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

特異性,記憶免疫,響應(yīng)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(guān)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(yīng)性免疫特異性,記憶TcellsandBcellsRECRUITS,MODULATESTYPEOFRESPONSERECRUITS,ENHANCESANTIMICROBICALACTIVITY適應(yīng)性免疫反應(yīng)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(dǎo)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(yīng)性免疫反應(yīng)的發(fā)展起關(guān)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(dǎo)致無效能

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

TCELLTCRCD28MicrobeSIGNAL1MHCMicrobialKillingSIGNAL2B7PatternRecognitionReceptorAbatacept(CTLA4-Ig)抑制共同刺激控制免疫反應(yīng):預(yù)防應(yīng)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(xùn)練”成不識別self-antigens中樞耐受對self-antigens反應(yīng)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(fù)刺激誘導(dǎo)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(yīng)免疫ResolutionWithMemory失調(diào)不當天生的激活適應(yīng)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(yīng)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(guān)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(fù)合體存入組織,然后導(dǎo)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(fù)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(yīng)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(xué)

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(xué)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