,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,病毒感染与自身免疫病,病毒感染与自身免疫病,1,Virus Infections and autoimmunity,Exogenous viruses:EBV,Molecular mechanism for autoimmunity,Enogenous viruses:HERV,Autoimmune disease:,A role for new antiviral therapies?,Outline,Outline,2,Virus Infections and autoimmunity(,Background,),自身免疫是机体失去对自身抗原的免疫耐受,自身免疫病因与发病机制十分复杂:,遗传背景，但环境因素和生活方式等的也有重要作用。,研究表明病毒和细菌等感染与自身免疫病的发生、发展密切关系。,一些病毒感染可导致机体失去对自身抗原免疫耐受，因而诱发、促进或加重自身免疫病。,已证明某些病毒感染与一些自身免疫病密切相关，并发现病毒与宿主细胞的某些基因或其蛋白分子之间存在着结构类似性，因而可发生交叉免疫反应性。这种分子模拟假说获动物实验的支持。,Virus Infections and autoim,3,少数,T,细胞克隆逃,避阴性选择,进入外周,识别自身抗原,通过激活诱导,细胞死亡（,AICD,),(FasL-Fas-,凋亡）,部分,T,细胞克隆,逃避,AICD,识别自身抗原,自身免疫病,(AID),T,细胞发育过程自身,耐受形成,及逃避机制,少数T细胞克隆逃识别自身抗原 通过激活诱导部分T细胞克,4,B细胞发育过程自身,耐受形成,及逃避机制,克隆清除,结合 克隆无能,克隆忽视,不结合 克隆发育成熟,激活,自身免疫病,自身免疫病,激活,B,细胞,骨髓细胞,表面抗原,B细胞发育过程自身耐受形成及逃避机制,5,Host,MHC,Loss of Tolerance,Immune system defects,Susceptibility Genes,Endogenous Viruses,Autoimmune,disease,Environment and,autoimmunity,Chemical substances,Microbial Agents,drugs,UVB light,Vaccines,typhoid,influenza,meningococcal,tetanus toxoid,measles,mumps,and rubella,Diet/Nutrition,HostEnvironment and autoimmuni,6,新西兰小鼠,(NzB),自发产生抗,DNA,抗红细胞抗体,溶血性贫血,狼疮性肾炎,自然发生,新西兰小鼠,(NZW),不发生系统性,红斑狼疮,(SLE),NZB X NZW(F1),杂交小鼠,抗,DNA,和其他核抗体与人类,SLE,类似,感染病毒,感染病毒,自身抗体效价更高,自身免疫病的发生更早,发生自身免疫病,These observations lend further support that both genetic and environmental factors play a role in,autoimmune disease,.,新西兰小鼠(NzB)自发产生抗DNA溶血性贫血自然发生新西兰,7,病毒感染与自身免疫病课件,8,Exogenous viruses,Exogenous microbial agents,such as bacteria or viruses,interact with and sometimes might override the human immune system to cause infectious diseases,cancers and autoimmunity.,Exogenous virusesExogenous mic,9,Exogenous viral agents have also been implicated as potential triggers or pathogenic agents of autoimmune conditions.,Viruses which have been linked to the pathogenesis of SLE include,EpsteinBarr Virus(EBV),Cytomegalovirus(CMV),parvovirus(细小)B19,Human Papilloma Virus(HPV),Human Herpes Virus(HHV6),HHV7,HHV8,Dengue virus,HIV,human T cell lymphotropic virus,(HTLV,人类嗜T细胞病毒),Exogenous viral agents have al,10,EBV as a potential viral agent in SLE,In SLE,EBV has been highlighted as a potential pathogenic agent through serological studies of patients that have shown antibodies to early antigens,capsid and latent membrane proteins in much higher frequency as compared to controls,in pediatric SLE,99%of patients are antiEBV Ab+compared to 70%of controls,In