An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.
An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.
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激活的 NLRC4 炎性体突变会导致自身炎症，并伴有复发性巨噬细胞激活综合征。
DOI：
10.1038/ng.3089
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发表时间：
2014-10
期刊：
影响因子：
30.8
通讯作者：
Goldbach-Mansky, Raphaela
中科院分区：
文献类型：
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作者：
Canna, Scott W.;de Jesus, Adriana A.;Gounil, Sushanth;Brooks, Stephen R.;Marrero, Bernadette;Liu, Yin;DiMattia, Michael A.;Zaal, Kristien J. M.;Sanchez, Gina A. Montealegre;Kim, Hanna;Chapelle, Dawn;Plass, Nicole;Huang, Yan;Villarinol, Alejandro V.;Biancotto, Angelique;Fleisher, Thomas A.;Duncan, Joseph A.;O'Shea, John J.;Benseler, Susanne;Grom, Alexei;Deng, Zuoming;Laxer, Ronald M.;Goldbach-Mansky, Raphaela
炎性小体是先天性免疫传感器，其通过半胱天冬酶-1活化、IL-1β和IL-18分泌以及巨噬细胞焦亡来响应病原体和损伤相关信号。发现NLRP 3中的显性功能获得性突变导致Cryopyrin相关周期性Syndrome（CAPS）并触发自发性炎性小体激活和IL-1β过度分泌，导致使用IL-1阻断剂的成功治疗。在此，我们报告了一个从头错义突变，c.1009A>T，p.Thr337Ser，在炎性小体成分NLRC 4（IPAF/CARD 12）的核苷酸结合结构域，导致早发性复发性发热和巨噬细胞活化综合征（MAS）。功能分析表明自发性炎性小体形成和炎性小体依赖性细胞因子IL-1β和IL-18的产生，后者超过CAPS中的水平。NLRC 4突变引起转导细胞中的组成型半胱天冬酶-1切割，并增加患者和NLRC 4突变体巨噬细胞的IL-18产生。因此，我们描述了一种新的单等位基因炎性小体缺陷，扩展了单基因自身炎性疾病谱，包括MAS，并提出了新的治疗靶点。
Inflammasomes are innate immune sensors that respond to pathogen and damage-associated signals with caspase-1 activation, IL-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the Cryopyrin Associated Periodic Syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion, led to successful treatment with IL-1 blocking agents. Herein, we report a de novo missense mutation, c.1009A>T, p.Thr337Ser, in the nucleotide-binding domain of inflammasome component NLRC4 (IPAF/CARD12) that causes early-onset recurrent fever flares and Macrophage Activation Syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, the latter exceeding levels in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in transduced cells and increased production of IL-18 by both patient and NLRC4 mutant macrophages. Thus, we describe a novel monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests novel targets for therapy.
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影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
158.5
作者：
Lachmann, Helen J.;Kone-Paut, Isabelle;Hawkins, Philip N.
通讯作者：
Hawkins, Philip N.
影响因子：
4.4
作者：
Russell, TD;Yan, QY;Walter, MJ
通讯作者：
Walter, MJ
通过Anakinra治疗的新生儿发作多系统炎症性疾病患者的持续反应和预防损伤进展：一项同类研究，以确定三年和五年结局。
影响因子：
--
作者：
Sibley, Cailin H.;Plass, Nikki;Snow, Joseph;Wiggs, Edythe A.;Brewer, Carmen C.;King, Kelly A.;Zalewski, Christopher;Kim, H. Jeffrey;Bishop, Rachel;Hill, Suvimol;Paul, Scott M.;Kicker, Patrick;Phillips, Zachary;Dolan, Joseph G.;Widemann, Brigitte;Jayaprakash, Nalini;Pucino, Frank;Stone, Deborah L.;Chapelle, Dawn;Snyder, Christopher;Butman, John A.;Wesley, Robert;Goldbach-Mansky, Raphaela
通讯作者：
Goldbach-Mansky, Raphaela
影响因子：
2.3
作者：
Sanchez, Gina A. Montealegre;de Jesus, Adriana Almeida;Goldbach-Mansky, Raphaela
通讯作者：
Goldbach-Mansky, Raphaela