Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling.
Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling.
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DOI：
10.1146/annurev-immunol-032414-112227
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发表时间：
2015
影响因子：
29.7
通讯作者：
Goldbach-Mansky R
中科院分区：
文献类型：
--
作者：
de Jesus AA;Canna SW;Liu Y;Goldbach-Mansky R
自身炎性疾病患者表现为非感染性发热和全身性和/或疾病特异性器官炎症。他们过度的促炎细胞因子和趋化因子反应可能危及生命，并随着时间的推移导致器官损伤。对这些患者的研究揭示了遗传缺陷，这些缺陷有助于解开关键的先天免疫途径，包括过度的IL-1信号传导、组成性NF-κB激活以及最近的慢性I型IFN信号传导。导致促炎细胞因子活化的单基因缺陷的发现激发了抗细胞因子导向治疗方法的使用，这些方法已经改变了许多患者的生活，并导致IL-1阻断剂被批准用于许多自身炎性病症。在这篇综述中，我们描述了具有遗传特征的自身炎症性疾病，我们总结了我们对驱动临床表型的分子途径的理解，并继续激发寻找新的治疗靶点，我们提供了一个分类的概念框架。
Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and/or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-κB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification.