Pathophysiology of systemic sclerosis

Abstract

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.

Keywords: Autoimmunity; Endothelium; Fibroblasts; Pathophysiology; Systemic sclerosis.