自身免疫性炎癥綜合癥培訓(xùn)課件

1、自身免疫性炎癥綜合癥自身免疫性炎癥綜合癥2自身免疫性炎癥綜合癥2自身免疫性炎癥綜合癥3自身免疫性炎癥綜合癥3自身免疫性炎癥綜合癥Autoinflammatory - 1999“ The autosomal dominantperiodic feverstherefore represent a class ofhumandisease shown to be caused by mutations inTNFreceptors. Autoantibodies are not a general feature of these illnesses or the recessively inhe

2、ritedFMF, and for this reason the termautoinflammatoryis preferable to autoimmunein describing these disorders.”“Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.” McDermott, et al., Cell.1999 Apr 2;

3、97(1):133-44.4自身免疫性炎癥綜合癥Autoinflammatory - 1999“ The“Autoinflammatory” DiseaseAt the time, autoinflammatory was coined to distinguish diseases involving innate immune dysregulation (FMF & TRAPS) from autoimmune diseases known to involve adaptive immune dysregulation (SLE & RA).Two premises of autoim

4、mune disease are unfulfilled in autoinflammatory disorders:The inflammation is seemingly “unprovoked”.Autoantibodies and antigen-specific T cells are absent.5自身免疫性炎癥綜合癥“Autoinflammatory” DiseaseAt t6自身免疫性炎癥綜合癥6自身免疫性炎癥綜合癥7自身免疫性炎癥綜合癥7自身免疫性炎癥綜合癥8自身免疫性炎癥綜合癥8自身免疫性炎癥綜合癥9自身免疫性炎癥綜合癥9自身免疫性炎癥綜合癥CytokineDiseas

5、e GeneProteinInherit. patternDisease onsetFever patternSpecific organ inflammationIL-1bCAPSFCASMWSCIAS1CIAS1CIAS1CryopyrinCryopyrinCryopyrinADADAD6 m, cold induced Infancy adolescenceNeonatal or early infancy24h24-48hContinuous with flaresSkin, eyes, joints,systemicSkin, eyes, joints, inner ears, me

6、ninges (mild),systemicSkin, eyes, joints, inner ears, meningges, bony epiphyseal hyperplasia,systemicIL-1b and IL-1aDIRAIL-1RNIL-1RaARNeonatal or early infancyContinuous with flaresskin, bones, lungs, vasculitisIL-1FCASNLRP12NLRP12ADNeonatal or early infancyContinous with flaresSkin, eyes, joints,Sy

7、stemicIL-1FMFMEFVPyrinAR80% 20yo1-3 daysSkin, joints, peritoneum, pleuraIL-1HIDSMVKMevalonate kinaseAR 6 months3-7 daysSkin, eyes, joints, prominent lymph nodesIL-1Majeeds syndromeLPIN2lipin2AR1-19 mWeeks-monthsBones, periosteum, anemiaIL-1 + TNFIL-1 + TNFTRAPSPAPATNFRSF1ACD2BP1TNFR1PSTPIP1ADAD3 yea

8、rsEarly childhood1-4 weeksCommonSkin, eyes, joints, peritoneum, pleuraSkin, jointsAID IL-1 PathwayGoldbach-Monsky, Clin Exp Immunol, 2011, 167:391-40410自身免疫性炎癥綜合癥CytokineDisease GeneProteinInhPro-IL-1bIL-1bInactiveactiveNLRP3 and IL-1Schroder and Tschopp, Cell, 2010, 140:821-82311自身免疫性炎癥綜合癥Pro-IL-1b

9、IL-1bInactiveactiveNLGoldbach-Mansky, Clin Exp Immunol, 2012, 167:391-404Activation of Inflammasome12自身免疫性炎癥綜合癥Goldbach-Mansky, Clin Exp Immu13自身免疫性炎癥綜合癥13自身免疫性炎癥綜合癥編碼不同蛋白的基因突變14自身免疫性炎癥綜合癥編碼不同蛋白的基因突變14自身免疫性炎癥綜合癥CytokineDisease GeneProteinInherit. patternDisease onsetFever patternSpecific organ infla

10、mmationTNF, IL-1PGANOD2nod2ADEarly childhooduncommonSkin, eyes, jointsTNFCherubismSH3BP2SH3BP2ADChildhood, spontaneous ression by 3rd decadeUncommonjaws, eyes Lack of IL-10 signallingEarly onset IBDIL10RAIL-10R, IL10RB also forms IL-12-26, 28, 29 RARNeonatal or early infancyContinuous with flaresCol

11、itis with fistula formation, folliculitis in patients with IL-10RB mutationsIL-36a, IL-36b, IL-36g DITRAIL10RB,IL-36RN/IL-1F5IL-36ARCarriable to adulthood, Flares of generalized and palmoplantar pustulosisSkin Increase in IFN signallingJMP, NNS, JASL, CANDLEPSMB8Inducible b5 subunit of immuno-protea

