The essential role of RasGRP1 in B1 cell autoreactivity and autoimmunity

描述（申请人提供）：RasGRP1是一种关键信号分子。RasGRP1的缺乏导致小鼠狼疮样自身免疫性疾病。RasGRP1异常表达仅与SLE患者相关。然而，潜在的机制仍然难以捉摸。我们的初步结果首次表明B1细胞唯一表达RasGRP1。缺乏RasGRP1会导致B1细胞发育受损，尤其是自身反应性PD-L2+ B1细胞亚群的发育受损，并导致天然IgM分泌受损。B1细胞是促进凋亡细胞清除的自身反应性天然IgM的主要来源。低效率的凋亡细胞清除被认为是狼疮自身免疫性疾病的一个重要原因。因此，我们假设B1细胞发育受损，特别是自身反应性PD-L2+ B1细胞亚群受损，导致天然IgM分泌受损，尤其是自身反应性天然IgM分泌受损，从而损害凋亡细胞的吞噬作用。因此，在RasGRP1缺陷小鼠中，自身抗原积累-淋巴细胞激活-自身抗体表达轴被激活。我们的研究结果证实了这一假设，即WT B1细胞的重组显著消除了自发生发中心B细胞和抗核自身抗体的表达。该提案的具体目的是：1)表征野生型B1细胞的性质，在RasGRP1缺陷小鼠中抵抗狼疮样自身免疫性疾病；2)测定天然IgM的自身反应性和RasGRP1缺陷小鼠凋亡细胞的吞噬能力。这一建议将阐明由RasGRP1异常表达引发的SLE的发病机制，并为进一步了解自身免疫性疾病提供新的见解。这些研究结果将为狼疮自身免疫性疾病的准确分类、早期诊断和改进治疗提供基础。

DESCRIPTION (provided by applicant): RasGRP1 is a key-signaling molecule. Deficiency of RasGRP1 results in lupus-like autoimmune disease in mice. Aberrant RasGRP1 expression is exclusively associated with SLE patients. However, the underlying mechanism remains elusive. Our preliminary results showed for the first time that B1 cells uniquely express RasGRP1. Deficiency of RasGRP1 leads to impaired B1 cell development, especially of the autoreactive PD-L2+ B1 cell subset, and impaired natural IgM secretion. B1 cells are the major source of autoreactive, natural IgM facilitating apoptotic cell clearance. Inefficient apoptotic cell clearane is considered a critical cause of lupus autoimmune disease. Thus, we hypothesize that impaired B1 cell development, especially of the autoreactive PD-L2+ B1 cell subset, results in impaired natural IgM, particularly of autoreactive natural IgM, secretion which impairs phagocytosis of apoptotic cells. Therefore, an autoantigen accumulation-lymphocyte activation-autoantibody expression axis is activated in RasGRP1 deficient mice. This hypothesis is validated by our findings that reconstitution of WT B1 cells significantly eliminates expression of spontaneous germinal center B cells and anti-nuclear autoantibodies. The specific aims of this proposal are to: 1) characterize the nature of wild-type B1 cells that counteract lupus-like autoimmune disease in RasGRP1 deficient mice; and, 2) determine autoreactivity of natural IgM and phagocytosis of apoptotic cells in RasGRP1 deficient mice. This proposal will elucidate the etiopathogenesis of SLE initiated by aberrant expression of RasGRP1 and provide novel insights into further understanding of autoimmune diseases. The results of these studies will provide the foundation for accurate classification, early diagnosis, and improved therapy of lupus autoimmune diseases.