The role of IL-10 and TGF-beta1 secretion by B lymphocytes in lupus prone mice

B细胞(B淋巴细胞)在系统性红斑狼疮和其他自身免疫性疾病的发病机制中起主要作用。B细胞调节疗法的临床成功促进了人们对B细胞参与自身免疫性疾病的发生和维持的机制的了解。最近的研究表明，与T细胞的情况类似，B细胞中不仅含有致病的B细胞，也含有调节性的B细胞(Bregs)。在类风湿性关节炎、多发性硬化、1型糖尿病、炎症性肠病和系统性红斑狼疮的小鼠模型中，Bregs的存在被证明是存在的。有证据表明，Bregs是在抗CD20介导的B细胞耗竭后的B细胞重建过程中产生的。B细胞的调节能力归因于分泌细胞因子白介素10(IL-10)和转化生长因子β-1(转化生长因子-β-1)。通过IL-10和转化生长因子-β-1的释放，激活的B细胞可以同时调节T细胞和自身。我们计划通过B细胞特异性缺失IL-10或转化生长因子-β1在系统性红斑狼疮小鼠模型中验证这一假说。此外，我们还将研究抗CD20介导的B细胞耗竭能否在系统性红斑狼疮/狼疮小鼠中诱导Bregs，以建立BREG诱导作为CD20靶向治疗的一般机制。我们将进行进一步的实验，以阐明布雷格分泌抗炎细胞因子的背景。

B cells (B lymphocytes) play a major role in the pathogenesis of systemic lupus erythematosus and other autoimmune disorders. Efforts to understand the mechanisms by which B cells participate in the development and maintenance of autoimmune diseases have been boosted by the clinical success of B cell modulatory therapies. Recent studies indicate that similar to the situation with T cells not only pathogenic but also regulatory B cells (Bregs) are contained in the B cell compartment. The existence of Bregs could be demonstrated in murine models of rheumatoid arthritis, multiple sclerosis, diabetes mellitus type 1, inflammatory bowel disease and systemic lupus erythematosus. There is evidence that Bregs are particularly generated during B cell reconstitution after anti-CD20 mediated B cell depletion. The regulatory capacity of B cells has been ascribed to the secretion of the cytokines Interleukin 10 (IL-10) and Transforming growth factor β1 (TGF-β1). It stands to reason that activated B cells could be regulating T cells and themselves at the same time by the release of IL-10 and TGF-β1. We plan to test this hypothesis in a murine model of systemic lupus erythematosus (MRL/lpr) by B cell specific deletion of IL-10 or TGF-β1. Moreover, we will investigate whether Bregs can be induced by anti-CD20 mediated B cell depletion in MRL/lpr mice to establish Breg induction as a general mechanism of CD20 targeted therapy. We will conduct further experiments to shed light on the context in which Bregs secrete anti-inflammatory cytokines.