Background/Purpose: Systemic sclerosis (SSc) is a connective tissue disease characterized by vascular damage, excessive deposition of extracellular matrix, and fibrosis in the several organs, including skin and lung, on an autoimmune background. Although the pathogenesis of SSc remains unknown, it has been proposed that oxidative stress play an important role in disease development. Many previous studies have confirmed that production of free radicals is enhanced in human SSc patients, due to ischemia and reperfusion injury following Raynaud’s phenomenon, an initial clinical manifestation. Recent studies indicated that specific B cell subsets can negatively regulate T cell immune responses, and have been termed regulatory B cells. Human and mouse regulatory Bcells with the ability to express the inhibitory cytokine interleukin (IL)-10 have been identified. Although rare, regulatory B cells are potent negative regulators of antigen-specific inflammation and T cell dependent autoimmune diseases in mice. However, how IL-10 producing regulatory B cells regulate antigen-specific immune responses in vivo without inducing systemic immunosuppression is unknown. In this study, we focused on the effect of antigen-specific regulatory B cells on oxidative stress.

Methods: In this study, bleomycin (BLM)-induced SSc model mice were used. CD5+ and CD1dhi regulatory B cells were obtained from BLM or PBS treated mice respectively and adoptively transferred to BLM-induced SSc mice. To assess the effect of regulatory B cells, serum levels of 8-isoprostane, a marker of oxidative stress, were measured. Furthermore, we assessed skin and lung fibrosis histologically. Protein and mRNA levels of profibrogenic cytokines, such as IL-4, IL-6, and IL-17, were measured using ELISA and real-time RT-PCR.

Results:  The regulatory B cells reduced skin and lung fibrosis and serum levels of profibrogenic cytokines in BLM-induced SSc model mice. Especially, serum levels of 8-isoprostane were decreased by adoptively transferred ex vivo-induced regulatory B cells compared with PBS injection. In addition, regulatory B cells significantly inhibited free radical production from inflammatory cells cultured with BLM. Interestingly, the regulatory B cells obtained from BLM-treated mice had more inhibitory effects than those from PBS-treated mice.

Conclusion:  These results suggest that the regulatory B cells inhibited free radical production from inflammatory cells, results in ameliorating the disease manifestations of SSc. These inhibitory effects of regulatory B cells may exert via the antigen-specific manner. Although further studies are needed, the autoantigen-specific regulatory B cell can be a novel therapeutic tool for treatment for SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-regulatory-b-cells-ameliorate-skin-sclerosis-lung-fibrosis-and-autoimmunity-via-an-anti-oxidative-effect-in-systemic-sclerosis-model-mice/