1、某些风湿性疾病的免疫问题披露非披露提纲n简要回顾免疫学重要概念n将这些概念应用于三种风湿性疾病n痛风n系统性红斑狼疮nRA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 无有先天免疫 第一道防线ADAPTIVE IMMUNITYSpecificity,MemoryRECRUITS,MODULA
2、TES TYPE OF RESPONSERECRUITS,ENHANCES ANTIMICROBICAL ACTIVITY 先天免疫系统的功能病原体病原体去除去除免疫免疫激活激活(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 activation -innate immune activation -increased microbial killing(3)微生物杀灭 -phagocytosis -complement,defensins(3
3、)趋化因子分泌 -recruitment innate and adaptive immune cells先天免疫的模式识别先天免疫的模式识别受体识别模式受体识别模式PRRsPAMPs 病原体相关分子模式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-ASSOCIATED分子模式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
4、helicases,Dectin,Mannose-binding受体先天免疫识别模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-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
5、原体相关分子模式 PAMPSDANGER-ASSOCIATEDDANGER-ASSOCIATED分子模式分子模式DAMPS对刺激的响应TNF,proIL-1,TNF,proIL-1,IL-6IL-6Type I Type I InterferonsInterferonsTNF,proIL-1,TNF,proIL-1,IL-6IL-6proIL-1 proIL-1 IL-1 IL-1RARASLESLEGoutGoutINNATE IMMUNITYFirst Line of Defense适应性免疫 特异性,记忆T cells and B cellsRECRUITS,MODULATES TYPE
6、 OF RESPONSERECRUITS,ENHANCES ANTIMICROBICAL ACTIVITY适应性免疫反应的多样性n107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n多样性通过体细胞遗传基因片段的重组Va1Vann=45Ja1Jann=55Ca人类人类T T细胞受体细胞受体,连锁连锁特定受体和抗原之间的相互作用导致克隆扩张T CELLST CELLSB CELLSB CELLST cell receptorCD4 or CD8B cell receptor(Immunoglobulin)ANTIGEN PRESENTING CELL(树突细胞,巨噬细胞、B细
7、胞)微生物微生物 增殖增殖 增殖增殖 MHCAntigenAntigen克隆扩张产生效应和记忆细胞APCAPCT CELLT CELL直接细胞裂解刺激B细胞刺激先天免疫系统效应效应T T细胞细胞记忆记忆T T细胞细胞 在他们再次暴露在抗原反应迅速B CELLB CELL分泌高亲和力抗体浆细胞浆细胞 记忆记忆B B细胞细胞 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 Upr
8、egulates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抗原提呈细胞 T CELLT CELLTCRTCRCD28CD28MicrobeSIGNAL 1MHCMicrobial KillingSIGNAL 2B7Pattern RecognitionReceptorAbatacept(CTLA4-Ig)抑制共同刺激抑制共同刺激控制免疫反应:限制对感染的反应机制包括:n清除感染限制抗原,移除刺激n表达式的抑制分子n早期的反应:APC B7 T细胞CD28 Costimulatoryn后来回应:A
9、PC B7 CTLA4抑制性T细胞n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细胞行动多形核细胞多形核细胞 细胞因子细胞因子 细胞因子细胞因子 趋化因子趋化因子 共同刺激共同刺激 先天免疫先天免疫识别识别感染感染APCT CELL多形核细胞多形核细胞 B CELL细胞活化细胞活
10、化细胞补充细胞补充发展发展适应适应免疫免疫ResolutionWithMemory失调失调不当不当天生的激活天生的激活适应缺失适应缺失耐受耐受Immune ResponseImmune ResponseGOUTnDisease of innate immunitynUric Acid acts as a DAMP（DANGER-DANGER-ASSOCIATEDASSOCIATED分子模式）分子模式）nNALP-3 inflammasome is the PRR（受体识别模受体识别模式）式）nInflammasome activation releases IL-1nIL-1 activate
11、s the synovium,recruiting neutrophils into the jointNALP-3 INFLAMMASOMELRRLRRNACHTNACHTPYRINPYRIN配体传感配体传感齐聚齐聚 效应器效应器 NALP-3NALP-3LRRLRRNACHTNACHTPYRINPYRINCARDCARDASCASC半胱天冬酶半胱天冬酶 (inactive)(inactive)URIC ACIDURIC ACIDPRO-IL-1PRO-IL-1IL-1IL-1IL-1IL-1INFLAMMSOMEINFLAMMSOMECASPASE-1CASPASE-1(active)(a
