Background/Purpose: Immune cells play a critical role in systemic sclerosis (SSc). B cells have more functions than producing antibodies, including antigen-presentation, various cytokine production, and T cell differentiation. In addition, abnormal B cell function can drive the development of autoimmunity. However, specific B-cell subsets can also play a protective role during T cell-mediated inflammation and have been termed regulatory B cells. Regulatory B cells with the ability to express the inhibitory cytokine interleukin (IL)-10 have been identified. Mice subcutaneously injected with topoisomerase-I and complete Freund’s adjuvant (CFA) develop skin and lung fibrosis and inflammatory infiltration with anti-topoisomerase I antibody and fibrogenic cytokine production, which more closely mimics the features of human SSc than traditional models, such as tight-skin mouse. However, the contribution of regulatory B cells and the mechanisms underlying suppression effects of immunological abnormalities in topoisomerase I and CFA-induced SSc remain unknown. Therefore, we investigated the role of regulatory B cells, in the development of fibrosis and autoimmunity induced by topoisomerase I and CFA.

Methods: Topoisomerase I and CFA were injected 4 times subcutaneously into the shaved back of the mice at an interval of 2 weeks. To assess the antigen-specific regulatory B cell function, wild type and activation-induced cytidine deaminase (AID)-deficient mice were used. AID is important molecules for inducing immunoglobulin class switch and somatic hypermutation. CD5+ and CD1dhi regulatory B cells were obtained from topoisomerase I and CFA-induced SSc model mice and adoptively transferred to these mice. Skin and lung sections were assessed histologically. Protein and mRNA levels of IL-4, IL-6, IL-17, tumor necrosis factor-α, transforming growth factor-β, and interferon-γ were measured using ELISA and real-time RT-PCR.

Results: In AID deficient mice, topoisomerase I and CFA treatment induced lower number of topoisomerase I-specific regulatory B cells than those in wild type mice. Furthermore, regulatory B cells obtained from wild type mice significantly attenuated the development of skin and lung fibrosis, skin expression of fibrogenic cytokines, especially IL-4, IL-6, and IL-17, and hyper-g-globulinemia compared with those from AID deficient mice.

Conclusion: Regulatory B cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmunity in topoisomerase I and CFA-induced SSc model mice. This study revealed fist that regulatory B cells ameliorate fibrosis and immunological abnormalities via an antigen-specific manner in SSc.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulatory-b-cells-regulate-skin-and-lung-fibrosis-and-immunological-abnormalities-in-a-topoisomerase-i-and-complete-freunds-adjuvant-induced-scleroderma-model-via-an-antigen-specific-manner/