生命科学基础综合自身免疫病-1110.

Howtotreatautoimmunedisease(AID)LiWang（王莉）,Ph.D.InstituteofImmunologyPLA,TMMUTel:752229E-mail:[e-mail]核心课程“生命科学综合”——疾病防治基础重症肌无力Myastheniagravis甲亢hyperthyroidism类风湿性关节炎Rheumatoidarthritis系统性红斑狼疮SystemiclupuserythematosusⅠ型糖尿病（Type1diabetes）银屑病psoriasis白癜风vitiligo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,IIcollagen•HumanCartilageglycoprotein39(HCgp-39)•Citrullinatedfibrinogen•HSPs•……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+TcellAutoantigensintype1diabetes•Insulin(Science,1983)•GlutamicAcidDecarboxylase65(GAD65)（Nature,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(NatImmunol.2010)ThedifferentiationofautoreactiveeffectorTcellsinAIDIFN-γkomouseAID↑IL-22IL-21IL-2Th17cellsplayacriticalroleinthepathogenesisofAIDSequentialrecruitmentofautoreactiveeffectorTcellsinthetargetorganduringinflammation胸腺树突状细胞deathSelftolerance自身抗原肽-MHC复合物中\低亲和力Potentialself-reactiveForeignantigensmatureTcellmatureTcell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细胞死亡（AICD）peripheralclonaldeletionRepeatedantigensignalAbsentcostimulatorysignalHowautoreactiveTcellsarecontrolled?胸腺树突状细胞deathSelftoleranceSelf-reactiveRegulatoryTcell自身抗原肽-MHC复合物中\低亲和力Potentialself-reactiveForeignantigensmatureTcellmatureTcell外周immatureTcellactivatedactiveinhibitionHowautoreactiveTcellsarecontrolled?Foxp3+WhatisregulatoryTcells（Treg）?RegulatoryTcellsEffectorTcellsnaturalinducedCD4+CD25+Foxp3+Treg，占外周CD4+T细胞5%～10%（1995）Tissue-residentTregs功能：免疫调节，抑制正应答，维持自身耐受HowdoTregcellswork?Immunology,2008,124,13–22ImpairedregulationbyCD4+CD25+FOXP3+regulatoryTcellsinautoimmunediseasesNatureReviewsImmunology2010,10:849-859OverviewofTregcellsinautoimmunityNatureReviewsImmunology2010,10:849-859抵抗易感年轻雄激素无易感基因避免微生物感染清新的环境良好的饮食习惯少有组织损伤好运气高龄雌激素易感基因组合诱病微生物感染环境因素（紫外线化学污染等）不良饮食习惯组织损伤运气不佳ThefactorseffectingautoimmunediseaseEffectofgenderontheprevalenceofautoimmunediseasesINSPTPN22IL2RASH2B3ERBB3PTPN2CLEC16ACTLA4IL18RAPPTPN2CCR5IFIH1CTSHCD226IL2RAPRKCQIL2BACH2UBASH3ARGS1IL7RACIQTNF6TNFAIP3TNFAIP3TAGAP0.000.250.500.751.001.251.501.752.002.252.50InsulinproductionandmetabolismUnknownfunctionImmunitycellapoptosisprotectionLocusOddsratioINSPTPN22IL2RASH2B3ERBB3PTPN2CLEC16ACTLA4IL18RAPPTPN2CCR5IFIH1CTSHCD226IL2RAPRKCQIL2BACH2UBASH3ARGS1IL7RACIQTNF6TNFAIP3TNFAIP3TAGAP0.000.250.500.751.001.251.501.752.002.252.50InsulinproductionandmetabolismUnknownfunctionImmunitycellapoptosisprotectionLocusOddsratioINSPTPN22IL2RASH2B3ERBB3PTPN2CLEC16ACTLA4IL18RAPPTPN2CCR5IFIH1CTSHCD226IL2RAPRKCQIL2BACH2UBASH3ARGS1IL7RACIQTNF6TNFAIP3TNFAIP3TAGAP0.000.250.500.751.001.251.501.752.002.252.50InsulinproductionandmetabolismUnknownfunctionImmunitycellapoptosisprotectionLocusOddsratio6.50-HLAOddsRatioGenome-WideAssociationsStudyinType1DiabetesModifiedfromConcannon,Rich,NepomNEJM360:16462009GeneticSusceptibilityforT1DMHC（HLA）genesCapacitytopresentantigensandinduceautoreactiveTcellsactivationFigure11-23AssociationofHLAallotypewithautoimmunediseasesNaturereviewsImmunol,2007,7:645-650介导外周组织抗原在胸腺上皮细胞（TEC）中的异位表达Aire突变导致T细胞阴性选择异常Autoimmuneregulator(Aire)自身免疫增多内分泌病变—念珠菌病—外胚层营养不良（APECED）①自身免疫性多种内分泌病变,包括甲状腺及甲状旁腺功能减退，肾上腺皮质衰竭，T1D，性腺衰竭，恶性贫血及自身免疫肝炎②慢性粘膜与皮肤白色念珠菌病③外胚层发育不良，而且一大部分病人会发生口腔粘膜鳞状细胞癌罕见人类单基因遗传性自身免疫疾病Scurfy小鼠Foxp3基因敲除小鼠功能：控制CD4+CD25+Treg的发育及功能FOXP3突变→Treg缺失→自身免疫病叉状头/翅膀状螺旋转录因子（Foxp3）WildtypeScurfyFoxp3mutation性联免疫失调综合征（IPEX）naturegenetics2001,27:20-21特点早发性顽固性腹泻、自身免疫性甲状腺炎、胰岛素依赖性糖尿病、高IgE、嗜酸性粒细胞升高、肾病、皮疹等，常导致患者在婴幼儿早期死亡。机制：Foxp3基因突变Wild-typeFas-knockoutFas-FasL介导的AICD是机体重要的外周免疫耐受机制，Fas基因突变，大量活化的淋巴细胞可持续存活，产生淋巴细胞增生（脾大、淋巴结肿大）和自身免疫现象Repeatedantigensignal活化诱导的细胞死亡（AICD）Fas-FasL自身免疫性淋巴细胞增生综合征Autoimmunelymphoproliferativesyndrome(ALPS)特点①淋巴细胞增生性表现：脾脏肿大；②自身免疫性疾病：自身免疫性溶血性贫血(75%)，免疫性血小板减少症(54%)，自身免疫性中性粒细胞减少症；其他有肾小球肾炎、多发性神经根炎和皮肤损害(包括荨麻疹和非特异性皮肤血管炎)机制：Fas基因突变EnvironmentfactorforT1D•饮食因素：Bovinemilk？Antibodiestocow’smilkproteinshavebeendetectedintheserumofindividualswithT1D•感染因素：?–CoxsackieB,Rubella,andmumps分子模拟Infection——molecularmimicry疾病受累器官靶