12、ctive)GOUT PATHOGENESISPRO-IL-1IL-1IL-1趋化因子细胞因子CHEMOKINESCYTOKINESSYNOVIUMSYNOVIUM滑膜液滑膜液巨噬细胞巨噬细胞 成纤维细胞成纤维细胞PMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNNALP-3NALP-3INFLAMMASOMEINFLAMMASOMEIL-1 拮抗剂拮抗剂NALP-3模式识别受体与遗传关联n突变增加NALP-3 Inflammasomes 活性n家族性地中海热(FMF)n在MEFV基因突变,n编码蛋白
13、pyrin,一个负调节inflammasome者nCryopyrin-associated周期综合征n家族冷autoinflammatory综合症,Muckle-Wells综合症,新生儿发病多系统炎性疾病n突变增加NALP-3 inflammasome活动NOD2 mutations associated with several diseasesnCrohns DiseasenGraft-Versus-Host DiseasenBlau SyndromenEarly-Onset Sarcoidosis遗传相关的其他模式识别受体TLR/NLRDisorderTLR2 哮喘、急性风湿热lepro
14、matous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SLE PATHOGENESISn四个因素在狼疮发病机制中起重要作用n减少细胞碎片清除nTLR-stimulated树突细胞的I型干扰素产生n损失B细胞和T细胞耐受n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THANK YOUSUCCESS2022-10-1625可编辑SLE PATHOGENESIS 减少细胞碎片的清除单核单核吞噬系统吞噬系统正常正常清除细胞碎片清除细胞碎片,免疫复合体免疫复合体无
15、共刺激的抗原呈递无共刺激的抗原呈递感染感染微生物杀灭微生物杀灭PRRPRR激活激活共刺激的抗原呈递共刺激的抗原呈递SLESLE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 cellT cellB cellB cellNORMAL NORMAL 外周耐受外周耐受 Weakly self-reactive B and T cells anergic抗原隔离OR Antigens presented without costimulationT cellT cellAPCAPCSLE SLE 耐受
16、丧失耐受丧失 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 cellT cellB cellB cellSLE PATHOGENESIS I型干扰素的响应IFN-a,bIFN-a,bIFN-a,ba,bTLR3/7/8/9
17、TLR3/7/8/9浆细胞样树突状细胞浆细胞样树突状细胞 VIRAL INFECTIONVIRAL 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 activatorTLR3/7/8/9TLR3/7/8/9浆细胞样树突状细胞浆细胞样树突状细胞 nucleic acid containing immun
18、e complexes stimulate TLR3/7/8/9 TLR stimulation leads to type I interferon production Type I interferons potent immune activator in absence of infectionSLESLESLE PATHOGENESISMONONUCLEAR MONONUCLEAR PHAGOCYTIC SYSTEMPHAGOCYTIC SYSTEMDecreased Clearance Cell DebrisDecreased Clearance Cell DebrisIFN-a
19、,bIFN-a,bPLASMACYTOID DENDRITIC CELLPLASMACYTOID DENDRITIC CELLB CELLB CELLIncreased Plasmacytoid DC Increased Plasmacytoid DC Type I Interferon Type I Interferon ProductionProductionIFN-a,bIFN-a,bIFN-a,bIFN-a,bLoss T and B Cell ToleranceLoss T and B Cell ToleranceAutoantibody ProductionAutoantibody
20、 ProductionT CELLT CELL狼疮遗传学狼疮遗传学 MONONUCLEAR PHAGOCYTIC SYSTEMIFN-a,ba,bPLASMACYTOID DENDRITIC CELLB CELLIFN-a,ba,bIFN-a,ba,bT CELLDecrease Clearance Cellular DebrisDecrease Clearance Cellular Debris Complement deficiencies(Complement deficiencies(C1q,C2,C4)C1q,C2,C4)SNP in FCGR2A SNP in FCGR2ALoss
