1、自身免疫性炎症综合自身免疫性炎症综合症症2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 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 th
2、is reason the term autoinflammatory is 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):133-44.4自身免疫性炎症综
3、合症“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 autoimmune disease are unfulfilled in autoinflammatory disorders:
4、1.The inflammation is seemingly“unprovoked”.2.Autoantibodies and antigen-specific T cells are absent.5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8自身免疫性炎症综合症9自身免疫性炎症综合症CytokineDisease GeneProteinInherit.patternDisease onsetFever patternSpecific organ inflammationIL-1b bCAPSFCASMWSCIAS1CIAS1CIAS1CryopyrinCryopyr
5、inCryopyrinADADAD6 m,cold induced Infancy adolescenceNeonatal or early infancy24h24-48hContinuous 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-1RaARNeon
6、atal or early infancyContinuous with flaresskin,bones,lungs,vasculitisIL-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 l
7、ymph nodesIL-1Majeeds syndromeLPIN2lipin2AR1-19 mWeeks-monthsBones,periosteum,anemiaIL-1+TNFIL-1+TNFTRAPSPAPATNFRSF1ACD2BP1TNFR1PSTPIP1ADAD3 yearsEarly childhood1-4 weeksCommonSkin,eyes,joints,peritoneum,pleuraSkin,jointsAID IL-1 PathwayGoldbach-Monsky,Clin Exp Immunol,2011,167:391-40410自身免疫性炎症综合症Pr
8、o-IL-1b bIL-1b bInactiveactiveNLRP3 and IL-1Schroder and Tschopp,Cell,2010,140:821-82311自身免疫性炎症综合症Goldbach-Mansky,Clin Exp Immunol,2012,167:391-404Activation of Inflammasome12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 patternS
9、pecific organ inflammationTNF,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 wit
10、h flaresColitis 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-pr
11、oteasomeAR 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隐热蛋白相关周期综合征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
12、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18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
13、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20自身免疫性炎症综合症NLRP3炎性体基因突变炎性体基因突变21自身免疫性炎症综合症22自身免疫性炎症综合症23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26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 C
14、anakinumab：IL-1单抗单抗 Rilonacept：IL-1Trap28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（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30自身免疫性炎症综合症31自身免疫性炎症综合症治疗：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：治疗反应良好个基因突变：治疗反应良好 H
15、478Y 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32自身免疫性炎症综合症激素有效（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33自身免疫性炎症综合症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）34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
16、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（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39自身免疫性炎症综合症40自身免疫性炎症综合症PAPAPAPA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)41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45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Schnitzlers syndrome 200 cases re
17、ported world wide de Koning et al,2007,Semin Arthritis Rheum48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Schnitzler SyndromeDifferential Diagnosis51自身免疫性炎症综合症NOD2 Associated Autoinflammatory DiseasesNOD2 gene:R702W and IVS8+158Yao et al,2013,J Am Acad Dermatol,68:624-3152自身免疫性炎症综合症53自身免疫性炎症综合症Table 1.Underly
18、ing mechanisms and causes of chronic urticarial rashMast cell mediatormediatedInterleukin-1-mediateda1.aInterleukin-1 may also be,at least in part,mast cell-derived.Chronic spontaneous urticaria(CSU)Cryopyrin-associated periodic syndrome(CAPS)CSU due to autoreactivitySchnitzlers syndrome(SchS)Other
19、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 kinase deficiency(MKD)TNF-receptor-associated periodic syndrome(TRAPS)54自身免疫性炎症综
20、合症Table 3.Clinical signs and symptoms of selected autoinflammatory diseases and possible differential diagnosesClinical signs and symptomsAutoinflammatory disorderDifferential diagnosisCAPSSchnitzlers syndromeNLRP12-associated FCASsoJIAAOSDMKDTRAPS1.The clinical signs and symptoms represent a select
21、ion 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 others as well.Chronic urticarial rashXXXXXXXUrticaria(spontaneous or induce
22、d,e.g.cold contact urticaria)Urticarial vasculitisEye redness and painX X Allergic conjunctivitisUveitis(autoimmune,infectious)Periorbital oedema XAngioedemaAllergic contact dermatitis55自身免疫性炎症综合症Flatter wheals,erythematous patches but also more solid and stable lesionsNo wheal with surrounding flar
23、eLocalizationAsymmetrical distribution commonRather symmetrical distributionDuration of single lesionTransient(minutes or few hours)Hours,up to 24 hPruritusSevereMay be absent,rather burning or painfulAngioedemaOften associatedRareSkin histopathologyDermal oedema;partly sparse inflammatory infiltrat
24、e 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(hereditary 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 positive56自身免疫性炎症综合症57自身免疫性炎症综合症58自身免疫性炎症综合症59自身免疫性炎症综合症
