Institut Cochin, Inserm U1016, CNRS UMR 8104,Université de Paris, Paris, France; Service de Médecine Interne, Centre de Référence Maladies Systémiques Autoimmunes Rares d'Ile de France, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Institut Cochin, Inserm U1016, CNRS UMR 8104,Université de Paris, Paris, France.
Presse Med. 2021 Apr;50(1):104087. doi: 10.1016/j.lpm.2021.104087. Epub 2021 Oct 28.
Systemic sclerosis (SSc) is a rare connective tissue disease characterized by vascular remodeling, fibroblast activation and extra-cellular matrix production in excess and autoimmunity. Environmental factors including mainly silica and solvents have been assumed to contribute to the development of SSc, together with genetic factors including gene variants implicated in innate immunity such as IRF5 and STAT4, and epigenetic factors including histone post-translational modifications, DNA hypomethylation, and microRNAs or long- non coding RNAs system were reported to participate in immune activation and fibrosis processes in patients with SSc. A number of animal models of SSc have been set up over the years, including genetic and induced SSc models. These models, together with data obtained from human SSc patients, contributed to better understand the mechanisms contributing to vasculopathy and fibrosis. Alongside the pathophysiological process of SSc, several cellular and molecular actors are involved, such as dysregulations in the innate and adaptive immune cells, of the fibroblast, the implication of pro-inflammatory and pro-fibrosing signaling pathways such as the Wnt, TGF-β pathways or other cytokines, with a strong imprint of oxidative stress. The whole lead to the overactivity of the fibroblast with genetic dysregulation, apoptosis defect, hyperproduction of elements of extracellular matrix, and finally the phenomena of vasculopathy and fibrosis. These advances contribute to open new therapeutic areas through the design of biologics and small molecules.
系统性硬化症（SSc）是一种罕见的结缔组织疾病，其特征是血管重构、成纤维细胞激活和细胞外基质过度产生以及自身免疫。环境因素，包括主要的二氧化硅和溶剂，被认为与遗传因素共同导致 SSc 的发生，其中包括与先天免疫相关的基因变异，如 IRF5 和 STAT4，以及表观遗传因素，如组蛋白翻译后修饰、DNA 低甲基化、微 RNA 或长非编码 RNA 系统，据报道这些因素参与了 SSc 患者的免疫激活和纤维化过程。多年来已经建立了许多 SSc 的动物模型，包括遗传和诱导性 SSc 模型。这些模型以及从人类 SSc 患者获得的数据有助于更好地理解导致血管病变和纤维化的机制。除了 SSc 的病理生理过程外，还涉及到几种细胞和分子因素，如先天和适应性免疫细胞的失调、成纤维细胞的失调、促炎和促纤维化信号通路的参与，如 Wnt、TGF-β 通路或其他细胞因子，以及强烈的氧化应激印记。所有这些都导致成纤维细胞过度活跃，出现基因失调、凋亡缺陷、细胞外基质成分过度产生，最终出现血管病变和纤维化。这些进展通过生物制剂和小分子的设计为开辟新的治疗领域做出了贡献。
