生命科学基础综合 自身免疫病 教育学习

,Howtotreatautoimmunedisease(AID),LiWang（王莉）,Ph.D.InstituteofImmunologyPLA,TMMUTel:752229E-mail:liwang118,核心课程“生命科学综合”疾病防治基础,1,优质课件,重症肌无力Myastheniagravis,甲亢hyperthyroidism,类风湿性关节炎Rheumatoidarthritis,系统性红斑狼疮Systemiclupuserythematosus,型糖尿病（Type1diabetes）,银屑病psoriasis,白癜风vitiligo,2,优质课件,非我物质,正免疫应答,自我物质,负免疫应答,免疫耐受,pathogens,tumor,3,优质课件,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,autoantibody,autoreactiveTcells,autoantigen/selfantigens自身抗原,4,优质课件,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,5,优质课件,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,6,优质课件,AutoreacitiveTcellandautoantibodymediateddamage,RheumatoidArthritis类风湿性关节炎,7,优质课件,AutoantigensinRA,变性IgG(anti-IgG:rheumatoidfactors)TypeI,IIcollagenHumanCartilageglycoprotein39(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,8,优质课件,NEnglJMed,1985.313:353360,Type1diabetes,AutoreacitiveTcell-mediateddamage,-cellantigensspecificCD8+/CD4+Tcell,9,优质课件,Autoantigensintype1diabetes,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),10,优质课件,ThedifferentiationofautoreactiveeffectorTcellsinAID,IFN-komouse,AID,IL-22IL-21,IL-2,11,优质课件,Th17cellsplayacriticalroleinthepathogenesisofAID,12,优质课件,SequentialrecruitmentofautoreactiveeffectorTcellsinthetargetorganduringinflammation,13,优质课件,胸腺,高亲和力识别,death,Selftolerance,自身抗原肽-MHC复合物,中低亲和力,无亲和力,Potentialself-reactive,Foreignantigens,matureTcell,matureTcell,外周,immatureTcell,HowperipheralautoreactiveTcellsaregenerated?,activated?,隐蔽自身抗原,14,优质课件,HowautoreactiveTcellsarecontrolled?,clonalanergy,15,优质课件,HowautoreactiveTcellsareactivated?,A:molecularmimicry,B:bystanderactivation,C:epitopespreading,NatureReviewsImmunology2009,9,246-258,16,优质课件,被动死亡,活化诱导的细胞死亡（AICD）,peripheralclonaldeletion,Repeatedantigensignal,Absentcostimulatorysignal,HowautoreactiveTcellsarecontrolled?,17,优质课件,胸腺,高亲和力识别,death,Selftolerance,Self-reactive,RegulatoryTcell,自身抗原肽-MHC复合物,中低亲和力,无亲和力,Potentialself-reactive,Foreignantigens,matureTcell,matureTcell,外周,immatureTcell,activated,activeinhibition,HowautoreactiveTcellsarecontrolled?,Foxp3+,18,优质课件,WhatisregulatoryTcells（Treg）?,RegulatoryTcells,EffectorTcells,natural,induced,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,19,优质课件,HowdoTregcellswork?,Immunology,2008,124,1322,20,优质课件,ImpairedregulationbyCD4+CD25+FOXP3+regulatoryTcellsinautoimmunediseases,NatureReviewsImmunology2010,10:849-859,21,优质课件,22,优质课件,OverviewofTregcellsinautoimmunity,NatureReviewsImmunology2010,10:849-859,23,优质课件,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,Thefactorseffectingautoimmunedisease,24,优质课件,Effectofgenderontheprevalenceofautoimmunediseases,25,优质课件,Genome-WideAssociationsStudyinType1Diabetes,ModifiedfromConcannon,Rich,NepomNEJM360:16462009,GeneticSusceptibilityforT1D,26,优质课件,MHC（HLA）genes