自身免疫性炎症综合症

AutoinflammatorySyndrome

自身免疫性炎症综合症第1页自身免疫性炎症综合症第2页自身免疫性炎症综合症第3页Autoinflammatory-1999“…Theautosomaldominant

periodicfevers

thereforerepresentaclassof

human

diseaseshowntobecausedbymutationsin

TNF

receptors.Autoantibodiesarenotageneralfeatureoftheseillnessesortherecessivelyinherited

FMF,andforthisreasontheterm

autoinflammatory

ispreferabletoautoimmune

indescribingthesedisorders.

”“Germlinemutationsintheextracellulardomainsofthe55kDaTNFreceptor,TNFR1,defineafamilyofdominantlyinheritedautoinflammatorysyndromes.”

McDermott,etal.,Cell.

1999Apr2;97(1):133-44.自身免疫性炎症综合症第4页“Autoinflammatory”DiseaseAtthetime,autoinflammatorywascoinedtodistinguishdiseasesinvolvinginnateimmunedysregulation(FMF&TRAPS)fromautoimmunediseasesknowntoinvolveadaptiveimmunedysregulation(SLE&RA).Twopremisesofautoimmunediseaseareunfulfilledinautoinflammatorydisorders:Theinflammationisseemingly“unprovoked”.Autoantibodiesandantigen-specificTcellsareabsent.自身免疫性炎症综合症第5页自身免疫性炎症综合症第6页自身免疫性炎症综合症第7页自身免疫性炎症综合症第8页自身免疫性炎症综合症第9页CytokineDiseaseGeneProteinInherit.patternDiseaseonsetFeverpatternSpecificorganinflammationIL-1bCAPSFCASMWSCIAS1CIAS1CIAS1CryopyrinCryopyrinCryopyrinADADAD6m,coldinducedInfancy–adolescenceNeonatalorearlyinfancy<24h24-48hContinuouswithflaresSkin,eyes,joints,systemicSkin,eyes,joints,innerears,meninges(mild),systemicSkin,eyes,joints,innerears,meningges,bonyepiphysealhyperplasia,systemicIL-1bandIL-1aDIRAIL-1RNIL-1RaARNeonatalorearlyinfancyContinuouswithflaresskin,bones,lungs,vasculitisIL-1FCASNLRP12NLRP12ADNeonatalorearlyinfancyContinouswithflaresSkin,eyes,joints,SystemicIL-1FMFMEFVPyrinAR80%<20yo1-3daysSkin,joints,peritoneum,pleuraIL-1HIDSMVKMevalonatekinaseAR6months3-7daysSkin,eyes,joints,prominentlymphnodesIL-1Majeed’ssyndromeLPIN2lipin2AR1-19mWeeks-monthsBones,periosteum,anemiaIL-1+TNFIL-1+TNFTRAPSPAPATNFRSF1ACD2BP1TNFR1PSTPIP1ADAD3yearsEarlychildhood1-4weeksCommonSkin,eyes,joints,peritoneum,pleuraSkin,jointsAID–IL-1PathwayGoldbach-Monsky,ClinExpImmunol,,167:391-404自身免疫性炎症综合症第10页Pro-IL-1bIL-1bInactiveactiveNLRP3andIL-1SchroderandTschopp,Cell,,140:821-823自身免疫性炎症综合症第11页Goldbach-Mansky,ClinExpImmunol,,167:391-404ActivationofInflammasome自身免疫性炎症综合症第12页自身免疫性炎症综合症第13页编码不一样蛋白基因突变自身免疫性炎症综合症第14页CytokineDiseaseGeneProteinInherit.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,lipodystrophyandmuscleatrophyAID–otherCytokinePathwaysGoldbach-Monsky,ClinExpImmunol,,167:391-404自身免疫性炎症综合症第15页隐热蛋白相关周期综合征自身免疫性炎症综合症第16页自身免疫性炎症综合症第17页Cryopyrin相关周期综合征（CAPS）炎性刺激含有cryopyrin炎症小体活化（CAPS）半胱天东酶1活化（IL-1β转化酶）产生IL-1β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cryopyrin作用：还未完全说明降低炎症活化阈值，使炎症触发愈加敏感炎症开启正常，但炎症关闭被干扰自身免疫性炎症综合症第18页自身免疫性炎症综合症第19页CAPS临床分型和疾病谱轻度表型中度表型重度表型FCAS

严寒诱发荨麻疹发烧关节痛MWS

荨麻疹低热关节炎淀粉样变耳聋NOMID

新生儿起病荨麻疹发烧关节病，可变形淀粉样变中枢神经系统表现脑膜炎视力障碍自身免疫性炎症综合症第20页NLRP3炎性体基因突变自身免疫性炎症综合症第21页自身免疫性炎症综合症第22页自身免疫性炎症综合症第23页自身免疫性炎症综合症第24页自身免疫性炎症综合症第25页自身免疫性炎症综合症第26页自身免疫性炎症综合症第27页IL-1阻滞剂治疗CAPS炎性刺激含有隐热蛋白炎症小体活化半胱天东酶1活化（IL-1β转化酶）产生IL-1β炎症免疫细胞活化组织损伤炎症小体IL-1阻滞剂

