B lymphocytes in systemic sclerosis: Abnormalities and therapeutic targets.

Abstract

Systemic sclerosis (SSc) is a connective tissue disease characterized by excessive extracellular matrix deposition in the skin and visceral organs with an autoimmune background. Although the pathogenic relationship between systemic autoimmunity and the clinical manifestations remains unknown, SSc patients have immunological abnormalities including the production of disease-specific autoantibodies. Recent studies have demonstrated that B cells play a crucial role in systemic autoimmunity and disease expression via various functions in addition to autoantibody production. Recent studies show that B cells from SSc patients demonstrate an upregulated CD19 signaling pathway, which is a crucial regulator of B-cell activation, that induces SSc-specific autoantibody production in SSc. In addition, B cells from SSc patients exhibit an overexpression of CD19. Consistently, in CD19 transgenic mice, CD19 overexpression induces SSc-specific autoantibody production. SSc patients have also intrinsic B-cell abnormalities characterized by chronic hyperreactivity of memory B cells, possibly due to CD19 overexpression. Similarly, B cells from a tight-skin mouse, a genetic model of SSc, show augmented CD19 signaling and chronic hyperreactivity. Furthermore, in bleomycin-induced SSc model mice, endogenous ligands for Toll-like receptors, induced by bleomycin treatment, stimulate B cells to produce various fibrogenic cytokines and autoantibodies. Remarkably, CD19 loss results in inhibition of B-cell hyperreactivity and elimination of autoantibody production, which is associated with improvement of fibrosis. Taken together, altered B-cell function may result in tissue fibrosis, as well as autoimmunity, in SSc. Although further studies and greater understanding are needed, B cells are potential therapeutic target in SSc.