Systemic sclerosis

Abstract Systemic sclerosis ( SS c) is a multisystem autoimmune disease characterized by vasculopathy and tissue fibrosis of the skin and various internal organs. A series of genetic and epidemiological studies have demonstrated that SS c onset is determined by the accumulation of predisposing factors related to environmental influences, while genetic factors affect the susceptibility to and the severity of this disease. This notion has been confirmed by recent advance in animal models. The initial trigger of SS c is believed to be autoimmune attacks to endothelial cells, which occur in individuals with the genetic susceptibility to autoimmune diseases and/or the cumulative exposure to certain SS c‐related environmental influences. Then, endothelial cells are aberrantly activated or damaged, leading to the development of vascular structural changes, such as destructive vasculopathy and proliferative obliterative vasculopathy, and tissue fibrosis. In parallel, inflammatory cells activate SS c fibroblasts and modify the metabolism of extracellular matrix by soluble factors and autoantibodies. Prior to or during these processes, SS c fibroblasts acquire the ability to selectively respond to profibrotic growth factors and cytokines, persistently producing excessive amount of extracellular matrix. SS c fibroblasts also modify immune responses, at least those of CD 4 + T cells, in the microenvironment through the secretion of immune regulatory molecules. Thus, various types of individually activated cells interact with each other and coordinately drive an SS c‐specific disease cascade, leading to the development of unique clinical symptoms. This article provides an overview of the current understanding of the pathogenesis of SS c with the recent advance in the research field of this disease.