某些风湿性疾病的免疫问题课件

1、某些风湿性疾病的免疫问题某些风湿性疾病的免疫问题披露非披露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提纲简要回顾免疫学重要概念先天免疫 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适应性免疫免疫, 响应的调节类型免疫,提高抗微生物活 先天免疫系统 适应性免疫系统组件补体天然抗体,吞噬细胞肥大细胞上皮细胞、成纤维细胞 B细胞 T细胞进化整个物种系统老整个物种系统新响应的时间早期(0-24小时)后来( 1天)识别广泛结构常见的微生物群体精细彼此不同的有机体多样性有限生殖细胞系编码大生殖细胞系重排记忆 无有 先天

2、免疫系统 适应性免疫系统组件补体 先天免疫 第一道防线ADAPTIVE IMMUNITYSpecificity, MemoryRECRUITS, MODULATES TYPE OF RESPONSERECRUITS, ENHANCES ANTIMICROBICAL ACTIVITY先天免疫ADAPTIVE IMMUNITYRECRUITS, 先天免疫系统的功能病原体去除免疫激活(1) 补体调理作用 -complement(1) 抗原递传和共刺激(2) 细胞裂解 -virally infected cells -tumor cells(2) 细胞因子分泌 -T and B cell activa

3、tion -innate immune activation -increased microbial killing(3) 微生物杀灭 -phagocytosis -complement, defensins(3) 趋化因子分泌 -recruitment innate and adaptive immune cells 先天免疫系统的功能病原体免疫(1) 补体先天免疫的模式识别受体识别模式PRRsPAMPs 病原体相关分子模式独特的微生物产生的物质e.g. LPS, zymosan, peptidoglycan, double-stranded RNADAMPsDANGER-ASSOCIAT

4、ED分子模式组织损伤产生、释放的自体分子e.g. heat shock proteins, matrix fragments, DNA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受体先天免疫的模式识别受体识别模式PRRsPAMPs 病原体相先天免疫识别模CELL SURFACE核内体 细胞质TLR-2 肽聚糖 (Gram(+) bacteria)Heat Shock Protein 70TLR-4脂多糖 (gram(-) bacteria)透明质酸碎片TLR-3 病毒性dsRNAmRNATLR

5、-7病毒ssRNARNATLR-9细菌CpG DNAIgG-Chromatin复合物细胞凋亡诱导蛋白NALP3 NALP-3 Bacterial RNAViral RNA, LPSUric Acid, ATPNOD-1胞壁酰二肽 ?视黄酸诱导基因蛋白I（RIG-I） Viral RNA?病原体相关分子模式 PAMPSDANGER-ASSOCIATED分子模式DAMPS对刺激的响应TNF, proIL-1,IL-6Type I InterferonsTNF, proIL-1,IL-6proIL-1 IL-1RASLEGout先天免疫识别模CELL SURFACE核内体 细胞质TLR-INNATE

6、 IMMUNITYFirst Line of Defense适应性免疫 特异性,记忆T cells and B cellsRECRUITS, MODULATES TYPE OF RESPONSERECRUITS, ENHANCES ANTIMICROBICAL ACTIVITYINNATE IMMUNITY适应性免疫RECRUITS, 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Va1Vann=45Ja1Jann=55Ca人类T细胞受体,连锁适应性免疫反应的多样性107年到109个不同的B细胞和T细胞特定受体和抗

7、原之间的相互作用导致克隆扩张T CELLSB CELLST cell receptorCD4 or CD8B cell receptor(Immunoglobulin)ANTIGEN PRESENTING CELL(树突细胞,巨噬细胞、B细胞)微生物 增殖 增殖 MHCAntigenAntigen特定受体和抗原之间的相互作用导致克隆扩张T CELLSB C克隆扩张产生效应和记忆细胞APCT 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克隆扩张产生效应和记忆细胞APCT

8、 CELL直接细胞裂解刺激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两种信号需要刺激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 CELLTCRCD28MicrobeSIGNAL 1MHCMicrobial KillingSIG

9、NAL 2B7Pattern RecognitionReceptorAbatacept(CTLA4-Ig)抑制共同刺激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:限制对感染的反应机制包括: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

10、-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)由多形核细胞 细胞因子 细胞因子 趋化因子 共同刺激 先天免疫识别感染APCT CELL多形核细胞 B CELL细胞活化细胞补充发展适应免疫ResolutionWithMemory失调不当天生的激活适应缺失耐受Immune Response多形核细胞 细胞因子 细胞因子 趋化因子 共同刺激 先天免疫GOUTDisease of innate immunityUric A

11、cid 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 jointGOUTDisease of innate immunityNALP-3 INFLAMMASOMELRRNACHTPYRIN配体传感齐聚 效应器 NALP-3LRRNACHTPYRINCARDASC半胱天冬酶 (inactive)UR

