T-bet expressing B cells in autoimmunity

系统性红斑狼疮(SLE)是一种潜在的致命性自身免疫性疾病，其特征是 能识别含有抗原的核酸的致病性自身抗体的产生。这些抗体 形成免疫复合体，促进多个器官的组织损伤，并使系统性 炎性环境。目前治疗系统性红斑狼疮的大多数方法都涉及到非特异性免疫抑制。 并有不良的副作用。因此，迫切需要更有针对性的治疗方法。最新研究 已经证明，自身反应性B细胞对其激活、参与 生发中心和分化为抗体分泌浆细胞与B细胞反应的比较 外来抗原。了解这些不同信号的后果可能会揭示新的治疗方法 预防自身免疫反应的策略，同时保持对感染的反应能力。这个 转录因子T-bet是一种受自身反应性B细胞特有的刺激上调的因子 在小鼠狼疮模型中，生发中心B细胞和ABC，以及在DN2细胞中， SLE患者。ABC和DN2s是B细胞亚群，在狼疮中蓄积，并有效地分化为 分泌高水平自身抗体的浆细胞。然而，T-bet表达B的程度 细胞对致病性自身抗体产生的作用尚不清楚，就像以前的结果一样。 自相矛盾。为了支持这些细胞作为治疗靶点，有必要更好地理解这一点。 治疗狼疮。我们假设T-bet的表达是狼疮模型中产生自身抗体的细胞的标志， 即使它本身并不是产生自身抗体所绝对需要的。我们将通过以下方式验证这一假设：1)使用 命运映射策略，以确定表达或曾经表达T-bet的细胞对 自身反应性浆细胞的聚集，以及2)阻止表达T-bet的B细胞分化为 狼疮模型中的浆细胞。这些研究的成功完成将突出T-bet表达B细胞或 诱导它们成为SLE潜在治疗靶点的刺激。在此开发的删除方法 在表达B细胞的T-bet中特异的基因也将对未来的机制研究有价值，包括 这些细胞在自身免疫性疾病和对感染的免疫反应中都有。

Systemic Lupus Erythematosus (SLE) is a potentially fatal autoimmune disease characterized by the production of pathogenic autoantibodies that recognize nucleic acid containing antigens. These antibodies form immune complexes that promote tissue damage in multiple organs and perpetuate a systemic inflammatory environment. The majority of current therapies for SLE involve non-specific immunosuppression and have undesirable side effects. Thus there is an urgent need for more targeted therapies. Recent studies have demonstrated that autoreactive B cells have unique requirements for their activation, participation in germinal centers, and differentiation into antibody secreting plasma cells compared to B cells reactive with foreign antigens. Understanding the consequences of these differential signals may reveal new therapeutic strategies to prevent autoimmune responses while maintaining the ability to respond to infection. The transcription factor T-bet is a) upregulated by stimuli that are uniquely required for autoreactive B cell responses and b) increased in germinal center B cells and ABCs in mouse lupus models and in DN2 cells from SLE patients. ABCs and DN2s are B cell subsets that accumulate in lupus and differentiate efficiently into plasma cells that secrete elevated levels of autoantibodies. However, the degree to which T-bet expressing B cells contribute to the production of pathogenic autoantibodies is unclear, as prior results have been contradictory. A better understanding of this is necessary in order to support these cells as a therapeutic target for lupus. We posit that T-bet expression is a marker for cells that give rise to autoantibodies in lupus models, even if it is not itself absolutely required for autoantibody production. We will test this hypothesis by 1) using a fate mapping strategy to determine the contribution of cells that express, or once expressed, T-bet to the accumulation of autoreactive plasma cells, and 2) preventing T-bet expressing B cells from differentiating into plasma cells in a lupus model. Successful completion of these studies will highlight T-bet expressing B cells or stimuli that induce them as potential therapeutic targets for SLE. The methods developed here to delete genes specifically in T-bet expressing B cells will also be valuable for future mechanistic studies involving these cells both in autoimmune disease and during immune response to infections.