21、 B and T cell Loss B and T cell ToleranceTolerance SNPs associated with SNPs associated with B and T cell signaling B and T cell signaling HLA-DR2 HLA-DR2 HLA-DR3 HLA-DR3 PTPN22 PTPN22 BANK1 BANK1 BLK BLK STAT4 STAT4Type I Interferon ReleaseType I Interferon Release Interferon signature in periphera
22、l blood cells of SLE patientsInterferon signature in peripheral blood cells of SLE patients Associated with SNPs in IRF5,IRAK1,and STAT4Associated with SNPs in IRF5,IRAK1,and STAT4RA PATHOGENESIS:正常SYNOVIUMSYNOVIAL FLUIDSYNOVIAL FLUIDSYNOVIUMSYNOVIUMSYNOVIAL FIBROBLASTSYNOVIAL FIBROBLASTRemodels ext
23、racellular matrix,Remodels extracellular matrix,Synthesize lubricin,hyaluronanSynthesize lubricin,hyaluronanSYNOVIAL MACROPHAGESYNOVIAL MACROPHAGESentinel cellSentinel cellPhagocytose debrisPhagocytose debrisSYNOVIAL LININGSYNOVIAL LININGSYNOVIAL SUBLININGSYNOVIAL SUBLININGBlood VesselsBlood Vessels
24、Scattered Fibroblasts,Scattered Fibroblasts,Macrophages,Mast CellsMacrophages,Mast CellsBONEBONEFormation ResorptionFormation Resorption(Osteoblasts)(Osteoblasts)(Osteoclasts)(Osteoclasts)CARTILAGECARTILAGEChondrocytesChondrocytesType II Collagen,AggrecanType II Collagen,AggrecanRA PATHOGENESIS KEY
25、FEATURESnsynovium免疫的渗透n滑膜增生与肉芽组织形成n骨的侵蚀,破骨细胞活性 成骨细胞的活性n软骨被侵蚀RA PATHOGENESIS 免疫渗透C5aC5aC5aC5aC5aSYNOVIUMSYNOVIAL FLUIDADAPTIVE IMMUNITYADAPTIVE IMMUNITYINNATE IMMUNITYINNATE IMMUNITYT CellsT CellsB CellsB Cells-Rheumatoid FactorRheumatoid Factor-anti-CCP antibodiesanti-CCP antibodiesNeutrophilsNeutro
26、philsComplement ActivationComplement ActivationMacrophagesMacrophagesImmune ComplexesImmune ComplexesDendritic CellsDendritic CellsMast CellsMast CellsRA PATHOGENESIS 滑膜增生SYNOVIUMSYNOVIUMSYNOVIAL FLUIDSYNOVIAL FLUIDC5aC5aC5aC5aC5aSYNOVIUMSYNOVIUMSYNOVIAL HYPERPLASIASYNOVIAL HYPERPLASIA Increased ang
27、iogenesis Increased angiogenesis Synovial lining hyperplasia Synovial lining hyperplasia Lining becomes an invasive tissue mass(pannus)that erodes cartilage and Lining becomes an invasive tissue mass(pannus)that erodes cartilage and bonebone Increased synovial macrophages Increased synovial macropha
28、ges TNF-a TNF-a Increased synovial fibroblasts Increased synovial fibroblasts IL-6 IL-6RA PATHOGENESIS 骨侵蚀SYNOVIUMSYNOVIUMSYNOVIAL FLUIDSYNOVIAL FLUIDC5aC5aC5aC5aC5aSYNOVIUMSYNOVIUMINCREASED BONE RESORPTION AND EROSIONINCREASED BONE RESORPTION AND EROSION IncreasedIncreased破骨细胞破骨细胞activityactivity P
29、ossible inhibition of osteoblast activity Possible inhibition of osteoblast activity Synovial Synovial血管翳血管翳 erosion erosion破骨细胞破骨细胞激活激活RANKLRANKLTNF-aTNF-aRA PATHOGENESIS 软骨侵蚀SYNOVIUMSYNOVIUMSYNOVIAL FLUIDSYNOVIAL FLUIDC5aC5aC5aC5aC5aC5aC5aC5aC5aC5aSYNOVIUMSYNOVIUMINCREASED CARTILAGE EROSONINCREASE