12、IC ACIDPRO-IL-1IL-1IL-1INFLAMMSOMECASPASE-1(active)NALP-3 INFLAMMASOMELRRNACHTPYRGOUT PATHOGENESISPRO-IL-1IL-1趋化因子细胞因子CHEMOKINESCYTOKINESSYNOVIUM滑膜液巨噬细胞 成纤维细胞PMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNNALP-3INFLAMMASOMEIL-1 拮抗剂GOUT PATHOGENESISPRO-IL-1IL-1趋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

13、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NALP-3模式识别受体与遗传关联突变增加NALP-3 InNOD2 mutations associated with several diseasesCrohns DiseaseGraft-Versus-Host DiseaseBlau SyndromeEarly-Onset Sarcoidosis遗传相

14、关的其他模式识别受体TLR/NLRDisorderTLR2哮喘、急性风湿热lepromatous麻风病TLR4哮喘、炎症性肠病TLR10哮喘、湿疹NOD1哮喘、湿疹、炎症性肠病NALP1白癫风、甲状腺疾病,爱迪生氏病、类风湿关节炎、牛皮癣、系统性红斑狼疮NOD2 mutations associated withSLE 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四个因素在狼疮发病机制中起重THAN

15、K YOUSUCCESS2022/10/725可编辑THANK YOUSUCCESS2022/10/22SLE 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 减少细胞碎片的清除单核正SLE PATHOGENESIS 耐受丧失与自身抗体产生T cellB cellNORMAL 外周耐受 Weakly self-reactive B and T cells anergic抗原

16、隔离OR Antigens presented without costimulationT cellAPCSLE 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 acidsT cellB cellSLE PATHOGENESI

17、S 耐受丧失与自身抗体产生SLE PATHOGENESIS I型干扰素的响应IFN-a,bIFN-a,bTLR3/7/8/9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 activatorTLR3/7/8/9浆细胞样树突状细胞 nucleic acid contain

18、ing immune complexes stimulate TLR3/7/8/9 TLR stimulation leads to type I interferon production Type I interferons potent immune activator in absence of infectionSLESLE PATHOGENESIS I型干扰素的响应IFNSLE PATHOGENESISMONONUCLEAR PHAGOCYTIC SYSTEMDecreased Clearance Cell DebrisIFN-a,bPLASMACYTOID DENDRITIC C

19、ELLB CELLIncreased Plasmacytoid DC Type I Interferon ProductionIFN-a,bIFN-a,bLoss T and B Cell ToleranceAutoantibody ProductionT CELLSLE PATHOGENESISMONONUCLEAR De狼疮遗传学 MONONUCLEAR PHAGOCYTIC SYSTEMIFN-a,bPLASMACYTOID DENDRITIC CELLB CELLIFN-a,bIFN-a,bT CELLDecrease Clearance Cellular Debris Complem

20、ent deficiencies (C1q, C2, C4) SNP in FCGR2ALoss B and T cell Tolerance SNPs associated with B and T cell signaling HLA-DR2 HLA-DR3 PTPN22 BANK1 BLK STAT4Type I Interferon Release Interferon signature in peripheral blood cells of SLE patients Associated with SNPs in IRF5, IRAK1, and STAT4狼疮遗传学 MONON

21、UCLEAR IFN-a,bPLASMRA PATHOGENESIS:正常SYNOVIUMSYNOVIAL FLUIDSYNOVIUMSYNOVIAL FIBROBLASTRemodels extracellular matrix, Synthesize lubricin, hyaluronanSYNOVIAL MACROPHAGESentinel cellPhagocytose debrisSYNOVIAL LININGSYNOVIAL SUBLININGBlood VesselsScattered Fibroblasts, Macrophages, Mast CellsBONEFormat

22、ion Resorption(Osteoblasts) (Osteoclasts)CARTILAGEChondrocytesType II Collagen, AggrecanRA PATHOGENESIS:正常SYNOVIUMSYNORA PATHOGENESIS KEY FEATURESsynovium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 KEY FEATURESRA PATHOGENESIS 免疫渗透C5aC5aC5aC5aC5aSYNOVIUMSYNOVIAL FLUIDADAPTIVE IMMUNITYINNA

23、TE IMMUNITYT CellsB CellsRheumatoid Factoranti-CCP antibodiesNeutrophilsComplement ActivationMacrophagesImmune ComplexesDendritic CellsMast CellsABATACEPT(CTLA4 Ig)RITUXIMAB(anti-CD20 mAb)RA PATHOGENESIS 免疫渗透C5aC5aC5aRA PATHOGENESIS 滑膜增生SYNOVIUMSYNOVIAL FLUIDC5aC5aC5aC5aC5aSYNOVIUMSYNOVIAL HYPERPLAS

