The essential role of RasGRP1 in B1 cell autoreactivity and autoimmunity

RasGRP1 在 B1 细胞自身反应性和自身免疫中的重要作用

• 批准号: 8967569
• 负责人: Benchang Guo
• 金额: $ 8.43万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967569
• 关键词: Advocate; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biological Assay; Cells; Classification; Clinical Trials; Complex; Development; Disease; Early Diagnosis; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Etiology; Event; Foundations; Functional disorder; Genetic; Health; Human; Immune system; Immunoglobulin M; In Vitro; Interleukin-10; Lead; Lupus; Lymphocyte Activation; MS4A1 gene; Mediating; Molecular Profiling; Mus; Natural Products; Nature; Nuclear; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Phenotype; Play; Population; Predisposition; Rheumatoid Arthritis; Role; Serum; Signaling Molecule; Source; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; Testing; Therapeutic; Time; Tissues; autoreactivity; disorder prevention; effective therapy; improved; in vivo; insight; lupus-like; macrophage; meetings; novel; reconstitution; secretory IgM; signature molecule; success

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.

描述（由申请人提供）：RasGRP 1是一种关键信号分子。RasGRP 1缺陷导致小鼠狼疮样自身免疫性疾病RasGRP 1异常表达仅与SLE患者相关。然而，根本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RasGRP 1。RasGRP 1的缺乏导致B1细胞发育受损，特别是自身反应性PD-L2+ B1细胞亚群，以及天然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细胞亚群的发育受损，导致天然IgM，特别是自身反应性天然IgM分泌受损，从而损害凋亡细胞的吞噬作用。因此，在RasGRP 1缺陷小鼠中，自身抗原积累-淋巴细胞活化-自身抗体表达轴被活化。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性生发中心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，其对抗RasGRP 1缺陷小鼠中的狼疮样自身免疫性疾病; 2）确定RasGRP 1缺陷小鼠中天然IgM的自身反应性和凋亡细胞的吞噬作用。本研究将阐明RasGRP 1异常表达引发的SLE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性自身免疫性疾病的准确分类、早期诊断和改善治疗提供基础。