自身免疫性炎症综合症培训课件

1、自身免疫性炎症综合症自身免疫性炎症综合症2自身免疫性炎症综合症2自身免疫性炎症综合症3自身免疫性炎症综合症3自身免疫性炎症综合症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自身免疫性炎症综合症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自身免疫性炎症综合症“Autoinflammatory” DiseaseAt t6自身免疫性炎症综合症6自身免疫性炎症综合症7自身免疫性炎症综合症7自身免疫性炎症综合症8自身免疫性炎症综合症8自身免疫性炎症综合症9自身免疫性炎症综合症9自身免疫性炎症综合症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自身免疫性炎症综合症CytokineDisease GeneProteinInhPro-IL-1bIL-1bInactiveactiveNLRP3 and IL-1Schroder and Tschopp, Cell, 2010, 140:821-82311自身免疫性炎症综合症Pro-IL-1b

9、IL-1bInactiveactiveNLGoldbach-Mansky, Clin Exp Immunol, 2012, 167:391-404Activation of Inflammasome12自身免疫性炎症综合症Goldbach-Mansky, Clin Exp Immu13自身免疫性炎症综合症13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编码不同蛋白的基因突变14自身免疫性炎症综合症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自身免疫性炎症综合症CytokineDisease GeneProteinInh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17自身免疫性炎症综合症17自身免疫性炎症综合症Cryopyrin

13、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cryopyrin作用：尚未完全阐明降低炎症活化的阈值，使炎症触发更加敏感炎症的启动正常，但炎症的关闭被干扰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cr19自身免疫性炎症综合症19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FCAS 寒冷诱发的荨麻疹 发热 关节痛MWS 荨麻疹 低热 关节炎 淀粉样变 耳聋NOMID 新生儿起病的荨麻疹

14、发热 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FCASMWNLRP3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22自身免疫性炎症综合症22自身免疫性炎症综合症23自身免疫性炎症综合症23自身免疫性炎症综合症24自身免疫性炎症综合症24自身免疫性炎症综合症25自身免疫性炎症综合症25自身免疫性炎症综合症26自身免疫性炎症综合症26自身免疫性炎症综合症27自身免疫性炎症综合症27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半胱天东酶

15、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IL-1阻滞剂 Anakinra：IL-1ra拮抗剂 Canakinumab：IL-1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29自身免疫性炎症综合症29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31自身免疫性

16、炎症综合症31自身免疫性炎症综合症治疗：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H478Y MEFV variant：秋水仙碱无效M694V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MKD（高IgD综合征，HIDS）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

17、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cryopyr35自身免疫性炎症综合症35自身免疫性炎症综合症36自身免疫性炎症综合症36自身免疫性炎症综合症37自身免疫性炎症综合症37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39自身免疫性炎症综合症39自身免疫性炎症综合症40自身免疫性炎症综合症40自身免疫性炎症综合症PAPA综合征炎性刺激含有cryopyrin的炎症小体活化半胱天东酶1活

18、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42自身免疫性炎症综合症42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自身免疫性炎症综合症培训课件45自身免疫性炎症综合症45自身免疫性炎症综合症46自身免疫性炎症综合症46自身免疫性炎症综合症47自身免疫性炎症综合症47自身免疫性炎症综合症Schnitzlers syndrome 200 cases reported world wide de Koning

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

20、 Dermatol, 68:624-3152自身免疫性炎症综合症NOD2 Associated Autoinflammato53自身免疫性炎症综合症53自身免疫性炎症综合症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自身免疫性炎症综合症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自身免疫性炎症综合症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