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，免疫复合物介导的多器官损伤。缺乏两种SLE易感基因（酪氨酸激酶Lyn和转录因子Ets1）的小鼠具有非常相似的表型。这些症状包括B细胞过度活跃、分泌igm的浆细胞早期积累、IgG自身抗体的产生和肾内免疫复合物的沉积。初步结果表明，Ets1在Lyn-/- B细胞中的表达显著降低。此外，在SLE患者的PBMCs中观察到这两个基因的表达降低。鉴于已知Ets1限制B细胞终末分化，我们假设Lyn通常通过促进B细胞中Ets1的表达来限制自身反应性浆细胞的形成。我们提出通过以下具体目的来表征Lyn和Ets1之间的功能相互作用：1)确定Lyn控制Ets1表达的机制；2)确定Ets1表达减少对Lyn-/-小鼠浆细胞积累和自身免疫表型的影响。这些研究将定义和表征两个SLE易感位点之间先前未被识别的相互作用，潜在地阐明一种可以靶向治疗的新途径。

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.