Functional Relationships Between the Lupus Susceptibility Loci Lyn and Ets1

描述（由申请人提供）：系统性红斑狼疮（SLE）的特征是对核抗原的耐受性丧失、自身抗体产生和免疫复合物介导的多器官损伤。两种SLE易感基因（酪氨酸激酶林恩和转录因子Ets 1）缺陷的小鼠具有非常相似的表型。这些包括B细胞过度活跃、分泌IgM的浆细胞的早期积累、IgG自身抗体的产生和免疫复合物在肾脏中的沉积。初步结果表明，Ets 1的表达显着降低林恩-/- B细胞。此外，在SLE患者的PBMC中观察到这两种基因的表达降低。鉴于已知Ets 1限制B细胞终末分化，我们假设林恩通常通过促进Ets 1在B细胞中的表达来限制自身反应性浆细胞的形成。我们建议通过以下特定目的来表征林恩和Ets 1之间的功能性相互作用：1）定义林恩控制Ets 1表达的机制，以及2）确定Ets 1表达降低对林恩-/-小鼠的浆细胞蓄积和自身免疫表型的影响。这些研究将定义和表征两个SLE易感基因座之间先前未识别的相互作用，可能阐明一种可用于治疗的新途径。 公共卫生相关性：系统性红斑狼疮（SLE）是一种潜在的致命性自身免疫性疾病，其特征是产生针对自身的抗体，然后引起组织损伤。我们建议测试的想法，两个狼疮易感基因，林恩和Ets 1，一起工作的分子途径，以防止分化的B细胞到自身抗体产生细胞。我们的研究可能会提出这样的想法，即通过新设计的治疗方案来限制自身抗体的分泌，从而靶向这种新的途径。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nuclear antigens, autoantibody production, and immune complex mediated damage to multiple organs. Mice deficient in two SLE susceptibility genes, the tyrosine kinase Lyn and the transcription factor Ets1, have remarkably similar phenotypes. These include B cell hyperactivity, early accumulation of IgM-secreting plasma cells, production of IgG autoantibodies, and immune complex deposition in the kidney. Preliminary results indicate that Ets1 expression is dramatically reduced in Lyn-/- B cells. Furthermore, decreased expression of both genes has been observed in PBMCs of SLE patients. Given that Ets1 is known to limit B cell terminal differentiation, we hypothesize that Lyn normally restricts the formation of autoreactive plasma cells by promoting expression of Ets1 in B cells. We propose to characterize the functional interaction between Lyn and Ets1 via the following Specific Aims: 1) to define the mechanism by which Lyn controls Ets1 expression, and 2) to determine the consequences of reduced Ets1 expression for the plasma cell accumulation and autoimmune phenotypes of Lyn-/- mice. These studies will define and characterize a previously unidentified interaction between two SLE susceptibility loci, potentially illuminating a novel pathway that can be targeted therapeutically. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease characterized by the production of antibodies against oneself, which then cause tissue damage. We propose to test the idea that two lupus susceptibility genes, Lyn and Ets1, work together in a molecular pathway to prevent the differentiation of B cells into autoantibody producing cells. Our studies may suggest ideas to allow targeting of this novel pathway with newly-designed therapeutic regimens designed to limit autoantibody secretion.