,CapacitytopresentantigensandinduceautoreactiveTcellsactivation,27,优质课件,Figure11-23,AssociationofHLAallotypewithautoimmunediseases,28,优质课件,NaturereviewsImmunol,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),29,优质课件,自身免疫增多内分泌病变念珠菌病外胚层营养不良（APECED）,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慢性粘膜与皮肤白色念珠菌病外胚层发育不良，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,30,优质课件,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）,Wildtype,ScurfyFoxp3mutation,31,优质课件,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,32,优质课件,Wild-type,Fas-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,Fas-FasL,33,优质课件,自身免疫性淋巴细胞增生综合征Autoimmunelymphoproliferativesyndrome(ALPS),特点淋巴细胞增生性表现：脾脏肿大；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,34,优质课件,EnvironmentfactorforT1D,饮食因素：Bovinemilk？AntibodiestocowsmilkproteinshavebeendetectedintheserumofindividualswithT1D感染因素：?CoxsackieB,Rubella,andmumps,分子模拟,35,优质课件,Infectionmolecularmimicry,分子模拟,36,优质课件,饮食、应激、损伤自身抗原性质改变,自身抗原修饰类型：磷酸化瓜氨酸化氧化乙酰化,37,优质课件,CurrentTherapies-非特异性免疫抑制剂以及抗炎疗法危害：感染、肿瘤的发生率增加、长期使用激素的副作用ExperimentalTherapeuticApproaches-trytotargetTcellsorBcells,HowtotreatAID？,38,优质课件,I.CurrentTherapies,免疫抑制剂（Immunosuppressivedrugs）-皮质类固醇corticosteroids，硫唑嘌呤azathioprine-slowstheproliferationoflymphocytes环孢菌素A（CyclosporinA）-blockssignaltransductionmediatedbytheTCR(inhibitsonlyantigen-activatedTcellswhilesparingnon-activatedones)胸腺切除（Thymectomy）-removalofthymusfrompatientswithmyastheniagravis血浆置换（Plasmapheresis）-removesantigen-antibodycomplexesforashort-termreductioninsymptoms,39,优质课件,1.靶向T/B细胞的非特异性治疗策略,antithymocyteglobulin(ATG)anti-CD3antibodyOKT3，humanizedFNBmAbOKT3g1ala-ala(teplizumab)retainedacombinationofrapamycinandanti-IL-2B-cell-depletingdrugrituximab（anti-CD20）,II.ExperimentalTherapeuticApproaches,体内剔除T/B细胞,40,优质课件,阻断T细胞共刺激、迁移及细胞因子,aCTLA4Igfusionprotein:blockingCD28/B7interactionsanLFA-3-Igfusionprotein:blockingtheinteractionofLFA-3onAPCswithcostimulatorymoleculeCD2onTcellsakaCD40L:blockinginteractionsofCD154onTcellsandCD40onAPCsfingolimod(FTY720),asmallcompound:affectingT-celltraffickingTNF-antagonistsAnti-IL-17mAbSecukinumab：Phase3studiesinPsoriasisandAScompleted,41,优质课件,2.细胞过继性治疗策略,Mesenchymalstemcells(MSCs)TolerogenicDCssuchasplasmacytoidDCs(pDCs)Tregs（thefirstU.S.clinicaltrialofTregcellulartherapyinpatientswithT1D，ClinicalTIdentifierNCT01210664）,42,优质课件,临床基于Treg的过继性治疗策略,体外活化和扩增,从病人体内分离出部分Treg,回输入病人体内,43,优质课件,Treg过继疗法的优势以及存在的问题,优势：与大多药物治疗相比，Treg过继转移可以最大程度的降低治疗毒性带来的副作用向病人回输Treg之前可以对细胞的表型和功能进行鉴定，并且准确的控制治疗用细胞的数量，增强了治疗的安全性和可操作性问题：这些Treg是否具有靶器官抗原特异性，是否能够归巢到局部效应靶器官？抗凋亡能力如何？如何获得抗原特异性Treg？体外扩增的Treg细胞是否有恢复为普通T细胞的可能？体内输入大量具有免疫抑制功能的Treg细胞，是否会增加感染和肿瘤发生的机会？,44,优质课件,3.Antigen-SpecificTherapeuticApproaches,Solubleautoantigensorpeptides(oral;i.v.;i.p)Alteredpeptideligandsor