自身免疫性炎症综合症培训ppt课件

自身免疫性炎症自身免疫性炎症综合合症症自身免疫性炎症综合症12自身免疫性炎症综合症2自身免疫性炎症综合症23自身免疫性炎症综合症3自身免疫性炎症综合症3Autoinflammatory-1999“TheautosomaldominantperiodicfeversthereforerepresentaclassofhumandiseaseshowntobecausedbymutationsinTNFreceptors.AutoantibodiesarenotageneralfeatureoftheseillnessesortherecessivelyinheritedFMF,andforthisreasonthetermautoinflammatoryispreferabletoautoimmuneindescribingthesedisorders.”“Germlinemutationsintheextracellulardomainsofthe55kDaTNFreceptor,TNFR1,defineafamilyofdominantlyinheritedautoinflammatorysyndromes.”McDermott,etal.,Cell.1999Apr2;97(1):133-44.4自身免疫性炎症综合症Autoinflammatory-1999“The4“Autoinflammatory”DiseaseAtthetime,autoinflammatorywascoinedtodistinguishdiseasesinvolvinginnateimmunedysregulation(FMF&TRAPS)fromautoimmunediseasesknowntoinvolveadaptiveimmunedysregulation(SLE&RA).Twopremisesofautoimmunediseaseareunfulfilledinautoinflammatorydisorders:1.Theinflammationisseemingly“unprovoked”.2.Autoantibodiesandantigen-specificTcellsareabsent.5自身免疫性炎症综合症“Autoinflammatory”DiseaseAtt56自身免疫性炎症综合症6自身免疫性炎症综合症67自身免疫性炎症综合症7自身免疫性炎症综合症78自身免疫性炎症综合症8自身免疫性炎症综合症89自身免疫性炎症综合症9自身免疫性炎症综合症9CytokineDiseaseGeneProteinInherit.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,2011,167:391-40410自身免疫性炎症综合症CytokineDiseaseGeneProteinInh10Pro-IL-1b bIL-1b bInactiveactiveNLRP3andIL-1SchroderandTschopp,Cell,2010,140:821-82311自身免疫性炎症综合症Pro-IL-1bIL-1bInactiveactiveNL11Goldbach-Mansky,ClinExpImmunol,2012,167:391-404ActivationofInflammasome12自身免疫性炎症综合症Goldbach-Mansky,ClinExpImmu1213自身免疫性炎症综合症13自身免疫性炎症综合症13编码不同蛋白的基因突变编码不同蛋白的基因突变14自身免疫性炎症综合症编码不同蛋白的基因突变14自身免疫性炎症综合症14CytokineDiseaseGeneProteinInherit.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,2011,167:391-40415自身免疫性炎症综合症CytokineDiseaseGeneProteinInh15隐热蛋白相关周期综合征隐热蛋白相关周期综合征16自身免疫性炎症综合症隐热蛋白相关周期综合征16自身免疫性炎症综合症1617自身免疫性炎症综合症17自身免疫性炎症综合症17Cryopyrin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18自身免疫性炎症综合症Cryopyrin相关周期综合征（CAPS）炎性刺激含有cr1819自身免疫性炎症综合症19自身免疫性炎症综合症19CAPS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20自身免疫性炎症综合症CAPS临床分型和疾病谱轻度表型中度表型重度表型FCASMW20NLRP3炎性体基因突变炎性体基因突变21自身免疫性炎症综合症NLRP3炎性体基因突变21自身免疫性炎症综合症2122自身免疫性炎症综合症22自身免疫性炎症综合症2223自身免疫性炎症综合症23自身免疫性炎症综合症2324自身免疫性炎症综合症24自身免疫性炎症综合症2425自身免疫性炎症综合症25自身免疫性炎症综合症2526自身免疫性炎症综合症26自身免疫性炎症综合症2627自身免疫性炎症综合症27自身免疫性炎症综合症27IL-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-1Trap28自身免疫性炎症综合症IL-1阻滞剂治疗CAPS炎性刺激含有隐热蛋白的炎症小体活化2829自身免疫性炎症综合症29自身免疫性炎症综合症29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30自身免疫性炎症综合症家族性地中海热（FMF）含有cryopyrin的炎症小体活化3031自身免疫性炎症综合症31自身免疫性炎症综合症31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32自身免疫性炎症综合症治疗：32自身免疫性炎症综合症32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33自身免疫性炎症综合症激素有效（3-5天），秋水仙碱无效33自身免疫性炎症综合症33MKDMKD（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）34自身免疫性炎症综合症MKD（高IgD综合征，HIDS）炎性刺激含有cryopyr3435自身免疫性炎症综合症35自身免疫性炎症综合症3536自身免疫性炎症综合症36自身免疫性炎症综合症3637自身免疫性炎症综合症37自身免疫性炎症综合症37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）38自身免疫性炎症综合症肿瘤坏死因子受体相关周期综合征（TRAPS）38自身免疫性炎3839自身免疫性炎症综合症39自身免疫性炎症综合症3940自身免疫性炎症综合症40自身免疫性炎症综合症40PAPAPAPA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)41自身免疫性炎症综合症PAPA 