1、Autoinflammatory SyndromeAutoinflammatory-1999“The autosomal dominant periodic fevers therefore“The autosomal dominant periodic fevers therefore represent a class of human disease shown to be caused represent a class of human disease shown to be caused by mutations in TNF receptors.Autoantibodies ar
2、e not by mutations in TNF receptors.Autoantibodies are not a general feature of these illnesses or the a general feature of these illnesses or the recessively inherited FMF,and for this reason the recessively inherited FMF,and for this reason the termtermautoinflammatoryautoinflammatory is preferabl
3、e to is preferable to autoimmuneautoimmune in in describing these disorders.”describing these disorders.”“Germline mutations in the extracellular domains of the 55 kDa“Germline mutations in the extracellular domains of the 55 kDa TNF receptor,TNFR1,define a family of dominantly inherited TNF recepto
4、r,TNFR1,define a family of dominantly inherited autoinflammatory syndromes.”autoinflammatory syndromes.”McDermott,et al.,Cell.1999 Apr 2;97(1):133-44.McDermott,et al.,Cell.1999 Apr 2;97(1):133-44.“Autoinflammatory”DiseaseAt the time,autoinflammatory was coined to distinguish diseases involving innat
5、e immune dysregulation(FMF&TRAPS)from autoimmune diseases known to involve adaptive immune dysregulation(SLE&RA).Two premises of autoimmune disease are unfulfilled in autoinflammatory disorders:The inflammation is seemingly“unprovoked”.Autoantibodies and antigen-specific T cells are absent.AID IL-1
6、PathwayGoldbach-Monsky,Clin Exp Immunol,2011,167:391-404Pro-IL-1b bIL-1b bInactiveactiveNLRP3 and IL-1Schroder and Tschopp,Cell,2010,140:821-823Goldbach-Mansky,Clin Exp Immunol,2012,167:391-404Activation of Inflammasome编码不同蛋白的基因突变编码不同蛋白的基因突变AID other Cytokine PathwaysGoldbach-Monsky,Clin Exp Immunol
7、,2011,167:391-404隐热蛋白相关周期综合征隐热蛋白相关周期综合征Cryopyrin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CAPSCAPS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
8、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NLRP3炎性体基因突变炎性体基因突变IL-1IL-1阻滞剂治疗阻滞剂治疗CAPSCAPS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 Canaki
9、numab：IL-1单抗单抗 Rilonacept：IL-1Trap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）炎症小体炎症小体治疗：治疗：NSAIDsNSAIDs：秋水仙碱：秋水仙碱：减缓减缓WBCWBC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-1IL-1拮抗剂拮抗剂 预后：预后：1 1个基因突变：治疗反应良好个基因突变：治疗反应良好 H478Y MEFV variantH478Y MEFV variant：秋水
10、仙碱无效：秋水仙碱无效 M694VM694V突变：易淀粉样变突变：易淀粉样变激素有效（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MKDMKD（高（高IgDIgD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）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（TRAPSTRAPS）PAPAPAPA综合征综合征炎性刺激含有cryopy
11、rin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)Schnitzlers syndrome 200 cases reported world wide de Koning et al,2007,Semin Arthritis RheumSchnitzler SyndromeDifferential DiagnosisNOD2 Associated Autoinflammatory DiseasesNOD2 gene:R702W and IVS8+158Yao et al,2013,J Am Acad Dermatol,68:624-31
