医学ppt课件自身免疫性炎症综合症

医学ppt课件自身免疫性炎症综合症1医学ppt课件自身免疫性炎症综合症2Autoinflammatory-1999“TheautosomaldominantperiodicfeversthereforerepresentaclassofhumandiseaseshowntobecausedbymutationsinTNFreceptors.AutoantibodiesarenotageneralfeatureoftheseillnessesortherecessivelyinheritedFMF,andforthisreasonthetermautoinflammatoryispreferabletoautoimmuneindescribingthesedisorders.”“Germlinemutationsintheextracellulardomainsofthe55kDaTNFreceptor,TNFR1,defineafamilyofdominantlyinheritedautoinflammatorysyndromes.”McDermott,etal.,Cell.1999Apr2;97(1):133-44.Autoinflammatory-1999“The3“Autoinflammatory”DiseaseAtthetime,autoinflammatorywascoinedtodistinguishdiseasesinvolvinginnateimmunedysregulation(FMF&TRAPS)fromautoimmunediseasesknowntoinvolveadaptiveimmunedysregulation(SLE&RA).Twopremisesofautoimmunediseaseareunfulfilledinautoinflammatorydisorders:1.Theinflammationisseemingly“unprovoked”.2.Autoantibodiesandantigen-specificTcellsareabsent.“Autoinflammatory”DiseaseAtt4医学ppt课件自身免疫性炎症综合症5医学ppt课件自身免疫性炎症综合症6医学ppt课件自身免疫性炎症综合症7医学ppt课件自身免疫性炎症综合症8CytokineDiseaseGeneProteinInherit.patternDiseaseonsetFeverpatternSpecificorganinflammationIL-1b bCAPSFCASMWSCIAS1CIAS1CIAS1CryopyrinCryopyrinCryopyrinADADAD6m,coldinducedInfancyadolescenceNeonatalorearlyinfancy24h24-48hContinuouswithflaresSkin,eyes,joints,systemicSkin,eyes,joints,innerears,meninges(mild),systemicSkin,eyes,joints,innerears,meningges,bonyepiphysealhyperplasia,systemicIL-1b bandIL-1a aDIRAIL-1RNIL-1RaARNeonatalorearlyinfancyContinuouswithflaresskin,bones,lungs,vasculitisIL-1FCASNLRP12NLRP12ADNeonatalorearlyinfancyContinouswithflaresSkin,eyes,joints,SystemicIL-1FMFMEFVPyrinAR80%20yo1-3daysSkin,joints,peritoneum,pleuraIL-1HIDSMVKMevalonatekinaseAR6months3-7daysSkin,eyes,joints,prominentlymphnodesIL-1MajeedssyndromeLPIN2lipin2AR1-19mWeeks-monthsBones,periosteum,anemiaIL-1+TNFIL-1+TNFTRAPSPAPATNFRSF1ACD2BP1TNFR1PSTPIP1ADAD3yearsEarlychildhood1-4weeksCommonSkin,eyes,joints,peritoneum,pleuraSkin,jointsAIDIL-1PathwayGoldbach-Monsky,ClinExpImmunol,2011,167:391-404CytokineDiseaseGeneProteinInh9Pro-IL-1b bIL-1b bInactiveactiveNLRP3andIL-1SchroderandTschopp,Cell,2010,140:821-823Pro-IL-1bIL-1bInactiveactiveNL10Goldbach-Mansky,ClinExpImmunol,2012,167:391-404ActivationofInflammasomeGoldbach-Mansky,ClinExpImmu11医学ppt课件自身免疫性炎症综合症12编码不同蛋白的基因突变编码不同蛋白的基因突变编码不同蛋白的基因突变13CytokineDiseaseGeneProteinInherit.patternDiseaseonsetFeverpatternSpecificorganinflammationTNF,IL-1PGANOD2nod2ADEarlychildhooduncommonSkin,eyes,jointsTNFCherubismSH3BP2SH3BP2ADChildhood,spontaneousressionby3rddecadeUncommonjaws,eyesLackofIL-10signallingEarlyonsetIBDIL10RAIL-10R,IL10RBalsoformsIL-12-26,28,29RARNeonatalorearlyinfancyContinuouswithflaresColitiswithfistulaformation,folliculitisinpatientswithIL-10RBmutationsIL-36a,IL-36b,IL-36gDITRAIL10RB,IL-36RN/IL-1F5IL-36ARCarriabletoadulthood,FlaresofgeneralizedandpalmoplantarpustulosisSkinIncreaseinIFNsignallingJMP,NNS,JASL,CANDLEPSMB8Inducibleb5subunitofimmuno-proteasomeARNeonatalorearlyinfancyContinuouswithflaresSkin,joints,lipodystrophyandmuscleatrophyAIDotherCytokinePathwaysGoldbach-Monsky,ClinExpImmunol,2011,167:391-404CytokineDiseaseGeneProteinInh14隐热蛋白相关周期综合征隐热蛋白相关周期综合征隐热蛋白相关周期综合征15医学ppt课件自身免疫性炎症综合症16Cryopyrin相关周期综合征（相关周期综合征（CAPS）炎性刺激含有cryopyrin的炎症小体活化（CAPS）半胱天东酶1活化（IL-1转化酶）产生IL-1炎症免疫细胞活化凋亡和组织损伤炎症小体pyrin类异戊二烯代谢 突变突变cryopyrin作用：作用：尚未完全阐明尚未完全阐明降低炎症活化的阈值，降低炎症活化的阈值，使炎症触发更加敏感使炎症触发更加敏感炎症的启动正常，但炎症的启动正常，但炎症的关闭被干扰炎症的关闭被干扰Cryopyrin相关周期综合征（CAPS）炎性刺激含有cr17医学ppt课件自身免疫性炎症综合症18CAPS临床分型和疾病谱临床分型和疾病谱轻度表型轻度表型中度表型中度表型重度表型重度表型FCAS 寒冷诱发的荨麻疹寒冷诱发的荨麻疹 发热发热 关节痛关节痛MWS 荨麻疹荨麻疹 低热低热 关节炎关节炎 淀粉样变淀粉样变 耳聋耳聋NOMID 新生儿起病的荨麻疹新生儿起病的荨麻疹 发热发热 关节病，可变形关节病，可变形 淀粉样变淀粉样变 中枢神经系统表现中枢神经系统表现脑膜炎脑膜炎视力障碍视力障碍CAPS临床分型和疾病谱轻度表型中度表型重度表型FCASMW19NLRP3炎性体基因突变炎性体基因突变NLRP3炎性体基因突变20医学ppt课件自身免疫性炎症综合症21医学ppt课件自身免疫性炎症综合症22医学ppt课件自身免疫性炎症综合症23医学ppt课件自身免疫性炎症综合症24医学ppt课件自身免疫性炎症综合症25医学ppt课件自身免疫性炎症综合症26IL-1阻滞剂治疗阻滞剂治疗CAPS炎性刺激含有隐热蛋白的炎症小体活化半胱天东酶1活化（IL-1转化酶）产生IL-1炎症免疫细胞活化组织损伤炎症小体炎症小体IL-1阻滞剂阻滞剂Anakinra：IL-1ra拮抗剂拮抗剂 Canakinumab：IL-1单抗单抗 Rilonacept：IL-1TrapIL-1阻滞剂治疗CAPS炎性刺激含有隐热蛋白的炎症小体活化27医学ppt课件自身免疫性炎症综合症28家族性地中海热（家族性地中海热（FMF）含有cryopyrin的炎症小体活化炎性刺激半胱天东酶1活化（IL-1转化酶）产生IL-1炎症免疫细胞活化凋亡和组织损伤pyrin（FMF）炎症小体炎症小体家族性地中海热（FMF）含有cryopyrin的炎症小体活化29医学ppt课件自身免疫性炎症综合症30治疗：治疗：NSAIDs：秋水仙碱：秋水仙碱：减缓减缓WBC趋化和炎性因子产生，预防淀粉样变趋化和炎性因子产生，预防淀粉样变神经病变神经病变IL-1拮抗剂拮抗剂预后：预后：1个基因突变：治疗反应良好个基因突变：治疗反应良好H478YMEFVvariant：秋水仙碱无效：秋水仙碱无效M694V突变：易淀粉样变突变：易淀粉样变治疗：31激素有效（激素有效（3-5天），天），秋水仙碱无效秋水仙碱无效TNFa拮抗剂和拮抗剂和IL-1拮拮抗剂部分有效抗剂部分有效激素有效（3-5天），秋水仙碱无效32MKDMKD（高（高IgD综合征，综合征，HIDSHIDS）炎性刺激含有cryopyrin的炎症小体活化（CAPS）半胱天东酶1活化（IL-1转化酶）产生IL-1炎症免疫细胞活化凋亡和组织损伤炎症小体pyrin类异戊二烯代谢MVK(甲羟戊酸激酶)（HIDS）MKD（高IgD综合征，HIDS）炎性刺激含有cryopyr33医学ppt课件自身免疫性炎症综合症34医学ppt课件自身免疫性炎症综合症35医学ppt课件自身免疫性炎症综合症36肿瘤坏死因子受体相关周期综合征（肿瘤坏死因子受体相关周期综合征（TRAPS）肿瘤坏死因子受体相关周期综合征（TRAPS）37医学ppt课件自身免疫性炎症综合症38医学ppt课件自身免疫性炎症综合症39PAPAPAPA综合征综合征炎性刺激含有cryopyrin的炎症小体活化半胱天东酶1活化（IL-1转化酶）产生IL-1炎症免疫细胞活化凋亡和组织损伤炎症小体pyrin类异戊二烯代谢 PSPSTPIP1(PAPA)PAPA 综合征炎性刺激含有cryopyrin的炎症小体活化半40医学ppt课件自身免疫性炎症综合症41医学ppt课件自身免疫性炎症综合症42医学ppt课件自身免疫性炎症综合症43医学ppt课件自身免疫性炎症综合症44医学ppt课件自身免疫性炎症综合症45医学ppt课件自身免疫性炎症综合症46Schnitzlerssyndrome200casesreportedworldwidedeKoningetal,2007,SeminArthritisRheumSchnitzlerssyndrome200c47医学ppt课件自身免疫性炎症综合症48医学ppt课件自身免疫性炎症综合症49SchnitzlerSyndromeDifferentialDiagnosisSchnitzlerSyndromeDifferentia50NOD2 Associated Autoinflammatory DiseasesNOD2gene:R702WandIVS8+158Yao et al,2013,J Am Acad