people with SLE,the number of EBV infected B cells is elevated 10 to 100 times over the levels in controls,and the amount of free virus,in serum is also elevated.,molecular analysis of complementary EBV transcripts appears to substantiate these observation,Increased virus levels are associated with disease flares LMP1 mRNA is the most frequently detected latent EBV product in the blood of SLE patients,a metaanalysis of serological studies revealed that antibodies to capsid and early antigen proteins were particularly prominent.,EBV is recognized as a strong polyclonal B cell activator and therefore could stimulate a substantial number of potentially autoreactive B cells.,EBV as a potential viral agent,11,EBV 结构和蛋白,（,Epstein-Barr virus,，,EBV,）,Epstein,和,Barr,：,1964,年首次成功地在,Burkitt,非洲儿童淋巴瘤细胞中发现,靶细胞：,B,细胞、鼻咽上皮细胞、胃上皮,感染类型：潜伏感染,核抗原（,EBNA,），潜伏膜蛋白（,LMP,）,增殖感染,早期蛋白（,EA,），病毒衣壳抗原（,VCA,）,膜抗原（,MA,）,受体：,CD21,分子,EBV 结构和蛋白（Epstein-Barr virus，E,12,增殖性感染表达的抗原,当EBV进入宿主细胞后，首先表达反式激活蛋白ZERBA，进而激活EBV早期基因，产生增殖性感染。,EBV早期抗原(early antigen,EA)增殖早期诱导的非结构蛋白，分为,EAR存在于细胞浆中,EAD存在于细胞浆和细胞核内，并具有EBV特异的DNA多聚酶活性。,EA表示EBV增殖活跃，是感染细胞进入溶解性周期的标志。,非洲儿童恶性淋巴瘤患者抗EAR抗体阳性，鼻咽癌患者抗EAD抗体阳性。,EBV衣壳抗原(viral capsid antigen,VCA):病毒增殖晚期合成的结构蛋白，存在于细胞浆和细胞核内。,VCA:与病毒DNA组成EBV的核衣壳，在核膜出芽时获得包膜装配成完整病毒体。VCAIgM:出现早，消失快，VCAIgG:出现晚，持续时间长。,EBV膜抗原(membrance antigen,MA)存在于细胞表面，为包膜糖蛋白，其中 糖蛋白gp320/220能诱导产生中和抗体。,MAIgM:用于早期诊断，MAIgG:可体内持续存在。,增殖性感染表达的抗原 当EBV进入宿主细胞后，首先表,13,潜伏性感染表达的抗原,EBV在记忆B细胞及某些上皮细胞中可表现为潜伏感染，仅部分表达基因发生转录，,选择性表达EBV潜伏感染期蛋白。,EBV核抗原（EB nuclear antigen,EBNA）:DNA结合蛋白，所有EBV感染,和转化的B细胞核内均可检出该抗原。(EBNA1,2,3A,3B,and 3C),EBNA1:与EBV基因组以环状附加体(episome)形式持续存在，对细,胞处理和抗原提呈功能具有抑制作用，从而逃避宿主细胞的,CTL杀伤作用，因此与维持EBV基因组在感染细胞内潜伏有关；,EBNA2和EBNA3为转录因子:可调控多种病毒蛋白和宿主细胞蛋白的表,达，与诱导B细胞转化有关。,潜伏感染膜蛋白(latent membrance protein,LMP):存在于潜伏感染B细胞表面，有LMP1和LMP2(LMP2A,LMP2B)两种。,LMP1:功能类似活化的生长因子受体，能与细胞抑癌蛋白（肿瘤坏死因子受体相关,因子，TRAF）相互作用，抑制细胞凋亡，诱导B细胞转化，是一种致癌蛋白；,LMP2:细胞酪氨酸激酶的底物，具有阻止潜伏病毒激活的作用。,潜伏性感染表达的抗原 EBV在记忆B细胞及某些上皮细,14,Gp350-CD21,BMRF2-,1,整合素,gp110-?,Gp350-CD21BMRF2-1整合素gp110-?,15,EBV specific CD8+Tcells are enriched in or near the diseased organs of patients with RA and MS.,膜抗原（MA）,Bystander Activation（旁路激活）,MSRV 体内外均可激活Tcells 并诱导产生 cytokines.,EBV as a potential viral agent in SLE,EBV 诱导内源性逆转录病毒产生 HERVK18,HERVK18编码超抗原激活 T细胞,HERV数量虽多，但大部分由于突变、缺失等的积累，已经没有编码能力。,in serum is also elevated.,domains,termed CTAR1,CTAR2 and CTAR3,which recruit TNFR-associated signalling adapter proteins,autoimmune disease.,抗DNA和其他核抗体与人类SLE类似,S