Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and lung fibrosis. More than 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). Interleukin-10 (IL-10)-producing Bregs negatively regulate the immune response, while IL-6-producing Beffs positively regulate it. Therefore, a protocol that selectively depletes Beffs would represent a potent therapy for SSc. The aims of this study were 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. A bleomycin-induced scleroderma model was induced in 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 the scleroderma model. IL-6-producing Beffs increased in number and infiltrated the inflamed skin in the 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. In addition, BAFF increased Beffs but suppressed Bregs. Furthermore, BAFF antagonist attenuated skin and lung fibrosis in the scleroderma model with reduction of Beffs but not of Bregs. The current study indicates that Beffs play a pathogenic role in the scleroderma model, while Bregs play a protective role. BAFF inhibition is a potential therapeutic strategy for SSc via alteration of B cell balance.

中文翻译：

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BAFF抑制通过调节调节性B细胞和效应B细胞的平衡来减轻硬皮病的纤维化。

系统性硬化症（SSc）是一种以皮肤和肺纤维化为特征的自身免疫性疾病。超过90％的SSc患者自身抗体呈阳性。此外，血清B细胞活化因子（BAFF）水平与SSc的严重程度和活性相关。因此，认为B细胞在SSc中发挥致病作用。但是，有两个相对的亚群：调节性B细胞（Bregs）和效应B细胞（Beffs）。产生白介素10（IL-10）的Breg负调节免疫反应，而产生白细胞介素6的Beffs积极调节免疫应答。因此，有选择地消耗Beffs的方案将代表SSc的有效疗法。这项研究的目的是调查Bregs和Beffs在SSc中的作用，并为制定针对B细胞的新治疗策略提供科学依据。在具有IL-6或IL-10的B细胞特异性缺陷的小鼠中诱导博来霉素诱导的硬皮病模型。我们还检查了BAFF是否调节产生细胞因子的B细胞及其对硬皮病模型的影响。在硬皮病模型中，产生IL-6的Beff数量增加并且浸润了发炎的皮肤。B细胞特异性IL-6缺陷小鼠的皮肤和肺纤维化减弱，而B细胞特异性IL-10缺陷小鼠表现出更严重的纤维化。此外，BAFF增加了Beff，但抑制了Breg。此外，BAFF拮抗剂在硬皮病模型中减弱了皮肤和肺纤维化，降低了Beffs，但没有降低Bregs。目前的研究表明，Beffs在硬皮病模型中起着致病作用，而Bregs起着保护作用。