某些風濕性疾病的免疫問題課件

某些風濕性疾病的免疫問題披露非披露提綱簡要回顧免疫學重要概念將這些概念應用于三種風濕性疾病痛風系統(tǒng)性紅斑狼瘡RA先天免疫第一道防線適應性免疫

特異性,記憶免疫,響應的調(diào)節(jié)類型免疫,提高抗微生物活性先天免疫系統(tǒng)的功能先天免疫的模式識別受體識別模式PRRsPAMPs

病原體相關分子模式獨特的微生物產(chǎn)生的物質(zhì)e.g.LPS,zymosan,peptidoglycan,double-strandedRNADAMPsDANGER-ASSOCIATED分子模式組織損傷產(chǎn)生、釋放的自體分子e.g.heatshockproteins,matrixfragments,DNA數(shù)量有限的受體包括叫做TLRs的toll樣受體,nod樣受體(NLRs),RNA

helicases,Dectin,Mannose-binding受體INNATEIMMUNITYFirstLineofDefense適應性免疫特異性,記憶TcellsandBcellsRECRUITS,MODULATESTYPEOFRESPONSERECRUITS,ENHANCESANTIMICROBICALACTIVITY適應性免疫反應的多樣性107年到109個不同的B細胞和T細胞的受體,并顯著的特異性區(qū)分微生物多樣性通過體細胞遺傳基因片段的重組Va1Vann=~45Ja1Jann=~55Ca人類T細胞受體,連鎖特定受體和抗原之間的相互作用導致克隆擴張TCELLSBCELLSTcellreceptorCD4orCD8Bcellreceptor(Immunoglobulin)ANTIGENPRESENTINGCELL(樹突細胞,巨噬細胞、B細胞)微生物

增殖增殖MHCAntigenAntigen先天免疫系統(tǒng)對適應性免疫反應的發(fā)展起關鍵作用兩種信號需要刺激B細胞和T細胞Signal1:抗原

Tcells->MHC分子提供的肽Bcells->交聯(lián)表面抗原IgSignal2:炎癥信號天生的激活模式識別受體co-stimulatoryUpregulates細胞表面的分子Upregulates激活細胞因子在缺乏信號2的情況下信號1導致無效能

先天免疫系統(tǒng)對適應性免疫反應的發(fā)展起關鍵作用抗原提呈細胞

TCELLTCRCD28MicrobeSIGNAL1MHCMicrobialKillingSIGNAL2B7PatternRecognitionReceptorAbatacept(CTLA4-Ig)抑制共同刺激控制免疫反應:預防應對自我抗原自我分子(蛋白,蛋白多糖等)由于免疫耐受都不具免疫原性，那是它“訓練”成不識別self-antigens中樞耐受對self-antigens反應強烈的淋巴細胞在時發(fā)展過程中被刪除外周耐受

外周self-reactive的淋巴細胞的刪除或無效化共刺激缺失無效重復刺激誘導凋亡調(diào)節(jié)性T細胞行動多形核細胞

細胞因子

細胞因子

趨化因子

共同刺激

先天免疫識別感染APCTCELL多形核細胞

BCELL細胞活化細胞補充發(fā)展適應免疫ResolutionWithMemory失調(diào)不當天生的激活適應缺失耐受ImmuneResponseGOUTDiseaseofinnateimmunityUricAcidactsasaDAMP（DANGER-ASSOCIATED分子模式）NALP-3inflammasomeisthePRR（受體識別模式）InflammasomeactivationreleasesIL-1IL-1activatesthesynovium,recruitingneutrophilsintothejointNALP-3INFLAMMASOMELRRNACHTPYRIN配體傳感齊聚

效應器

NALP-3LRRNACHTPYRINCARDASC半胱天冬酶

(inactive)URICACIDPRO-IL-1IL-1IL-1INFLAMMSOMECASPASE-1(active)GOUTPATHOGENESISPRO-IL-1IL-1趨化因子細胞因子CHEMOKINESCYTOKINESSYNOVIUM滑膜液巨噬細胞

成纖維細胞PMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNPMNNALP-3INFLAMMASOMEIL-1拮抗劑NALP-3模式識別受體與遺傳關聯(lián)突變增加NALP-3

Inflammasomes活性家族性地中海熱(FMF)在MEFV基因突變,——編碼蛋白pyrin,一個負調(diào)節(jié)inflammasome者Cryopyrin-associated周期綜合征——家族冷autoinflammatory綜合癥,Muckle-Wells綜合癥,新生兒發(fā)病多系統(tǒng)炎性疾病——突變增加NALP-3inflammasome活動SLEPATHOGENESIS四個因素在狼瘡發(fā)病機制中起重要作用減少細胞碎片清除TLR-stimulated樹突細胞的I型干擾素產(chǎn)生損失B細胞和T細胞耐受增加對核酸的自體抗體免疫復合體存入組織,然后導致激活補充與損傷SLEPATHOGENESIS–減少細胞碎片的清除單核吞噬系統(tǒng)正常清除細胞碎片,免疫復合體無共刺激的抗原呈遞感染微生物殺滅PRR激活共刺激的抗原呈遞SLE減少清理碎片增加self-antigens池為B細胞和T細胞增加DAMPS池為PRR的激活SLEPATHOGENESIS–I型干擾素的響應IFN-a,bIFN-a,bTLR3/7/8/9漿細胞樣樹突狀細胞

