Molecular mechanisms of autoreactive B cell activation

描述(由申请人提供)：我们最近的研究表明，T-box转录因子T-bet在调节B细胞的类别转换以及系统性自身免疫病的自身抗体产生方面发挥了关键作用：T-bet缺陷显著削弱了干扰素-伽玛介导的类别转换为IgG2a以及狼疮MRL/IPR小鼠模型中自身抗体的产生，并反过来增强了IL-4相关反应，如IgE的产生。利用基因突变的小鼠和体外细胞培养系统，我们建议通过定义和表征这种新的致病和治疗靶点调节同型转换、细胞增殖和成熟的、自身反应性B淋巴细胞的激活的分子途径，进一步描述T-bet在传统和自身免疫B细胞反应中的作用。

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.