The Role of B Cells in Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is an autoimmune disease marked by excessive extracellular matrix deposition in the skin and internal organs. Three major abnormalities, including autoimmunity, vasculopathy, and fibrosis, are considered to play important roles in the pathophysiology of SSc. A variety of immunological abnormalities of T and B cells have been detected in SSc. Over 90 % of the patients are positive for autoantibodies, which react to various intracellular components. Hyper-γ-globulinemia and B cell hyperactivity have also been detected in SSc patients. SSc patients have been reported to show distinct abnormalities in blood B lymphocyte compartments, characterized by expanded naive B cells and activated memory B cells. In addition, B cells from SSc patients overexpress CD19, a critical cell-surface signal transduction molecule, by ~20 %. Furthermore, a B cell activating factor belonging to the tumor necrosis factor family (BAFF) has been reported to be elevated in patients with SSc and to be correlated with the severity of SSc. In the tight-skin mouse model of SSc, chronic B cell activation is critical not only for the induction of autoantibodies but also for the development of skin fibrosis. In particular, an absence of CD19 or B cell depletion therapy, with an anti-CD20 antibody or a BAFF antagonist, suppresses the development of skin fibrosis and autoimmunity in mouse models of SSc. A number of recent studies on human SSc have shown that B cell depletion therapy has beneficial effects on skin and lung fibrosis in patients with SSc. However, B cells play not only a disease-promoting role but also an inhibitory role in autoimmune diseases. Regulatory B cells negatively regulate inflammation and autoimmunity and are present in human SSc patients. Furthermore, regulatory B cells have been shown to have an inhibitory function in the mouse model of SSc. Thus, depletion of regulatory B cells may worsen autoimmune diseases. Therefore, selective B cell depletion, which retains regulatory B cells, may be a potential therapy for autoimmune diseases, including SSc.