综合征炎性刺激含有cryopyrin的炎症小体活化半4142自身免疫性炎症综合症42自身免疫性炎症综合症4243自身免疫性炎症综合症43自身免疫性炎症综合症43自身免疫性炎症综合症培训ppt课件4445自身免疫性炎症综合症45自身免疫性炎症综合症4546自身免疫性炎症综合症46自身免疫性炎症综合症4647自身免疫性炎症综合症47自身免疫性炎症综合症47Schnitzlerssyndrome200casesreportedworldwidedeKoningetal,2007,SeminArthritisRheum48自身免疫性炎症综合症Schnitzlerssyndrome200c4849自身免疫性炎症综合症49自身免疫性炎症综合症4950自身免疫性炎症综合症50自身免疫性炎症综合症50SchnitzlerSyndromeDifferentialDiagnosis51自身免疫性炎症综合症SchnitzlerSyndromeDifferentia51NOD2 Associated Autoinflammatory DiseasesNOD2gene:R702WandIVS8+158Yao et al,2013,J Am Acad Dermatol,68:624-3152自身免疫性炎症综合症NOD2AssociatedAutoinflammato5253自身免疫性炎症综合症53自身免疫性炎症综合症53Table1.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)54自身免疫性炎症综合症Table1.Underlyingmechanisms54Table3.ClinicalsignsandsymptomsofselectedautoinflammatorydiseasesandpossibledifferentialdiagnosesClinicalsignsandsymptomsAutoinflammatorydisorderDifferentialdiagnosisCAPSSchnitzlerssyndromeNLRP12-associatedFCASsoJIAAOSDMKDTRAPS1.TheclinicalsignsandsymptomsrepresentaselectionofcommonfeaturesandarefoundinothernonurticarialautoinflammatorydiseasessuchasfamilialMediterraneanfever(FMF),periodicfever,aphthousstomatitis,pharyngitisandadenitissyndrome(PFAPA),Behcetsdiseaseandothersaswell.ChronicurticarialrashXXXXXXXUrticaria(spontaneousorinduced,e.g.coldcontacturticaria)UrticarialvasculitisEyerednessandpainXXAllergicconjunctivitisUveitis(autoimmune,infectious)PeriorbitaloedemaXAngioedemaAllergiccontactdermatitisSerositisXAutoimmuneconnectivetissuedisorderStomatitis,aphthaeXAllergyAutoimmunedisorderInfectionAbdominalpain,diarrhoeaXXFoodallergyInflammatoryboweldiseaseProteinuria XXXAutoimmuneconnectivetissuedisorderLymphadenopathyXXXXXXXInfectionMalignancyAutoimmuneconnectivetissuedisorderMyalgiaXXXXInfectionAutoimmuneconnectivetissuedisorderArthralgia/arthritisXXXXXXXRheumatoidarthritisJIAReactivearthritisAutoimmuneconnectivetissuedisorderHeadacheandotherCNSsymptomsXXXMigraineFeverXXXXXXXInfectionMalignancyImmunodeficiencyAutoimmuneconnectivetissuedisorder55自身免疫性炎症综合症Table3.Clinicalsignsandsy55Table4.DistinguishingcriteriaofchronicurticariaandautoinflammatorysyndromesCharacteristicsofurticarialrashChronicurticariaAutoinflammatorysyndromeAppearancePapularwhealsWheal-and-flarereactionFlatterwheals,erythematouspatchesbutalsomoresolidandstablelesionsNowhealwithsurroundingflareLocalizationAsymmetricaldistributioncommonRathersymmetricaldistributionDurationofsinglelesionTransient(minutesorfewhours)Hours,upto24hPruritusSevereMaybeabsent,ratherburningorpainfulAngioedemaOftenassociatedRareSkinhistopathologyDermaloedema;partlysparseinflammatoryinfiltrateofperivasculareosinophils,neutrophilsandlymphocytesNosignificantdermaloedema;denseneutrophil-richperivascularandinterstitialinfiltrates,butcanalsoberathernonspecificStartofsymptomsAllagesChildhood(hereditaryfeversyndromes)Adulthood(acquiredcomplexdisorders)DiseasedurationFewyearsUsuallylife-longResponsetoantihistaminesModerategoodDosedependentMissingSystemicsymptomsNoneRecurrentfever,fatigue,arthralgiaandothersInflammationmarkersWithinnormalrange(Continuously)elevatedFamilyhistoryNegativeOftenpositive56自身免疫性炎症综合症Table4.Distinguishingcriter5657自身免疫性炎症综合症57自身免疫性炎症综合症5758自身免疫性炎症综合症58自身免疫性炎症综合症5859自身免疫性炎症综合症59自身免疫性炎症综合症59