12、someAR Neonatal or early infancyContinuous with flaresSkin, joints, lipodystrophy and muscle atrophyAID other Cytokine PathwaysGoldbach-Monsky, Clin Exp Immunol, 2011, 167:391-40415自身免疫性炎癥綜合癥CytokineDisease GeneProteinInh隱熱蛋白相關(guān)周期綜合征16自身免疫性炎癥綜合癥隱熱蛋白相關(guān)周期綜合征16自身免疫性炎癥綜合癥17自身免疫性炎癥綜合癥17自身免疫性炎癥綜合癥Cryopyrin

13、相關(guān)周期綜合征（CAPS）炎性刺激含有cryopyrin的炎癥小體活化（CAPS）半胱天東酶1活化（IL-1轉(zhuǎn)化酶）產(chǎn)生IL-1炎癥免疫細(xì)胞活化凋亡和組織損傷炎癥小體pyrin類異戊二烯代謝 突變cryopyrin作用：尚未完全闡明降低炎癥活化的閾值，使炎癥觸發(fā)更加敏感炎癥的啟動(dòng)正常，但炎癥的關(guān)閉被干擾18自身免疫性炎癥綜合癥Cryopyrin相關(guān)周期綜合征（CAPS）炎性刺激含有cr19自身免疫性炎癥綜合癥19自身免疫性炎癥綜合癥CAPS臨床分型和疾病譜輕度表型中度表型重度表型FCAS 寒冷誘發(fā)的蕁麻疹 發(fā)熱 關(guān)節(jié)痛MWS 蕁麻疹 低熱 關(guān)節(jié)炎 淀粉樣變 耳聾NOMID 新生兒起病的蕁麻疹

14、發(fā)熱 關(guān)節(jié)病，可變形 淀粉樣變 中樞神經(jīng)系統(tǒng)表現(xiàn)腦膜炎視力障礙20自身免疫性炎癥綜合癥CAPS臨床分型和疾病譜輕度表型中度表型重度表型FCASMWNLRP3炎性體基因突變21自身免疫性炎癥綜合癥NLRP3炎性體基因突變21自身免疫性炎癥綜合癥22自身免疫性炎癥綜合癥22自身免疫性炎癥綜合癥23自身免疫性炎癥綜合癥23自身免疫性炎癥綜合癥24自身免疫性炎癥綜合癥24自身免疫性炎癥綜合癥25自身免疫性炎癥綜合癥25自身免疫性炎癥綜合癥26自身免疫性炎癥綜合癥26自身免疫性炎癥綜合癥27自身免疫性炎癥綜合癥27自身免疫性炎癥綜合癥IL-1阻滯劑治療CAPS炎性刺激含有隱熱蛋白的炎癥小體活化半胱天東酶

15、1活化（IL-1轉(zhuǎn)化酶）產(chǎn)生IL-1炎癥免疫細(xì)胞活化組織損傷炎癥小體IL-1阻滯劑 Anakinra：IL-1ra拮抗劑 Canakinumab：IL-1單抗 Rilonacept：IL-1Trap28自身免疫性炎癥綜合癥IL-1阻滯劑治療CAPS炎性刺激含有隱熱蛋白的炎癥小體活化29自身免疫性炎癥綜合癥29自身免疫性炎癥綜合癥家族性地中海熱（FMF）含有cryopyrin的炎癥小體活化炎性刺激半胱天東酶1活化（IL-1轉(zhuǎn)化酶）產(chǎn)生IL-1炎癥免疫細(xì)胞活化凋亡和組織損傷pyrin（FMF）炎癥小體30自身免疫性炎癥綜合癥家族性地中海熱（FMF）含有cryopyrin的炎癥小體活化31自身免疫性

16、炎癥綜合癥31自身免疫性炎癥綜合癥治療：NSAIDs：秋水仙堿：減緩WBC趨化和炎性因子產(chǎn)生，預(yù)防淀粉樣變神經(jīng)病變IL-1拮抗劑預(yù)后：1個(gè)基因突變：治療反應(yīng)良好H478Y MEFV variant：秋水仙堿無(wú)效M694V突變：易淀粉樣變32自身免疫性炎癥綜合癥治療：32自身免疫性炎癥綜合癥激素有效（3-5天），秋水仙堿無(wú)效TNFa拮抗劑和IL-1拮抗劑部分有效33自身免疫性炎癥綜合癥激素有效（3-5天），秋水仙堿無(wú)效33自身免疫性炎癥綜合癥MKD（高IgD綜合征，HIDS）炎性刺激含有cryopyrin的炎癥小體活化（CAPS）半胱天東酶1活化（IL-1轉(zhuǎn)化酶）產(chǎn)生IL-1炎癥免疫細(xì)胞活化凋亡

