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， 医疗保健系统的负担。系统性红斑狼疮（SLE）是一种由自身抗体介导的免疫复合物性肾小球肾炎为特征的原型自身免疫性疾病。我们最近的研究表明，Fli-1，Ets转录因子家族的成员，对自身抗体的产生，疾病的发展和MRL//pr小鼠的生存有深远的影响， 自身免疫性疾病模型Fli-1在MRL//pr小鼠中的表达降低， 血清总IgG和抗dsDNA抗体水平，与对照组相比， 同窝野生型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（Fli-1 rec/rec小鼠）。Fli-1 rec/rec小鼠表达缺少羧基末端反式激活结构域的截短的Fli 1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展中起关键作用。本研究拟探讨Fli-1影响自身反应性B细胞产生的机制以及Fli-1在MRL//pr小鼠B细胞增殖中的作用。我们的研究将为疾病的发病机制和了解自身免疫性疾病的发展提供新的见解。这些新的发现将有助于开发针对特定炎症途径的新疗法

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