Beyond the NLRP3 Inflammasome Autoinflammatory Diseases Reach Adolescence
Beyond the NLRP3 Inflammasome Autoinflammatory Diseases Reach Adolescence
复制标题
DOI：
10.1002/art.37882
复制
发表时间：
2013-05-01
影响因子：
--
通讯作者：
Martini, Alberto
中科院分区：
文献类型：
--
作者：
Gattorno, Marco;Martini, Alberto
自 MEFV 被鉴定为导致家族性地中海热 (FMF) 的基因以来，已经过去 15 年了 (1, 2)。这一发现是鉴定许多其他遗传疾病分子缺陷的第一步，这些疾病统称为自身炎症性疾病，其特征是继发于先天免疫系统明显失调的慢性炎症。出于多种原因，自身炎症性疾病的鉴定代表了临床医学的最新重大进展。首先，在未来的几年里，许多其他原因不明的罕见炎症综合征很可能会成为具有明确遗传病因的自身炎症性疾病，因此具有潜在的靶向治疗。其次，这些疾病的遗传基础的发现已被证明是发现调节先天免疫以及可能涉及许多其他炎症性疾病的新机制的有力工具。第三，越来越清楚的是，几种常见的多因素疾病具有很强的自身炎症成分，可以使用与自身炎症性疾病相同的疗法成功地靶向这些成分。最初发现的与自身炎症性疾病相关的最典型的临床特征是反复发作发热，随后出现持续时间不等的无症状期。因此，这些疾病通常被定义为周期性发烧。关于这些疾病的功能后果的第一个研究揭示了内源性和外源性刺激导致的先天免疫系统细胞异常激活的主要致病作用。与自身免疫性风湿性疾病相比，这组疾病的特点是免疫反应的适应性分支具有明显的次要作用，如循环自身抗体和/或自身反应性 T 细胞的缺乏以及与 II 类主要组织相容性复合体分子缺乏明确关联所表明的那样 (3)。正如我们将在下面讨论的，这些疾病的原型是继发于 NLRP3 基因（或冷冻蛋白）突变的一小群疾病，NLRP3 基因是 NLRP3 炎性体的关键组成部分。对这种多蛋白细胞内复合物激活机制的研究代表了理解炎症发展的一个里程碑，不仅在罕见的遗传性疾病中，而且在大范围的多因素疾病中。在过去 15 年中，许多其他自身炎症性疾病及其相关基因缺陷已被确定（表 1）。新疾病的临床异质性表明，除了周期性发热的“经典”表型（皮疹、关节痛/肌痛和胸/腹痛）之外，多种临床表现可能与这组疾病相关（表2）。这些不同的表现取决于所涉及的基因以及该基因所在的细胞和组织
Fifteen years have elapsed since the identification of MEFV as the gene responsible for familial Mediterranean fever (FMF)(1, 2). This finding was the first step forward in the identification of the molecular defect in a number of other genetic diseases, which are collectively known as the autoinflammatory diseases and are characterized by chronic inflammation secondary to a marked dysregulation of the innate immune system. The identification of autoinflammatory diseases represents a major recent advance in clinical medicine for several reasons. First, it is very probable that in the years to come, many other rare inflammatory syndromes of unknown cause will turn out to be autoinflammatory diseases with a defined genetic etiology and, therefore, with potential targeted therapies. Second, the discovery of the genetic basis of these diseases has proven to be a powerful tool for discovering new mechanisms that regulate innate immunity and that can be involved in many other inflammatory conditions. Third, it has become increasingly clear that several common multifactorial diseases have a strong autoinflammatory component that can be successfully targeted with the same therapies that are used in autoinflammatory diseases.The most typical clinical feature associated with the autoinflammatory diseases that was initially identified was the occurrence of recurrent bouts of fever followed by symptom-free periods of variable duration. For this reason, these disorders were generically defined as periodic fevers. The first studies on the functional consequences of these disorders revealed the primary pathogenic role of an abnormal activation of the cells of the innate immune system by endogenous and exogenous stimuli. Compared to autoimmune rheumatic conditions, this group of diseases is characterized by an apparent secondary role of the adaptive branch of the immune response, as suggested by the lack of circulating autoantibodies and/or self-reactive T cells and by the absence of a clear association with class II major histocompatibility complex molecules (3). As we will discuss below, a prototype of these diseases was a small group of disorders occurring secondary to mutations in the NLRP3 gene (or cryopyrin), a pivotal component of the NLRP3 inflammasome. The study of the mechanisms of activation of this multiprotein intracellular complex represented a milestone for the understanding of the development of inflammation not only in rare inherited diseases, but also in a large spectrum of multifactorial disorders. During the last 15 years, many other autoinflammatory diseases and their associated gene defects have been identified (Table 1). The clinical heterogeneity of the new diseases showed that, besides the “classic” phenotype of periodic fevers (skin rash, arthralgia/myalgia, and chest/abdominal pain), a variety of clinical manifestations may be associated with this group of conditions (Table 2). These different manifestations depend on the gene that is involved and on the cells and tissues in which that gene