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ADAPTIVEIMMUNITYSpecificity,MemoryRECRUITS,MODULATESTYPEOFRESPONSERECRUITS,ENHANCESANTIMICROBICALACTIVITY先天免疫系统的功能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-strandedRNADAMPsDANGER-ASSOCIATED分子模式组织损伤产生、释放的自体分子e.g.heatshockproteins,matrixfragments,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受体先天免疫识别模CELLSURFACE核内体

细胞质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-6TypeIInterferonsTNF,proIL-1,IL-6proIL-1IL-1RASLEGoutINNATEIMMUNITYFirstLineofDefense适应性免疫特异性,记忆TcellsandBcellsRECRUITS,MODULATESTYPEOFRESPONSERECRUITS,ENHANCESANTIMICROBICALACTIVITY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,连锁特定受体和抗原之间的相互作用导致克隆扩张TCELLSBCELLSTcellreceptorCD4orCD8Bcellreceptor(Immunoglobulin)ANTIGENPRESENTINGCELL(树突细胞,巨噬细胞、B细胞)微生物

增殖增殖MHCAntigenAntigen克隆扩张产生效应和记忆细胞APCTCELL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BCELL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Signal1:抗原

Tcells->MHC分子提供的肽Bcells->交联表面抗原IgSignal2:炎症信号天生的激活模式识别受体co-stimulatoryUpregulates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

TCELLTCRCD28MicrobeSIGNAL1MHCMicrobialKillingSIGNAL2B7PatternRecognitionReceptorAbatacept(CTLA4-Ig)抑制共同刺激控制免疫反应: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:APCB7

T细胞CD28Costimulatory后来回应:APCB7

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APCTCELL多形核细胞

BCELL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ImmuneResponseGOUTDiseaseofinnateimmunityUricAcidactsasaDAMP（DANGER-ASSOCIATED分子模式）NALP-3inflammasomeisthePRR（受体识别模式）InflammasomeactivationreleasesIL-1IL-1activatesthesynovium,recruitingneutrophilsintothejointNALP-3INFLAMMASOMELRRNACHTPYRIN配体传感齐聚

效应器

NALP-3LRRNACHTPYRINCARDASC半胱天冬酶

(inactive)URICACIDPRO-IL-1IL-1IL-1INFLAMMSOMECASPASE-1(active)GOUTPATHOGENESISPRO-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-3inflammasome活动NOD2mutationsassociatedwithseveraldiseasesCrohn’sDiseaseGraft-Versus-HostDiseaseBlauSyndromeEarly-OnsetSarcoidosis遗传相关的其他模式识别受体SLEPATHOGENESIS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SLEPATHOGENESIS–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SLEPATHOGENESIS–耐受丧失与自身抗体产生TcellBcellNORMAL–外周耐受

Weaklyself-reactiveBandTcellsanergic抗原隔离ORAntigenspresentedwithoutcostimulationTcellAPCSLE–耐受丧失

Increaesd

stimulatioofself-reactiveBandTcellswithself-antigensIncreasedinnateactivationwithselfDAMPsincreasescostimulationIncreaseautoantibodyproductiontoselfantigenssuchasnucleicacidsTcellBcellSLEPATHOGENESIS–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

VIRALINFECTION

majorproducerstypeIinterferonsviralnucleicacidsstimulateTLR3/7/8/9TLRstimulationleadstotypeIinterferonproductionTypeIinterferonspotentimmuneactivatorTLR3/7/8/9浆细胞样树突状细胞

nucleicacidcontainingimmunecomplexesstimulateTLR3/7/8/9TLRstimulationleadstotypeIinterferonproductionTypeIinterferonspotentimmuneactivatorinabsenceofinfectionSLESLEPATHOGENESISMONONUCLEARPHAGOCYTICSYSTEMDecreasedClearanceCellDebrisIFN-a,bPLASMACYTOIDDENDRITICCELLBCELLIncreasedPlasmacytoidDCTypeIInterferonProductionIFN-a,bIFN-a,bLossTandBCellToleranceAutoantibodyProductionTCELL狼疮遗传学

MONONUCLEARPHAGOCYTICSYSTEMIFN-a,bPLASMACYTOIDDENDRITICCELLBCELLIFN-a,bIFN-a,bTCELLDecreaseClearanceCellularDebris

Complementdeficiencies(C1q,C2,C4)SNPinFCGR2ALossBandTcellTolerance

SNPsassociatedwithBandTcellsignalingHLA-DR2HLA-DR3PTPN22BANK1BLKSTAT4TypeIInterferonRelease

InterferonsignatureinperipheralbloodcellsofSLEpatients

AssociatedwithSNPsinIRF5,IRAK1,andSTAT4RAPATHOGENESIS:正常SYNOVIUMSYNOVIALFLUIDSYNOVIUMSYNOVIALFIBROBLASTRemodelsextracellularmatrix,Synthesizelubricin,hyaluronanSYNOVIALMACROPHAGESentinelcellPhagocytosedebrisSYNOVIALLININGSYNOVIALSUBLININGBloodVesselsScatteredFibroblasts,Macrophages,MastCellsBONEFormation~Resorption(Osteoblasts)(Osteoclasts)CARTILAGEChondrocytesTypeIICollagen,AggrecanRAPATHOGENESIS–KEYFEATURESsynovium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RAPATHOGENESIS–免疫渗透C5aC5aC5aC5aC5aSYNOVIUMSYNOVIALFLUIDADAPTIVEIMMUNITYINNATEIMMUNITYTCellsBCellsRheumatoidFactoranti-CCPantibodiesNeutrophils ComplementActivationMacrophages ImmuneComplexesDendriticCellsMastCellsABATACEPTRITUXIMABRAPATHOGENESIS–滑膜增生SYNOVIUMSYNOVIALFLUIDC5aC5aC5aC5aC5aSYNOVIUMSYNOVIALHYPERPLASIA

IncreasedangiogenesisSynoviallininghyperplasiaLiningbecomesaninvasivetissuemass(pannus)thaterodescartilageandboneIncreasedsynovialmacrophagesTNF-aIncreasedsynovialfibroblastsIL-6TNFinhibitorsTocilizumab(anti-IL-6RmAb)RAPATHOGENESIS–骨侵蚀SYNOVIUMSYNOVIALFLUIDC5aC5aC5aC5aC5aSYNOVIUMINCREASEDBONERESORPTIONANDEROSION

Increased破骨细胞activityPossibleinhibitionofosteoblastactivitySynovial血管翳

erosionTNFinhibitorsDenosumab(anti-RANKLmAb)破骨细胞激活RANKLTNF-aRAPATHOGENESIS–软骨侵蚀SYNOVIUMSYNOVIALFLUIDC5aC5aC5aC5aC5aSYNOVIUMINCREASEDCARTILAGEEROSON

Cartilagesurfacemodifiedbyimmunecomplexes,extracellularmatrixfragments,enzymaticdigestionInflammatorycytokinesinhibitchondrocytematrixrepairSynovialpannuserodescartilagematrixRAPATHOGENESIS-概述ActivationofSynovialTissuesbytheImmuneSystemActivationoftheImmuneSystembySynovialTissuesCYTOKINEANDCHEMOKINENETWORKSC5aC5aC5aC5aTNF-aIL-6TNF-aIL-17IFN-gIL-17IFN-gTNF-aTNF-aIL-1TNF-aRANKLRAPATHOGENESIS-遗传学Currentlyidentifiedgeneticriskallelesonlyexplain10-20%ofgeneticriskFunctionofriskallelesisnotknownStrongestriskallele“SharedEpitope”ConservedsequenceincertainHLA-DRbchainsMHCmoleculesinvolvedinantigenpresentationtoTcells

Examples:DRB*0101,DRB*0401,DRB*0404,DRB*1402Moststronglyassoc