NLRP3 and IL-1
Pro-IL-1b IL-1b
Inactive
active
Schroder and Tschopp, Cell, 2010, 140:821-823
Activation of Inflammasome
Goldbach-Mansky, Clin Exp Immunol, 2012, 167:391-404
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
产生IL-1β
•炎症 •免疫细胞活化 •凋亡和组织损伤 类异戊二烯代谢
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
PAPA综合征
炎症小体
炎性 刺激
含有 cryopyrin的 炎症小体活 化 pyrin 半胱天东酶1 活化（IL-1β 转化酶）
产生IL-1β
PSPSTPIP1 (PAPA)
•炎症 •免疫细胞活化 •凋亡和组织损伤 类异戊二 烯代谢
Schnitzler’s syndrome
~ 200 cases reported world wide
产生IL-1β
半胱天东酶1 活化（IL-1β 转化酶）
IL-1阻滞剂 • Anakinra：IL-1ra拮抗剂 • Canakinumab：IL-1β单抗 • Rilonacept：IL-1Trap
•炎症 •免疫细胞活化 •组织损伤
家族性地中海热（FMF）
炎症小体 炎性 刺激 含有cryopyrin的 炎症小体活化 pyrin （FMF） 半胱天东酶1 活化（IL-1β 转化酶）
编码不同蛋白的基因突变
AID – other Cytokine Pathways
Cytokine TNF, IL-1 TNF Disease PGA Cherubism Gene NOD2 SH3BP2 Protein nod2 SH3BP2 Inherit. pattern AD AD Disease onset Early childhood Childhood, spontaneous ression by 3rd decade Neonatal or early infancy Fever pattern uncommon Uncommon Specific organ inflammation Skin, eyes, joints jaws, eyes
1. The inflammation is seemingly “unprovoked”. 2. Autoantibodies and antigen-specific T cells are absent.
AID – IL-1 Pathway
Cytokine IL-1b Disease CAPS Gene CIAS1 Protein Cryopyrin Inherit. pattern AD Disease onset 6 m, cold induced Fever pattern <24h Specific organ inflammation Skin, eyes, joints, systemic Skin, eyes, joints, inner ears, meninges (mild), systemic Skin, eyes, joints, inner ears, meningges, bony epiphyseal hyperplasia, systemic skin, bones, lungs, vasculitis Skin, eyes, joints, Systemic Skin, joints, peritoneum, pleura Skin, eyes, joints, prominent lymph nodes Bones, periosteum, anemia Skin, eyes, joints, peritoneum, pleura Skin, joints
Autoinflammatory Syndrome
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 is preferable to autoimmune in describing these disorders. ”
Goldbach-Monsky, Clin Exp Immunol, 2011, 167:391-404
隐热蛋白相关周期综合征
Cryopyrin相关周期综合征（CAPS） 炎症小体 炎性 刺激 含有cryopyrin的 炎症小体活化 （CAPS） pyrin 半胱天东酶1 活化（IL-1β 转化酶）
MWS • 荨麻疹
NOMID • 新生儿起病的荨麻疹 • 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
• 低热
• 关节炎 • 淀粉样变 • 耳聋
NLRP3炎性体基因突变
IL-1阻滞剂治疗CAPS
炎症小体 炎性 刺激 含有隐热蛋 白的炎症小 体活化
FCAS
CIAS1
Cryopyrin
AD
Infancy – adolescence
24-48h
MWS
CIAS1
Cryopyrin
AD
Neonatal or early infancy
Continuous with flares
IL-1b and IL-1a IL-1 IL-1 IL-1 IL-1 IL-1 + TNF IL-1 + TNF
1.aInterleukin-1 may also be, at least in part, mast cell-derived. Chronic spontaneous urticaria (CSU) Cryopyrin-associated periodic syndrome (CAPS) Schnitzler's syndrome (SchS) CSU due to autoreactivity Other autoinflammatory disorders: NLRP12-associated cold-induced autoinflammatory syndrome (FCAS2)
McDermott, et al., Cell. 1999 Apr 2;97(1):133-44.
“Autoinflammatory” Disease
At 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:
产生IL-1β
•炎症 •免疫细胞活化 •凋亡和组织损伤
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
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
140 120 100 80 60 40 20 0
Oct-06
Dec-06
Feb-07
Apr-07
Jun-07
IgM (mg/dl)
1800
1200
600
0 Jan-07 Mar-07 May-07 Jul-07
NOD2 Associated Autoinflammatory Diseases
NOD2 gene: R702W and IVS8 +158
de Koning et al, 2007, Semin Arthritis Rheum
Schnitzler Syndrome Differential Diagnosis
CRP (mg/L)14来自 12010080 60 40 20 0
Aug-06 Nov-06 Feb-07 May-07
ESR
Yao et al, 2013, J Am Acad Dermatol, 68:624-31
Table 1. Underlying mechanisms and causes of chronic urticarial rash Mast cell mediator–mediated Interleukin-1-mediateda
DIRA FCAS FMF HIDS Majeed’s syndrome TRAPS
IL-1RN NLRP12 MEFV MVK LPIN2 TNFRSF1A
IL-1Ra NLRP12 Pyrin Mevalonate kinase lipin2 TNFR1