Molecular mechanisms of autoreactive B cell activation

描述（由申请人提供）：我们最近的研究已经表明T盒转录因子T-bet在调节B细胞中的类别转换以及在系统性自身免疫疾病中的自身抗体产生中的关键作用：T-bet缺陷显著损害IFN-γ介导的向IgG 2a的类别转换以及狼疮的MRL/Ipr鼠模型中自身抗体的产生，并且相反地增强IL-4相关的应答，例如IgE的产生。使用遗传突变小鼠和体外细胞培养系统，我们建议在这里进一步描绘的作用，T-bet在常规和自身免疫性B细胞反应的定义和表征的分子途径，这种新的致病性和治疗性靶点调节同种型转换，细胞增殖，并激活成熟的，自身反应性B淋巴细胞。

DESCRIPTION (provided by applicant): Our recent studies have indicated a critical role for the T-box transcription factor T-bet in the regulation of class switching in B cells as well as in autoantibody production in systemic autoimmune disease: T-bet deficiency dramatically impairs IFN-gamma-mediated class switching to IgG2a as well as the generation of autoantibodies in the MRL/Ipr murine model of lupus, and conversely enhances IL-4-related responses, such as IgE production. Using genetically mutant mice and in vitro cell culture systems, we propose here to further delineate the role of T-bet in both conventional and autoimmune B cell responses by defining and characterizing the molecular pathways in which this novel pathogenic and therapeutic target regulates isotype switching, cellular proliferation, and the activation of mature, autoreactive B lymphocytes.