风湿性疾病的免疫PPT课件

某些风湿性疾病的免疫问题,披露,非披露,提纲,简要回顾免疫学重要概念将这些概念应用于三种风湿性疾病痛风系统性红斑狼疮RA,先天免疫 第一道防线,适应性免疫 特异性,记忆,免疫, 响应的调节类型,免疫,提高抗微生物活性,先天免疫 第一道防线,ADAPTIVE IMMUNITYSpecificity, Memory,RECRUITS, MODULATES TYPE OF RESPONSE,RECRUITS, ENHANCES ANTIMICROBICAL ACTIVITY,先天免疫系统的功能,先天免疫的模式识别,受体识别模式,PRRs,数量有限的受体包括叫做TLRs的toll样受体,nod样受体(NLRs),RNA helicases,Dectin,Mannose-binding受体,先天免疫识别模,CELL SURFACE,核内体,细胞质,病原体相关分子模式 PAMPS,DANGER-ASSOCIATED分子模式DAMPS,对刺激的响应,TNF, proIL-1,IL-6,Type I Interferons,TNF, proIL-1,IL-6,proIL-1 IL-1,RA,SLE,Gout,INNATE IMMUNITYFirst Line of Defense,适应性免疫 特异性,记忆T cells and B cells,RECRUITS, MODULATES TYPE OF RESPONSE,RECRUITS, ENHANCES ANTIMICROBICAL ACTIVITY,适应性免疫反应的多样性,107年到109个不同的B细胞和T细胞的受体,并显著的特异性区分微生物多样性通过体细胞遗传基因片段的重组,Va1,Van,n=45,Ja1,Jan,n=55,Ca,人类T细胞受体,连锁,特定受体和抗原之间的相互作用导致克隆扩张,T CELLS,B CELLS,T cell receptor,CD4 or CD8,B cell receptor(Immunoglobulin),增殖,增殖,克隆扩张产生效应和记忆细胞,APC,T CELL,直接细胞裂解刺激B细胞刺激先天免疫系统,效应T细胞,记忆T细胞,在他们再次暴露在抗原反应迅速,B CELL,分泌高亲和力抗体,浆细胞,记忆B细胞,在他们再次暴露在抗原反应迅速,先天免疫系统对适应性免疫反应的发展起关键作用,两种信号需要刺激B细胞和T细胞Signal 1:抗原 T cells -MHC分子提供的肽B cells -交联表面抗原IgSignal 2:炎症信号天生的激活模式识别受体co-stimulatory Upregulates细胞表面的分子Upregulates激活细胞因子,在缺乏信号2的情况下信号1导致无效能,先天免疫系统对适应性免疫反应的发展起关键作用,抗原提呈细胞,T CELL,TCR,CD28,控制免疫反应:限制对感染的反应,机制包括:清除感染限制抗原,移除刺激表达式的抑制分子早期的反应:APC B7 T细胞CD28 Costimulatory后来回应:APC B7 CTLA4抑制性T细胞调节性T细胞(群)采取行动抑制炎症,控制免疫反应:预防应对自我抗原,自我分子(蛋白,蛋白多糖等)由于免疫耐受都不具免疫原性，那是它“训练”成不识别self-antigens中枢耐受对self-antigens反应强烈的淋巴细胞在时发展过程中被删除外周耐受 外周self-reactive的淋巴细胞的删除或无效化共刺激缺失 无效重复刺激 诱导凋亡调节性T细胞行动,失调,不当天生的激活,适应缺失耐受,Immune Response,GOUT,Disease of innate immunityUric Acid acts as a DAMP（ DANGER-ASSOCIATED分子模式）NALP-3 inflammasome is the PRR（受体识别模式）Inflammasome activation releases IL-1IL-1 activates the synovium, recruiting neutrophils into the joint,NALP-3 INFLAMMASOME,LRR,NACHT,PYRIN,配体传感,齐聚,效应器,NALP-3,LRR,NACHT,PYRIN,CARD,ASC,半胱天冬酶 (inactive),URIC ACID,PRO-IL-1,IL-1,IL-1,INFLAMMSOME,CASPASE-1(active),GOUT PATHOGENESIS,PRO-IL-1,IL-1,趋化因子细胞因子,CHEMOKINESCYTOKINES,SYNOVIUM,滑膜液,巨噬细胞,成纤维细胞,PMN,PMN,PMN,PMN,PMN,PMN,PMN,PMN,PMN,PMN,PMN,PMN,NALP-3INFLAMMASOME,NALP-3模式识别受体与遗传关联,突变增加NALP-3 Inflammasomes 活性家族性地中海热(FMF)在MEFV基因突变,编码蛋白pyrin,一个负调节inflammasome者Cryopyrin-associated周期综合征家族冷autoinflammatory综合症,Muckle-Wells综合症,新生儿发病多系统炎性疾病突变增加NALP-3 inflammasome活动,NOD2 mutations associated with several diseasesCrohns DiseaseGraft-Versus-Host DiseaseBlau SyndromeEarly-Onset Sarcoidosis,遗传相关的其他模式识别受体,SLE PATHOGENESIS,四个因素在狼疮发病机制中起重要作用减少细胞碎片清除TLR-stimulated树突细胞的I型干扰素产生损失B细胞和T细胞耐受增加对核酸的自体抗体免疫复合体存入组织,然后导致激活补充与损伤,SLE PATHOGENESIS 减少细胞碎片的清除,单核吞噬系统,正常清除细胞碎片,免疫复合体无共刺激的抗原呈递,感染微生物杀灭PRR激活共刺激的抗原呈递,SLE减少清理碎片增加self-antigens池为B细胞和T细胞增加DAMPS池为PRR的激活,SLE PATHOGENESIS 耐受丧失与自身抗体产生,T cell,B cell,NORMAL 外周耐受 Weakly