1、Autoinflammatory - 1999“ The autosomal dominant periodic fevers therefore represent a class of human disease shown to be caused by mutations in TNF receptors. Autoantibodies are not a general feature of these illnesses or the recessively inherited FMF, and for this reason the term autoinflammatory i
2、s preferable to autoimmune in 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;97(1):133-44.“Autoinflammatory” DiseaseAt the time,
3、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 autoimmune disease are unfulfilled in autoinflammatory disorders: The inflammation is seemingly “
4、unprovoked”. Autoantibodies and antigen-specific T cells are absent.CytokineDisease GeneProteinInherit. patternDisease onsetFever patternSpecific organ inflammationIL-1b bCAPSFCASMWSCIAS1CIAS1CIAS1CryopyrinCryopyrinCryopyrinADADAD6 m, cold induced Infancy adolescenceNeonatal or early infancy24h24-48
5、hContinuous with flaresSkin, eyes, joints,systemicSkin, eyes, joints, inner ears, meninges (mild),systemicSkin, eyes, joints, inner ears, meningges, bony epiphyseal hyperplasia,systemicIL-1b b and IL-1a aDIRAIL-1RNIL-1RaARNeonatal or early infancyContinuous with flaresskin, bones, lungs, vasculitisI
6、L-1FCASNLRP12NLRP12ADNeonatal or early infancyContinous with flaresSkin, eyes, joints,SystemicIL-1FMFMEFVPyrinAR80% 20yo1-3 daysSkin, joints, peritoneum, pleuraIL-1HIDSMVKMevalonate kinaseAR 6 months3-7 daysSkin, eyes, joints, prominent lymph nodesIL-1Majeeds syndromeLPIN2lipin2AR1-19 mWeeks-monthsB
7、ones, periosteum, anemiaIL-1 + TNFIL-1 + TNFTRAPSPAPATNFRSF1ACD2BP1TNFR1PSTPIP1ADAD3 yearsEarly childhood1-4 weeksCommonSkin, eyes, joints, peritoneum, pleuraSkin, jointsAID IL-1 PathwayGoldbach-Monsky, Clin Exp Immunol, 2011, 167:391-404Pro-IL-1b bIL-1b bInactiveactiveNLRP3 and IL-1Schroder and Tsc
8、hopp, 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CytokineDisease GeneProteinInherit. patternDisease onsetFever patternSpecific organ inflammationTNF, IL-1PGANOD2nod2ADEarly childhooduncommonSkin, eyes, jointsTNFCherubism
9、SH3BP2SH3BP2ADChildhood, 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 flaresColitis with fistula formation, folliculitis in patients with IL-10RB mutationsIL-36a
10、, 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-proteasomeAR Neonatal or early infancyContinuous with flaresSkin, joints, lipodystrophy
11、and muscle atrophyAID other Cytokine PathwaysGoldbach-Monsky, Clin Exp Immunol, 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
12、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CAPS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NLRP3炎性体基因突变炎性体基因突变IL-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
13、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-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： NSAIDs： 秋水仙碱：秋水仙碱：减缓减缓WBC趋化和炎性因子产生，预防淀粉样趋化和炎性因子产生，预防淀粉样变神经病变变神经病变 IL-1拮抗剂拮抗剂 预后：预后： 1个基因突变：治疗
14、反应良好个基因突变：治疗反应良好 H478Y MEFV variant：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）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）P
15、APAPAPA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)Schnitzlers syndrome 200 cases reported world wide de Koning et al, 2007, Semin Arthritis RheumSchnitzler SyndromeDifferential DiagnosisNOD2 Associated Autoinflammatory DiseasesNOD2 gene: R702W a
16、nd IVS8 +158Yao et al, 2013, J Am Acad Dermatol, 68:624-31Table 1. 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)Cryopyrin-associated perio
17、dic 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 disease (AOSD)Mevalonate
18、kinase deficiency (MKD)TNF-receptor-associated periodic syndrome (TRAPS)Table 3. Clinical signs and symptoms of selected autoinflammatory diseases and possible differential diagnosesClinical signs and symptomsAutoinflammatory disorderDifferential diagnosisCAPSSchnitzlers syndromeNLRP12-associated FC
19、ASsoJIAAOSDMKDTRAPSThe 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, pharyngitis and adenitis syndrome (PFAPA), Behcets disease and o
20、thers as well.Chronic urticarial rashXXXXXXXUrticaria (spontaneous or induced, e.g. cold contact urticaria)Urticarial vasculitisEye redness and painX X Allergic conjunctivitisUveitis (autoimmune, infectious)Periorbital oedema XAngioedemaAllergic contact dermatitisFlatter wheals, erythematous patches
21、 but also more solid and stable lesionsNo wheal with surrounding flareLocalizationAsymmetrical distribution commonRather symmetrical distributionDuration of single lesionTransient (minutes or few hours)Hours, up to 24 hPruritusSevereMay be absent, rather burning or painfulAngioedemaOften associatedR
22、areSkin histopathologyDermal oedema; partly sparse inflammatory infiltrate of perivascular eosinophils, neutrophils and lymphocytesNo significant dermal oedema; dense neutrophil-rich perivascular and interstitial infiltrates, but can also be rather nonspecificStart of symptomsAll agesChildhood (here
23、ditary fever syndromes)Adulthood (acquired complex disorders)Disease durationFew yearsUsually life-longResponse to antihistaminesModerate goodDose dependentMissingSystemic symptomsNoneRecurrent fever, fatigue, arthralgia and othersInflammation markersWithin normal range(Continuously) elevatedFamily historyNegativeOften positive
