Mechanisms of autoreative B cell development in a lupus animal model

描述(由申请人提供)： 自身免疫性疾病影响了近10%的美国人口，使巨大的 医疗保健系统的负担。系统性红斑狼疮(SLE)是一种由致病自身抗体介导的以免疫复合体肾炎为特征的自身免疫性疾病。我们最近的研究表明，ETS转录因子家族成员Fli-1对mrl//pr小鼠自身抗体的产生、疾病的发展和存活具有深远的影响。 自身免疫性疾病模型。MRL//PR小鼠Fli-1表达下调显著降低 血清总免疫球蛋白和抗dsDNA抗体水平与对照组相比显著提高 产仔野生型MRL/LPR小鼠。我们最近用截短的Fli-1基因产生了基因突变小鼠 蛋白质(Fli-1rec/rec小鼠)。Fli-1rec/rec小鼠表达一种截短的缺少羧基末端反式激活结构域的FLI1蛋白。Fli-1通过调节自身反应性B细胞的发育和增殖，在狼疮疾病的发生发展中发挥重要作用。我们建议研究Fli-1影响自身反应性B细胞产生的机制，以及Fli-1在MRL//prs小鼠B细胞增殖中的作用。我们的研究将为了解疾病的发病机制和了解自身免疫性疾病的发展提供新的视角。这些新发现将使针对特定炎症途径的新疗法的开发成为可能

DESCRIPTION (provided by applicant): Autoimmune diseases affect almost 10% of the United States population, placing an enormous burden on health care systems. Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by immune complex glomerulonephritis, mediated by pathogenic autoantibodies. Our recent studies have demonstrated a profound effect of Fli-1, a member of the Ets transcription factor family, on autoantibody production, disease development and survival in MRL//pr mice, a murine autoimmune disease model. Reduced expression of Fli-1 in MRL//pr mice had significantly decreased serum levels of total IgG and anti-dsDNA antibodies and markedly increased survival compared with littermate wild-type MRL/lpr mice. We recently generated genetically mutant mice with truncated Fli-1 protein (Fli-1rec/rec mice). Fli-1rec/rec mice express a truncated Fli1 protein that lacks the carboxy terminal transactivation domain. Fli-1 plays a critical role in the lupus disease development through its effects on the regulating autoreactive B cell development and proliferation. We propose here to investigate the mechanisms in which Fli-1 affects production of autoreactive B cells and the role of Fli-1 in B cell proliferation in MRL//prmice. Our study will provide new insight into disease pathogenesis and understanding the development of autoimmune disease. These new findings will enable development of novel therapeutics that target the specific inflammation pathway