self-reactive B and T cells anergic抗原隔离OR Antigens presented without costimulation,T cell,APC,SLE 耐受丧失 Increaesd stimulatio of self-reactive B and T cells with self-antigens Increased innate activation with self DAMPs increases costimulation Increase autoantibody production to self antigens such as nucleic acids,T cell,B cell,SLE PATHOGENESIS I型干扰素的响应,IFN-a,b,TLR3/7/8/9,浆细胞样树突状细胞,VIRAL INFECTION,major producers type I interferons viral nucleic acids stimulate TLR3/7/8/9 TLR stimulation leads to type I interferon production Type I interferons potent immune activator,TLR3/7/8/9,浆细胞样树突状细胞,nucleic acid containing immune complexes stimulate TLR3/7/8/9 TLR stimulation leads to type I interferon production Type I interferons potent immune activator in absence of infection,SLE,SLE PATHOGENESIS,MONONUCLEAR PHAGOCYTIC SYSTEM,Decreased Clearance Cell Debris,IFN-a,b,PLASMACYTOID DENDRITIC CELL,B CELL,Increased Plasmacytoid DC Type I Interferon Production,IFN-a,b,IFN-a,b,Loss T and B Cell ToleranceAutoantibody Production,T CELL,狼疮遗传学,Decrease Clearance Cellular Debris,Complement deficiencies (C1q, C2, C4) SNP in FCGR2A,Loss B and T cell Tolerance,SNPs associated with B and T cell signaling HLA-DR2 HLA-DR3 PTPN22 BANK1 BLK STAT4,Type I Interferon Release Interferon signature in peripheral blood cells of SLE patients Associated with SNPs in IRF5, IRAK1, and STAT4,RA PATHOGENESIS:正常SYNOVIUM,SYNOVIAL FLUID,SYNOVIUM,SYNOVIAL FIBROBLASTRemodels extracellular matrix, Synthesize lubricin, hyaluronan,SYNOVIAL MACROPHAGESentinel cellPhagocytose debris,SYNOVIAL LINING,SYNOVIAL SUBLINING,Blood VesselsScattered Fibroblasts, Macrophages, Mast Cells,BONE,Formation Resorption(Osteoblasts) (Osteoclasts),CARTILAGE,ChondrocytesType II Collagen, Aggrecan,RA PATHOGENESIS KEY FEATURES,synovium免疫的渗透滑膜增生与肉芽组织形成骨的侵蚀,破骨细胞活性 成骨细胞的活性软骨被侵蚀,RA PATHOGENESIS 免疫渗透,ADAPTIVE IMMUNITY,INNATE IMMUNITY,T CellsB CellsRheumatoid Factoranti-CCP antibodies,NeutrophilsComplement ActivationMacrophagesImmune ComplexesDendritic CellsMast Cells,RA PATHOGENESIS 滑膜增生,SYNOVIUM,SYNOVIAL FLUID,SYNOVIUM,SYNOVIAL HYPERPLASIA,Increased angiogenesis Synovial lining hyperplasia Lining becomes an invasive tissue mass (pannus) that erodes cartilage and bone Increased synovial macrophages TNF-a Increased synovial fibroblasts IL-6,RA PATHOGENESIS 骨侵蚀,SYNOVIUM,SYNOVIAL FLUID,SYNOVIUM,INCREASED BONE RESORPTION AND EROSION,Increased破骨细胞activity Possible inhibition of osteoblast activity Synovial血管翳 erosion,破骨细胞激活RANKLTNF-a,RA PATHOGENESIS 软骨侵蚀,SYNOVIUM,SYNOVIAL FLUID,C5a,C5a,C5a,C5a,C5a,SYNOVIUM,INCREASED CARTILAGE EROSON,Cartilage surface modified by immune complexes, extracellular matrix fragments, enzymatic