Background/Purpose: Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and lung fibrosis. Over 90% of patients with SSc are positive for autoantibodies. In addition, serum B cell activating factor (BAFF) level is correlated with SSc severity and activity. Thus, B cells are considered to play a pathogenic role in SSc. However, there are two opposing subsets: regulatory B cells (Bregs) and effector B cells (Beffs). IL-10-producing Bregs negatively regulate the immune response, while IL-6-producing Beffs positively regulate. Therefore, a protocol that selectively depletes Beffs would represent a potent therapy for SSc. The aim of this study was to investigate the roles of Bregs and Beffs in SSc, and to provide a scientific basis for developing a new treatment strategy targeting B cells.

Methods: The bleomycin-induced scleroderma model was induced in the mice with a B cell-specific deficiency in IL-6 or IL-10. We also examined whether BAFF regulates cytokine-producing B cells and its effects on scleroderma model.

Results: Serum IL-6 levels gradually increased with the development of fibrosis in bleomycin-induced scleroderma mice, while serum IL-10 levels did not. IL-6-producing Beffs increased in Spleen and the inflamed skin of scleroderma model. The skin and lung fibrosis was attenuated in B cell-specific IL-6-deficient mice, whereas B cell-specific IL-10-deficient mice showed more severe fibrosis. BAFF stimulation increased Beffs and decreased Bregs. By contrast, BAFF antagonist (BAFFR-Fc) increased Bregs and decreased Beffs (Fig 1). Furthermore, BAFF antagonist attenuated skin and lung fibrosis in scleroderma model via modulating the regulatory and effector B-cell balance (Fig 2).

Conclusion: The current study indicates that Beffs play a pathogenic role in scleroderma model while Bregs play a protective role (Fig 3). BAFF inhibition is a potential therapeutic strategy for SSc via alteration of B cell balance.