24、IA 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-6TNF inhibitorsTocilizumab (anti-IL-6R mAb)RA PATHOGENESIS 滑膜增生SYNOVIUMSRA PATHOGENESIS 骨侵蚀SYNOV

25、IUMSYNOVIAL FLUIDC5aC5aC5aC5aC5aSYNOVIUMINCREASED BONE RESORPTION AND EROSION Increased破骨细胞activity Possible inhibition of osteoblast activity Synovial血管翳 erosionTNF inhibitorsDenosumab (anti-RANKL mAb)破骨细胞激活RANKLTNF-aRA PATHOGENESIS 骨侵蚀SYNOVIUMSYRA PATHOGENESIS 软骨侵蚀SYNOVIUMSYNOVIAL FLUIDC5aC5aC5aC5

26、aC5aSYNOVIUMINCREASED CARTILAGE EROSON Cartilage surface modified by immune complexes, extracellular matrix fragments, enzymatic digestion Inflammatory cytokines inhibit chondrocyte matrix repair Synovial pannus erodes cartilage matrixRA PATHOGENESIS 软骨侵蚀SYNOVIUMSRA PATHOGENESIS -概述Activation of Syn

27、ovial Tissues by the Immune SystemActivation of the Immune System by Synovial TissuesCYTOKINE AND CHEMOKINE NETWORKSC5aC5aC5aC5aTNF-aIL-6TNF-aIL-17IFN-gIL-17IFN-gTNF-aTNF-aIL-1TNF-aRANKLRA PATHOGENESIS -概述CYTOKINE ANRA PATHOGENESIS -遗传学Currently identified genetic risk alleles only explain 10-20% of

28、 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 a

29、lleles shared between autoimmune diseasesTNFS14 PADI4 PTPN22FCGR2A STAT4 CD28CTLA4 HLA-DR1 HLA-DR4TNFAIP3 IRF5 CCR6BLK TRAF1 CD40BANK1 PTPN22 ITGAMFCGR2A STAT4 BLKTNFSF4 HLA-DR2 HLA-DR3TNFAIP3 IRF5 IRAK1RA RISK ALLELE SAMPLESLE RISK ALLELE SAMPLERA PATHOGENESIS -遗传学Currently SUMMARYImmunology Innate

30、 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

31、 SystemRole of Cytokine NetworksSUMMARYImmunologyQuestion 1Macrophages 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 tak

32、es several daysAnswer:C: Recognizes conserved microbial patternsQuestion 1Macrophages and neutINNATE IMMUNITYADAPTIVE IMMUNITYComponentsComplementNatural antibodies, Phagocytic cellsMast cellEpithelia, Fibroblasts B cellsT cellsEvolutionPhylogenetically oldPhylogenetically newerTiming of ResponseEar

33、ly (0-24 hours)Later (1 day)RecognitionBroadStructures common to groups of microbesFineDistinguishes one organism from anotherDiversityLimitedGermline CodedLargeGermline RearrangedMemoryNoYesINNATE IMMUNITYADAPTIVE IMMUNIQuestion 2Inflammasome activation is central to disease pathogenesis in gout an

34、d which of the following diseases?Blau SyndromeCrohns DiseaseMuckle-Wells SyndromePsoriasisSLEAnswer:C: Muckle-Wells SyndromeQuestion 2Inflammasome activatNOD2 mutations associated the following diseasesCrohns Disease, Graft-Versus-Host Disease, Blau Syndrome, Early-Onset SarcoidosisGENETIC ASSOCIAT

35、IONS WITH OTHER PATTERN RECOGNITION RECEPTORSTLR/NLRDisorderTLR2Asthma, acute rheumatic fever, lepromatous leprosyTLR4Asthma, inflammatory bowel diseaseTLR10Asthma, eczemaNOD1Asthma, eczema, inflammatory bowel diseaseNALP1Vitiligo, thyroid disease, Addison disease, RA, psoriasis, SLENALP-3 activatio

36、n associated with goutMutations with NALP-3 or associated proteins associated withFMF, Cryopyrin-Associated Periodic Fever SyndromesNOD2 mutations associated the Question 3Gene profiling of the peripheral blood mononuclear cells has shown that SLE patients have activation of which of the following c

37、ytokine pathways?IFN-aIFN-gIL-1IL-6IL-17Answer:A: IFN-aQuestion 3Gene profiling of thSLE PATHOGENESISMONONUCLEAR PHAGOCYTIC SYSTEMDecreased Clearance Cell DebrisIFN-a,bPLASMACYTOID DENDRITIC CELLB CELLIncreased Plasmacytoid DC Type I Interferon ProductionIFN-a,bIFN-a,bLoss T and B Cell ToleranceAutoantibody ProductionT CELLSLE PATHOGENESISMONONUCLEAR DeQuestion 4The shared epitope risk allele in RA is most directly assoicated with which of the following pathogenic mechanis