17、和組織損傷炎癥小體pyrin類異戊二烯代謝MVK(甲羥戊酸激酶)（HIDS）34自身免疫性炎癥綜合癥MKD（高IgD綜合征，HIDS）炎性刺激含有cryopyr35自身免疫性炎癥綜合癥35自身免疫性炎癥綜合癥36自身免疫性炎癥綜合癥36自身免疫性炎癥綜合癥37自身免疫性炎癥綜合癥37自身免疫性炎癥綜合癥腫瘤壞死因子受體相關(guān)周期綜合征（TRAPS）38自身免疫性炎癥綜合癥腫瘤壞死因子受體相關(guān)周期綜合征（TRAPS）38自身免疫性炎39自身免疫性炎癥綜合癥39自身免疫性炎癥綜合癥40自身免疫性炎癥綜合癥40自身免疫性炎癥綜合癥PAPA綜合征炎性刺激含有cryopyrin的炎癥小體活化半胱天東酶1活

18、化（IL-1轉(zhuǎn)化酶）產(chǎn)生IL-1炎癥免疫細(xì)胞活化凋亡和組織損傷炎癥小體pyrin類異戊二烯代謝 PSPSTPIP1(PAPA)41自身免疫性炎癥綜合癥PAPA綜合征炎性刺激含有cryopyrin的炎癥小體活化半42自身免疫性炎癥綜合癥42自身免疫性炎癥綜合癥43自身免疫性炎癥綜合癥43自身免疫性炎癥綜合癥自身免疫性炎癥綜合癥培訓(xùn)課件45自身免疫性炎癥綜合癥45自身免疫性炎癥綜合癥46自身免疫性炎癥綜合癥46自身免疫性炎癥綜合癥47自身免疫性炎癥綜合癥47自身免疫性炎癥綜合癥Schnitzlers syndrome 200 cases reported world wide de Koning

19、et al, 2007, Semin Arthritis Rheum48自身免疫性炎癥綜合癥Schnitzlers syndrome 200 c49自身免疫性炎癥綜合癥49自身免疫性炎癥綜合癥50自身免疫性炎癥綜合癥50自身免疫性炎癥綜合癥Schnitzler SyndromeDifferential Diagnosis51自身免疫性炎癥綜合癥Schnitzler SyndromeDifferentiaNOD2 Associated Autoinflammatory DiseasesNOD2 gene: R702W and IVS8 +158Yao et al, 2013, J Am Acad

20、 Dermatol, 68:624-3152自身免疫性炎癥綜合癥NOD2 Associated Autoinflammato53自身免疫性炎癥綜合癥53自身免疫性炎癥綜合癥Table1.Underlying mechanisms and causes of chronic urticarial rashMast cell mediatormediatedInterleukin-1-mediatedaaInterleukin-1 may also be, at least in part, mast cell-derived.Chronic spontaneous urticaria (CSU)

21、Cryopyrin-associated periodic syndrome (CAPS)CSU due to autoreactivitySchnitzlers syndrome (SchS)Other autoinflammatory disorders:NLRP12-associated cold-induced autoinflammatory syndrome (FCAS2)CSU due to functional autoantibodiesSystemic-onset juvenile idiopathic arthritis (soJIA)Adult-onset Stills

22、 disease (AOSD)Mevalonate kinase deficiency (MKD)TNF-receptor-associated periodic syndrome (TRAPS)54自身免疫性炎癥綜合癥Table1.Underlying mechanismsTable3.Clinical signs and symptoms of selected autoinflammatory diseases and possible differential diagnosesClinical signs and symptomsAutoinflammatory disorderDi

23、fferential diagnosisCAPSSchnitzlers syndromeNLRP12-associated FCASsoJIAAOSDMKDTRAPSThe clinical signs and symptoms represent a selection of common features and are found in other nonurticarial autoinflammatory diseases such as familial Mediterranean fever (FMF), periodic fever, aphthous stomatitis,

24、pharyngitis and adenitis syndrome (PFAPA), Behcets disease and others as well.Chronic urticarial rashXXXXXXXUrticaria (spontaneous or induced, e.g. cold contact urticaria)Urticarial vasculitisEye redness and painXXAllergic conjunctivitisUveitis (autoimmune, infectious)Periorbital oedemaXAngioedemaAl

25、lergic contact dermatitisSerositisXAutoimmune connective tissue disorderStomatitis, aphthaeXAllergyAutoimmune disorderInfectionAbdominal pain, diarrhoeaXXFood allergyInflammatory bowel diseaseProteinuriaXXXAutoimmune connective tissue disorderLymphadenopathyXXXXXXXInfectionMalignancyAutoimmune conne

26、ctive tissue disorderMyalgiaXXXXInfectionAutoimmune connective tissue disorderArthralgia/arthritisXXXXXXXRheumatoid arthritisJIAReactive arthritisAutoimmune connective tissue disorderHeadache and other CNS symptomsXXXMigraineFeverXXXXXXXInfectionMalignancyImmunodeficiencyAutoimmune connective tissue

27、 disorder55自身免疫性炎癥綜合癥Table3.Clinical signs and syTable4.Distinguishing criteria of chronic urticaria and autoinflammatory syndromesCharacteristics of urticarial rashChronic urticariaAutoinflammatory syndromeAppearancePapular whealsWheal-and-flare reactionFlatter wheals, erythematous patches but also more solid and stable lesionsNo wheal with surrounding flareLocalizationAsymmetrical distribution commonRather symmet