From the clinical standpoint, systemic sclerosis (SSc) is characterized by skin and internal organ fibrosis, diffuse fibroproliferative vascular modifications, and autoimmunity. Clinical presentation and course are highly heterogenous and life expectancy variably affected mostly dependent on lung and heart involvement. SSc touches more women than men with differences in disease severity and environmental exposure. Pathogenetic events originate from altered homeostasis favored by genetic predisposition, environmental cues and a variety of endogenous and exogenous triggers. Epigenetic modifications modulate SSc pathogenesis which strikingly associate profound immune-inflammatory dysregulation, abnormal endothelial cell behavior, and cell trans-differentiation into myofibroblasts. SSc myofibroblasts show enhanced survival and enhanced extracellular matrix deposition presenting altered structure and altered physicochemical properties. Additional cell types of likely pathogenic importance are pericytes, platelets, and keratinocytes in conjunction with their relationship with vessel wall cells and fibroblasts. In SSc, the profibrotic milieu is favored by cell signaling initiated in the one hand by transforming growth factor-beta and related cytokines and in the other hand by innate and adaptive type 2 immune responses. Radical oxygen species and invariant receptors sensing danger participate to altered cell behavior. Conventional and SSc-specific T cell subsets modulate both fibroblasts as well as endothelial cell dysfunction. Beside autoantibodies directed against ubiquitous antigens important for enhanced clinical classification, antigen-specific agonistic autoantibodies may have a pathogenic role. Recent studies based on single-cell RNAseq and multi-omics approaches are revealing unforeseen heterogeneity in SSc cell differentiation and functional states. Advances in system biology applied to the wealth of data generated by unbiased screening are allowing to subgroup patients based on distinct pathogenic mechanisms. Deciphering heterogeneity in pathogenic mechanisms will pave the way to highly needed personalized therapeutic approaches.

从临床角度来看，系统性硬化症 (SSc) 的特征是皮肤和内脏器官纤维化、弥漫性纤维增生性血管改变和自身免疫。临床表现和病程具有高度异质性，预期寿命的不同程度影响主要取决于肺和心脏受累情况。SSc 接触的女性多于男性，在疾病严重程度和环境暴露方面存在差异。致病事件源于遗传易感性、环境线索和各种内源性和外源性触发因素所支持的体内平衡改变。表观遗传修饰调节 SSc 发病机制，后者与严重的免疫炎症失调、异常内皮细胞行为和细胞转分化为肌成纤维细胞显着相关。SSc 肌成纤维细胞显示出增强的存活率和增强的细胞外基质沉积，呈现出改变的结构和改变的物理化学性质。其他可能具有致病重要性的细胞类型是周细胞、血小板和角质形成细胞，以及它们与血管壁细胞和成纤维细胞的关系。在 SSc 中，一方面通过转化生长因子-β 和相关细胞因子启动的细胞信号传导有利于促纤维化环境，另一方面通过先天性和适应性 2 型免疫反应启动。自由基氧和感知危险的不变受体参与改变细胞行为。常规和 SSc 特异性 T 细胞亚群调节成纤维细胞和内皮细胞功能障碍。除了针对对增强临床分类很重要的普遍存在抗原的自身抗体外，抗原特异性激动性自身抗体可能具有致病作用。最近基于单细胞 RNAseq 和多组学方法的研究揭示了 SSc 细胞分化和功能状态中不可预见的异质性。系统生物学的进步应用于无偏倚筛查产生的大量数据，允许根据不同的致病机制对患者进行亚组分析。破译致病机制的异质性将为急需的个性化治疗方法铺平道路。系统生物学的进步应用于无偏倚筛查产生的大量数据，允许根据不同的致病机制对患者进行亚组分析。破译致病机制的异质性将为急需的个性化治疗方法铺平道路。系统生物学的进步应用于无偏倚筛查产生的大量数据，允许根据不同的致病机制对患者进行亚组分析。破译致病机制的异质性将为急需的个性化治疗方法铺平道路。