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Autoinflammation: Lessons from the study of familial Mediterranean fever.
Journal of Autoimmunity ( IF 12.8 ) Pub Date : 2019-07-20 , DOI: 10.1016/j.jaut.2019.102305
Panagiotis Skendros 1 , Charalampos Papagoras 1 , Ioannis Mitroulis 1 , Konstantinos Ritis 1
Affiliation  

Autoinflammatory disorders represent a heterogeneous group of systemic inflammatory diseases caused by genetic or acquired defects in key components of the innate immunity. Familial Mediterranean fever (FMF) is the most common among the other clinical phenotypes of the rare hereditary periodic fevers (HPFs) syndromes. FMF is associated with mutations in the MEFV gene encoding pyrin and is characterized by recurrent, often stress-provoked attacks of fever and serositis, but sometimes also by chronic subclinical inflammation. FMF is prevalent in Greece and other countries of the eastern Mediterranean region. Over the last 17 years, our group has focused on FMF as a model suitable for the research on innate immunity and particularly the role of neutrophils. Therefore, the study of Greek patients with FMF has yielded lessons across several levels: the epidemiology of the disease in Greece, the spectrum of its clinical manifestations and potential overlaps with other idiopathic inflammatory conditions, the demonstration of its rather complex and heterogeneous genetic background and the suggestion of a novel mechanism involved in the crosstalk between environmental stress and inflammation. Mechanistically, during FMF attack, neutrophils release chromatin structures called neutrophil extracellular traps (NETs), which are decorated with bioactive IL-1β. REDD1 (regulated in development and DNA damage responses 1), that encodes a stress-related mTOR repressor, has been found to be the most significantly upregulated gene in neutrophils during disease attacks. Upon adrenergic stress, REDD1-induced autophagy triggers a pyrin-driven IL-1β maturation, and the release of IL-1β-bearing NETs. Consequently, not only the mode of action of IL-1β-targeting therapies is explained, but also new treatment prospects emerge with the evaluation of old or the design of new drugs targeting autophagy-induced NETosis. Information gained from FMF studies may subsequently be applied in more complex but still relevant inflammatory conditions, such as adult-onset Still's disease, gout, ulcerative colitis and Behçet's disease.

中文翻译:

自发炎症:研究家族性地中海热的经验教训。

自身炎性疾病代表由先天性免疫的关键组成部分的遗传或获得性缺陷引起的系统性炎性疾病的异质性组。在罕见的遗传性周期性发烧(HPFs)综合征的其他临床表型中,家族性地中海热(FMF)是最常见的。FMF与编码吡啶的MEFV基因突变有关,其特征是发烧和浆膜炎的反复发作(通常是由压力引起),但有时也表现为慢性亚临床炎症。FMF在希腊和东地中海地区的其他国家中很普遍。在过去的17年中,我们小组一直将FMF视为适合于先天免疫尤其是嗜中性粒细胞作用研究的模型。因此,对希腊FMF患者的研究产生了以下几个方面的经验教训:该病在希腊的流行病学,其临床表现的范围以及与其他特发性炎症性疾病的潜在重叠,其相当复杂且异质的遗传背景的证明以及暗示环境压力与炎症之间相互影响的新机制的暗示。从机制上讲,在FMF攻击过程中,嗜中性粒细胞释放出染色质结构,称为中性粒细胞胞外陷阱(NETs),并被具有生物活性的IL-1β修饰。REDD1(在发育和DNA损伤反应中受到调节1),它编码与压力相关的mTOR阻遏物,是疾病发作期间嗜中性粒细胞中最显着上调的基因。在肾上腺素应激时,REDD1诱导的自噬触发了由吡啶驱动的IL-1β成熟,并释放了带有IL-1β的NETs。因此,不仅说明了靶向IL-1β的疗法的作用方式,而且随着针对自噬引起的NETosis的旧药物或新药物的评估,新的治疗方法也应运而生。从FMF研究中获得的信息可随后应用于更复杂但仍具有相关性的炎性疾病,例如成人发作的Still病,痛风,溃疡性结肠炎和Behçet病。
更新日期:2019-11-18
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