Anakinra：IL-1ra拮抗剂

Canakinumab：IL-1β单抗

Rilonacept：IL-1Trap自身免疫性炎症综合症第28页自身免疫性炎症综合症第29页家族性地中海热（FMF）含有cryopyrin炎症小体活化炎性刺激半胱天东酶1活化（IL-1β转化酶）产生IL-1β炎症免疫细胞活化凋亡和组织损伤pyrin（FMF）炎症小体自身免疫性炎症综合症第30页自身免疫性炎症综合症第31页治疗：NSAIDs：秋水仙碱：减缓WBC趋化和炎性因子产生，预防淀粉样变神经病变IL-1拮抗剂预后：≤1个基因突变：治疗反应良好H478YMEFVvariant：秋水仙碱无效M694V突变：易淀粉样变自身免疫性炎症综合症第32页激素有效（3-5天），秋水仙碱无效TNFa拮抗剂和IL-1拮抗剂部分有效自身免疫性炎症综合症第33页MKD（高IgD综合征，HIDS）炎性刺激含有cryopyrin炎症小体活化（CAPS）半胱天东酶1活化（IL-1β转化酶）产生IL-1β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）自身免疫性炎症综合症第34页自身免疫性炎症综合症第35页自身免疫性炎症综合症第36页自身免疫性炎症综合症第37页肿瘤坏死因子受体相关周期综合征（TRAPS）自身免疫性炎症综合症第38页自身免疫性炎症综合症第39页自身免疫性炎症综合症第40页PAPA综合征炎性刺激含有cryopyrin炎症小体活化半胱天东酶1活化（IL-1β转化酶）产生IL-1β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)自身免疫性炎症综合症第41页自身免疫性炎症综合症第42页自身免疫性炎症综合症第43页自身免疫性炎症综合症第44页自身免疫性炎症综合症第45页自身免疫性炎症综合症第46页自身免疫性炎症综合症第47页Schnitzler’ssyndrome

~200casesreportedworldwidedeKoningetal,,SeminArthritisRheum自身免疫性炎症综合症第48页自身免疫性炎症综合症第49页自身免疫性炎症综合症第50页SchnitzlerSyndromeDifferentialDiagnosis自身免疫性炎症综合症第51页NOD2AssociatedAutoinflammatoryDiseasesNOD2gene:R702WandIVS8+158Yaoetal,,JAmAcadDermatol,68:624-31自身免疫性炎症综合症第52页自身免疫性炎症综合症第53页Table

1.

UnderlyingmechanismsandcausesofchronicurticarialrashMastcellmediator–mediatedInterleukin-1-mediatedaaInterleukin-1mayalsobe,atleastinpart,mastcell-derived.Chronicspontaneousurticaria(CSU)Cryopyrin-associatedperiodicsyndrome(CAPS)CSUduetoautoreactivitySchnitzler'ssyndrome(SchS)Otherautoinflammatorydisorders:NLRP12-associatedcold-inducedautoinflammatorysyndrome(FCAS2)CSUduetofunctionalautoantibodiesSystemic-onsetjuvenileidiopathicarthritis(soJIA)Adult-onsetStill'sdisease(AOSD)Mevalonatekinasedeficiency(MKD)TNF-receptor-associatedperiodicsyndrome(TRAPS)自身免疫性炎症综合症第54页Table

3.

ClinicalsignsandsymptomsofselectedautoinflammatorydiseasesandpossibledifferentialdiagnosesClinicalsignsandsymptomsAutoinflammatorydisorderDifferentialdiagnosisCAPSSchnitzler'ssyndromeNLRP12-associatedFCASsoJIAAOSDMKDTRAPSTheclinicalsignsandsymptomsrepresentaselectionofcommonfeaturesandarefoundinothernonurticarialautoinflammatorydiseasessuchasfamilialMediterraneanfever(FMF),periodicfever,aphthousstomatitis,pharyngitisandadenitissyndrome(PFAPA),Behcet'sdiseaseandothersaswell.ChronicurticarialrashXXXXXXXUrticaria(spontaneousorinduced,e.g.coldcontacturticaria)UrticarialvasculitisEyerednessandpainX

X

AllergicconjunctivitisUveitis(autoimmune,infectious)Periorbitaloedema

XAngioedemaAllergiccontactdermatitisSerositis

XAutoimmuneconnectivetissuedisorderStomatitis,aphthae

X

AllergyAutoimmunedisorderInfectionAbdominalpain,diarrhoea

XXFoodallergyInflammatoryboweldiseaseProteinuriaX

XXAutoimmuneconnectivetissuedisorderLymphadenopathyXXXXXXXInfectionMalignancyAutoimmuneconnectivetissuedisorderMyalgiaXX

XXInfectionAutoimmuneconnectivetissuedisorderArthralgia/arthritisXXXXXXXRheumatoidarthritisJIAReactivearthritisAutoimmuneconnectivetissuedisorderHeadacheandotherCNSsymptomsX

XXMigraineFeverXXXXXXXInfectionMalignancyImmunodeficiencyAutoimmuneconnectivetissuedisorder自身免疫性炎症综合症第55页Table

4.

DistinguishingcriteriaofchronicurticariaandautoinflammatorysyndromesCharacteristicsofurticarialrashChronicurticariaAutoinflammatorysyndromeAppearancePapularwhealsWheal-and-flarereactionFlatterwheals,erythematouspatchesbutalsomoresolidandstablelesionsNowhealwithsurroundingflareLocalizationAsymmetricaldistributioncommonRathersymmetri