30、D CARTILAGE EROSON Cartilage surface modified by immune complexes,extracellular matrix Cartilage surface modified by immune complexes,extracellular matrix fragments,enzymatic digestionfragments,enzymatic digestion Inflammatory cytokines inhibit chondrocyte matrix repair Inflammatory cytokines inhibi
31、t chondrocyte matrix repair Synovial pannus erodes cartilage matrix Synovial pannus erodes cartilage matrixRA PATHOGENESIS-概述Activation of Synovial Tissues by the Immune SystemActivation of Synovial Tissues by the Immune SystemActivation of the Immune System by Synovial TissuesActivation of the Immu
32、ne System by Synovial TissuesCYTOKINE AND CHEMOKINE NETWORKSCYTOKINE AND CHEMOKINE NETWORKSC5aC5aC5aC5aTNF-a aIL-6TNF-a aIL-17IFN-g gIL-17IFN-g gTNF-a aTNF-a aIL-1TNF-a aRANKLRA PATHOGENESIS-遗传学nCurrently identified genetic risk alleles only explain 10-20%of genetic risknFunction of risk alleles is
33、not knownnStrongest 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 antibodiesnMany risk alleles shared between autoimmune diseasesTN
34、FS14TNFS14 PADI4 PADI4 PTPN22 PTPN22FCGR2A STAT4 FCGR2A STAT4 CD28CD28CTLA4CTLA4 HLA-DR1HLA-DR1 HLA-DR4HLA-DR4TNFAIP3TNFAIP3 IRF5 IRF5 CCR6CCR6BLK BLK TRAF1TRAF1 CD40CD40BANK1BANK1 PTPN22 PTPN22 ITGAMITGAMFCGR2A STAT4 BLKFCGR2A STAT4 BLKTNFSF4TNFSF4 HLA-DR2HLA-DR2 HLA-DR3HLA-DR3TNFAIP3TNFAIP3 IRF5 I
35、RF5 IRAK1IRAK1RA RISK ALLELE SAMPLERA RISK ALLELE SAMPLESLE RISK ALLELE SAMPLESLE RISK ALLELE SAMPLESUMMARYnImmunology Innate vs.Adaptive Immunity Pattern Recognition Receptors in Innate Immune System Tolerance and Memory in Adaptive Immune SystemnGoutInflammasome Activation of IL-1nSLELoss of Immun
36、e ToleranceInterferon SignatureDefects in Debris ClearancenRAImmune Activation of Synovial TissuesSynovial Activation of Immune SystemRole of Cytokine NetworksQuestion 1Macrophages and neutrophils are cells in the branch of the immune with which of the following characteristics?A.Found only in verte
37、bratesB.Generates immunity to specific pathogensC.Recognizes conserved microbial patternsD.Development of response takes several daysAnswer:C:Recognizes conserved microbial patternsINNATE IMMUNITYADAPTIVE IMMUNITYComponentsComplementNatural antibodies,Phagocytic cellsMast cellEpithelia,Fibroblasts B
38、 cellsT cellsEvolutionPhylogenetically oldPhylogenetically newerTiming of ResponseEarly(0-24 hours)Later(1 day)RecognitionBroadStructures common to groups of microbesFineDistinguishes one organism from anotherDiversityLimitedGermline CodedLargeGermline RearrangedMemoryNoYesQuestion 2Inflammasome act
