAD65)（Natur

4、e,1990)The60kDaheat-shockprotein(hsp60)(PNAS,1990)Tyrosinephosphatase(IA-2)(J.Clin.Invest,1995)The38kDisletmitochondrialantigen(Imogen38)(J.Clin.Invest,1996)Islet-specificglucose-6-phosphatasecatalyticsubunit-relatedprotein(IGRP)(PNAS,2003)Preproinsulin(PNAS.2003)ZnT8(PNAS,2007)ChromograninA(NatIm

5、munol.2010)ThedifferentiationofautoreactiveeffectorTcellsinAIDIFN-γkomouseAID↑IL-22IL-21IL-2Th17cellsplayacriticalroleinthepathogenesisofAIDSequentialrecruitmentofautoreactiveeffectorTcellsinthetargetorganduringinflammation胸腺树突状细胞高亲和力识别deathSelftolerance自身抗原肽-MHC复合物中低亲和力无亲和力Potentialself-reacti

6、veForeignantigensmatureTcellmatureTcell外周immatureTcellHowperipheralautoreactiveTcellsaregenerated?activated?隐蔽自身抗原HowautoreactiveTcellsarecontrolled?clonalanergyHowautoreactiveTcellsareactivated?A:molecularmimicryB:bystanderactivationC:epitopespreadingNatureReviewsImmunology2009,9,246-258被动死亡活化诱导的

7、细胞死亡（AICD）peripheralclonaldeletionRepeatedantigensignalAbsentcostimulatorysignalHowautoreactiveTcellsarecontrolled?胸腺树突状细胞高亲和力识别deathSelftoleranceSelf-reactiveRegulatoryTcell自身抗原肽-MHC复合物中低亲和力无亲和力Potentialself-r