digestion Inflammatory cytokines inhibit chondrocyte matrix repair Synovial pannus erodes cartilage matrix,RA PATHOGENESIS -概述,Activation of Synovial Tissues by the Immune SystemActivation of the Immune System by Synovial Tissues,CYTOKINE AND CHEMOKINE NETWORKS,RA PATHOGENESIS -遗传学,Currently identified genetic risk alleles only explain 10-20% of genetic riskFunction of risk alleles is not knownStrongest risk allele “Shared Epitope”Conserved sequence in certain HLA-DR b chains MHC molecules involved in antigen presentation to T cells Examples: DRB*0101, DRB*0401, DRB*0404, DRB*1402Most strongly associated with anti-CCP antibodiesMany risk alleles shared between autoimmune diseases,TNFS14 PADI4 PTPN22FCGR2A STAT4 CD28CTLA4 HLA-DR1 HLA-DR4TNFAIP3 IRF5 CCR6BLK TRAF1 CD40,BANK1 PTPN22 ITGAMFCGR2A STAT4 BLKTNFSF4 HLA-DR2 HLA-DR3TNFAIP3 IRF5 IRAK1,RA RISK ALLELE SAMPLE,SLE RISK ALLELE SAMPLE,SUMMARY,Immunology Innate vs. Adaptive Immunity Pattern Recognition Receptors in Innate Immune System Tolerance and Memory in Adaptive Immune SystemGoutInflammasome Activation of IL-1SLELoss of Immune ToleranceInterferon SignatureDefects in Debris ClearanceRAImmune Activation of Synovial TissuesSynovial Activation of Immune SystemRole of Cytokine Networks,Question 1,Macrophages and neutrophils are cells in the branch of the immune with which of the following characteristics?Found only in vertebratesGenerates immunity to specific pathogensRecognizes conserved microbial patternsDevelopment of response takes several days,Answer:C: Recognizes conserved microbial patterns,Question 2,Inflammasome activation is central to disease pathogenesis in gout and which of the following diseases?Blau SyndromeCrohns DiseaseMuckle-Wells SyndromePsoriasisSLE,Answer:C: Muckle-Wells Syndrome,NOD2 mutations associated the following diseasesCrohns Disease, Graft-Versus-Host Disease, Blau Syndrome, Early-Onset Sarcoidosis,GENETIC ASSOCIATIONS WITH OTHER PATTERN RECOGNITION RECEPTORS,NALP-3 activation associated with goutMutations with NALP-3 or associated proteins associated withFMF, Cryopyrin-Associated Periodic Fever Syndromes,Question 3,Gene profiling of the peripheral blood mononuclear cells has shown that SLE patients have activation of which of the following cytokine pathways?IFN-aIFN-gIL-1IL-6IL-17,Answer:A: IFN-a,SLE PATHOGENESIS,MONONUCLEAR PHAGOCYTIC SYSTEM,Decreased Clearance Cell Debris,IFN-a,b,PLASMACYTOID DENDRITIC CELL,B CELL,Increased Plasmacytoid DC Type I Interferon Production,IFN-a,b,IFN-a,b,Loss T and B Cell ToleranceAutoantibody Production,T CELL,Question 4,The shared epitope risk allele in RA is most directly assoicated with which of the following pathogenic mechanis