Current perspectives on the immunopathogenesis of systemic sclerosis

Abstract

Systemic sclerosis (SSc or scleroderma) is a progressive and highly debilitating autoimmune disorder characterized by inflammation, vasculopathy, and extensive fibrosis. SSc is highly heterogeneous in its clinical presentation, extent and severity of skin and internal organ involvement, and clinical course and has the highest fatality rate among connective tissue diseases. While clinical outcomes have improved in recent years, no current therapy is able to reverse or slow the natural progression of SSc, a reflection of its complex pathogenesis. Although activation of the immune system has long been recognized, the mechanisms responsible for the initiation of autoimmunity and the role of immune effector pathways in the pathogenesis of SSc remain incompletely understood. This review summarizes recent progress in disease pathogenesis with particular focus on the immunopathogenetic mechanisms of SSc.

Keywords: autoimmunity; immune mediators; inflammation; scleroderma.

Figure 1

Etiopathogenesis of SSc. Notes: Environmental and genetic factors contribute to the etiology of SSc. The pathogenesis of SSc involves an interplay between vascular, immunological, and fibrotic processes. Vascular injury and endothelial damage are the earliest events in the pathogenesis of SSc. Activated endothelial cells upregulate the expression of adhesion molecules and secrete chemokines, leading to inflammation and autoimmunity. Macrophages and T-cells are the predominant inflammatory cell types of the inflammatory infiltrates and produce cytokines and growth factors that drive the synthesis of extracellular matrix proteins by fibroblasts, resulting in progressive fibrosis. T-cells have also been implicated in autoantibodies production. Abbreviations: ECM, extracellular matrix; IFN, interferon; IL, interleukin; MMP-1, matrix metalloproteinases-1; PDGF, platelet-derived growth factor; SSc, systemic sclerosis; TGFβ, transforming growth factor beta; Treg, T-regulatory cell; ?, role unknown.