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基因缺失可导致小鼠狼疮样自身免疫性疾病。RASGRP1的异常表达仅与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细胞唯一地表达RASGRP1。RASGRP1缺陷导致B1细胞发育受损，尤其是PD-L2+B1细胞亚群的自身反应性受损，并损害自然的IgM分泌。B1细胞是自身反应的主要来源，天然的IgM促进了细胞的凋亡清除。低效的细胞凋亡被认为是狼疮自身免疫性疾病的关键原因。因此，我们推测，B1细胞的发育受损，尤其是PD-L2+B1细胞亚群的自身反应性受损，会导致自然IgM，特别是自身反应性天然IgM的分泌受损，从而损害凋亡细胞的吞噬功能。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。我们的发现证实了这一假设，即WT B1细胞的重建显著消除了自发生发中心B细胞和抗核自身抗体的表达。这项建议的具体目的是：1)鉴定野生型B1细胞在RASGRP1缺陷小鼠中对抗狼疮样自身免疫性疾病的性质；以及2)确定RASGRP1缺陷小鼠中天然IgM的自身反应性和凋亡细胞的吞噬能力。本研究将阐明RASGRP1基因异常表达所致SLE的发病机制，并为进一步认识自身免疫性疾病提供新的思路。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.