VIRALINFECTION

majorproducerstypeIinterferonsviralnucleicacidsstimulateTLR3/7/8/9TLRstimulationleadstotypeIinterferonproductionTypeIinterferonspotentimmuneactivatorTLR3/7/8/9漿細胞樣樹突狀細胞

nucleicacidcontainingimmunecomplexesstimulateTLR3/7/8/9TLRstimulationleadstotypeIinterferonproductionTypeIinterferonspotentimmuneactivatorinabsenceofinfectionSLESLEPATHOGENESISMONONUCLEARPHAGOCYTICSYSTEMDecreasedClearanceCellDebrisIFN-a,bPLASMACYTOIDDENDRITICCELLBCELLIncreasedPlasmacytoidDCTypeIInterferonProductionIFN-a,bIFN-a,bLossTandBCellToleranceAutoantibodyProductionTCELL狼瘡遺傳學

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免疫的滲透滑膜增生與肉芽組織形成骨的侵蝕,破骨細胞活性>>成骨細胞的活性軟骨被侵蝕RAPATHOGENESIS–免疫滲透C5aC5aC5aC5aC5aSYNOVIUMSYNOVIALFLUIDADAPTIVEIMMUNITYINNATEIMMUNITYTCellsBCellsRheumatoidFactoranti-CCPantibodiesNeutrophils ComplementActivationMacrophages ImmuneComplexesDendriticCellsMastCellsABATACEPTRITUXIMABRAPATHOGENESIS–滑膜增生SYNOVIUMSYNOVIALFLUIDC5aC5aC5aC5aC5aSYNOVIUMSYNOVIALHYPERPLASIA

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

Increased破骨細胞activityPossibleinhibitionofosteoblastactivitySynovial血管翳

erosionTNFinhibitorsDenosumab(anti-RANKLmAb)破骨細胞激活RANKLTNF-aRAPATHOGENESIS–軟骨侵蝕SYNOVIUMSYNOVIALFLUIDC5aC5aC5aC5aC5aSYNOVIUMINCREASEDCARTILAGEEROSON

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

Examples:DRB*0101,DRB*0401,DRB*0404,DRB*1402Moststronglyassociatedwithanti-CCPantibodiesManyriskallelessharedbetweenautoimmunediseasesTNFS14

PADI4PTPN22FCGR2ASTAT4CD28CTLA4

HLA-DR1

HLA-DR4TNFAIP3 IRF5CCR6BLKTRAF1

CD40BANK1PTPN22ITGAMFCGR2ASTAT4BLKTNFSF4

HLA-DR2

HLA-DR3TNFAIP3 IRF5IRAK1RARISKALLELESAMPLESLERISKALLELESAMPLESUMMARYImmunologyInnatevs.AdaptiveImmunityPatternRecognitionReceptorsinInnateImmuneSystemToleranceandMemoryinAdaptiveImmuneSystemGoutInflammasomeActivationofIL-1SLELossofImmuneToleranceInterferonSignatureDefectsinDebrisClearanceRAImmuneActivationofSynovialTissuesSynovialActivationofImmuneSystemRoleofCytokineNetworksQuestion1Macrophagesandneutrophilsarecellsinthebranchoftheimmunewithwhichofthefollowingcharacteristics?FoundonlyinvertebratesGeneratesimmunitytospecificpathogensRecognizesconservedmicrobialpatternsDevelopmentofresponsetakesseveraldaysAnswer:C:RecognizesconservedmicrobialpatternsQuestion2Inflammasomeactivationiscentraltodiseasepathogenesisingoutandwhichofthefollowingdiseases?BlauSyndromeCrohn’sDiseaseMuckle-WellsSyndromePsoriasisSLEAnswer:C:Muckle-WellsSyndromeNOD2mutationsassociatedthefollowingdiseasesCrohn’sDisease,Graft-Versus-HostDisease,BlauSyndrome,Early-OnsetSarcoidosisGENETICASSOCIATIONSWITHOTHERPATTERNRECOGNITIONRECEPTORSNALP-3activationassociatedwithgoutMutationswithNALP-3orassociatedproteinsassociatedwithFMF,Cryopyrin-AssociatedPeriodicFeverSyndromesQuestion3GeneprofilingoftheperipheralbloodmononuclearcellshasshownthatSLEpatientshaveactivationofwhichofthefollowingcytokinepathways?IFN-aIFN-gIL-1IL-6IL-17Answer:A:IFN-aSLEPATHOGENESISMONONUCLEARPHAGOCYTICSYSTEMDecreasedClearanceCellDebrisIFN-a,bPLASMACYTOIDDENDRITICCELLBCELLIncreasedPlasmacytoidDCTypeIInterferonProductionIFN-a,bIFN-a,bLossTandBCellToleranceAutoantibodyProductionTCELLQuestion4ThesharedepitoperiskalleleinRAismostdirectlyassoicatedwithwhichofthefollowingpathogenicmechanisms?An