Dermatol,68:624-31NOD2AssociatedAutoinflammato51医学ppt课件自身免疫性炎症综合症52Table1.UnderlyingmechanismsandcausesofchronicurticarialrashMastcellmediatormediatedInterleukin-1-mediateda1.aInterleukin-1mayalsobe,atleastinpart,mastcell-derived.Chronicspontaneousurticaria(CSU)Cryopyrin-associatedperiodicsyndrome(CAPS)CSUduetoautoreactivitySchnitzlerssyndrome(SchS)Otherautoinflammatorydisorders:NLRP12-associatedcold-inducedautoinflammatorysyndrome(FCAS2)CSUduetofunctionalautoantibodiesSystemic-onsetjuvenileidiopathicarthritis(soJIA)Adult-onsetStillsdisease(AOSD)Mevalonatekinasedeficiency(MKD)TNF-receptor-associatedperiodicsyndrome(TRAPS)Table1.Underlyingmechanisms53Table3.ClinicalsignsandsymptomsofselectedautoinflammatorydiseasesandpossibledifferentialdiagnosesClinicalsignsandsymptomsAutoinflammatorydisorderDifferentialdiagnosisCAPSSchnitzlerssyndromeNLRP12-associatedFCASsoJIAAOSDMKDTRAPS1.TheclinicalsignsandsymptomsrepresentaselectionofcommonfeaturesandarefoundinothernonurticarialautoinflammatorydiseasessuchasfamilialMediterraneanfever(FMF),periodicfever,aphthousstomatitis,pharyngitisandadenitissyndrome(PFAPA),Behcetsdiseaseandothersaswell.ChronicurticarialrashXXXXXXXUrticaria(spontaneousorinduced,e.g.coldcontacturticaria)UrticarialvasculitisEyerednessandpainXXAllergicconjunctivitisUveitis(autoimmune,infectious)PeriorbitaloedemaXAngioedemaAllergiccontactdermatitisSerositisXAutoimmuneconnectivetissuedisorderStomatitis,aphthaeXAllergyAutoimmunedisorderInfectionAbdominalpain,diarrhoeaXXFoodallergyInflammatoryboweldiseaseProteinuria XXXAutoimmuneconnectivetissuedisorderLymphadenopathyXXXXXXXInfectionMalignancyAutoimmuneconnectivetissuedisorderMyalgiaXXXXInfectionAutoimmuneconnectivetissuedisorderArthralgia/arthritisXXXXXXXRheumatoidarthritisJIAReactivearthritisAutoimmuneconnectivetissuedisorderHeadacheandotherCNSsymptomsXXXMigraineFeverXXXXXXXInfectionMalignancyImmunodeficiencyAutoimmuneconnectivetissuedisorderTable3.Clinicalsignsandsy54Table4.DistinguishingcriteriaofchronicurticariaandautoinflammatorysyndromesCharacteristicsofurticarialrashChronicurticariaAutoinflammatorysyndromeAppearancePapularwhealsWheal-and-flarereactionFlatterwheals,erythematouspatchesbutalsomoresolidandstablelesionsNowhealwithsurroundingflareLocalizationAsymmetricaldistributioncommonRathersymmetricaldistributionDurationofsinglelesionTransient(minutesorfewhours)Hours,upto24hPruritusSevereMaybeabsent,ratherburningorpainfulAngioedemaOftenassociatedRareSkinhistopathologyDermaloedema;partlysparseinflammatoryinfiltrateofperivasculareosinophils,neutrophilsandlymphocytesNosignificantdermaloedema;denseneutrophil-richperivascularandinterstitialinfiltrates,butcanalsoberathernonspecificStartofsymptomsAllagesChildhood(hereditaryfeversyndromes)Adulthood(acquiredcomplexdisorders)DiseasedurationFewyearsUsuallylife-longResponsetoantihistaminesModerategoodDosedependentMissingSystemicsymptomsNoneRecurrentfever,fatigue,arthralgiaandothersInflammationmarkersWithinnormalrange(Continuously)elevatedFamilyhistoryNegativeOftenpositiveTable4.Distinguishingcriter55医学ppt课件自身免疫性炎症综合症56医学ppt课件自身免疫性炎症综合症57医学ppt课件自身免疫性炎症综合症58