39、ivation is central to disease pathogenesis in gout and which of the following diseases?A.Blau SyndromeB.Crohns DiseaseC.Muckle-Wells SyndromeD.PsoriasisE.SLEAnswer:C:Muckle-Wells SyndromeNOD2 mutations associated the following diseasesnCrohns Disease,Graft-Versus-Host Disease,Blau Syndrome,Early-Ons
40、et SarcoidosisGENETIC ASSOCIATIONS WITH OTHER PATTERN RECOGNITION RECEPTORSTLR/NLRDisorderTLR2 Asthma,acute rheumatic fever,lepromatous leprosyTLR4 Asthma,inflammatory bowel diseaseTLR10 Asthma,eczemaNOD1 Asthma,eczema,inflammatory bowel diseaseNALP1 Vitiligo,thyroid disease,Addison disease,RA,psori
41、asis,SLENALP-3 activation associated with goutMutations with NALP-3 or associated proteins associated withn FMF,Cryopyrin-Associated Periodic Fever SyndromesQuestion 3Gene profiling of the peripheral blood mononuclear cells has shown that SLE patients have activation of which of the following cytoki
42、ne pathways?A.IFN-aB.IFN-gC.IL-1D.IL-6E.IL-17Answer:A:IFN-aSLE PATHOGENESISMONONUCLEAR MONONUCLEAR PHAGOCYTIC SYSTEMPHAGOCYTIC SYSTEMDecreased Clearance Cell DebrisDecreased Clearance Cell DebrisIFN-a,bIFN-a,bPLASMACYTOID DENDRITIC CELLPLASMACYTOID DENDRITIC CELLB CELLB CELLIncreased Plasmacytoid DC
43、 Increased Plasmacytoid DC Type I Interferon Type I Interferon ProductionProductionIFN-a,bIFN-a,bIFN-a,bIFN-a,bLoss T and B Cell ToleranceLoss T and B Cell ToleranceAutoantibody ProductionAutoantibody ProductionT CELLT CELLQuestion 4The shared epitope risk allele in RA is most directly assoicated wi
44、th which of the following pathogenic mechanisms?A.Antigen presentation to T cellsB.Rheumatoid factor production by B cellsC.Cytokine secretion by synovial macrophagesD.Bone resorption by osteoclastsAnswer:A:Antigen presentation to T cellsRA PATHOGENESIS-GENETICSStrongest risk等位基因“Shared Epitope”Cons
45、erved 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 antibodiesREFERENCESnGeneral ImmunologyDelves,P.J.and Roitt,I.M.New England Journal of Medicine 2000.343343:37-49Medz
46、hitov,R.and Janeway,C.New England Journal of Medicine 2000.343343:338-344nGoutFukata,M.,Vamadevan,A.S.,Abreu,M.Semin Immunol.2009.2121:242-53So,A.Arth Res Therapy.2008,1010:221-227.nSLERnnblom,L.Arth Res Therapy.2010,12(Suppl 1)12(Suppl 1):S3nRheumatoid ArthritisFirestein,G.S.Nature.2003.423 423:356-361.DISCLOSURESNo disclosuresp 经常不断地学习,你就什么都知道。你知道得越多,你就越有力量p Study Constantly,And You Will Know Everything.The More You Know,The More Powerful You Will Be写在最后谢谢大家荣幸这一路，与你同行ItS An Honor To Walk With You All The Way演讲人：XXXXXX 时 间：XX年XX月XX日
