B Lymphocytes in Autoimmune Disease

类风湿性关节炎(RA)是由一系列破坏免疫的复杂事件引起的 耐受性，最终破坏滑膜组织。遗传的和环境的 导致疾病的因素。B淋巴细胞(B细胞)起着关键作用，产生 引发关节炎的自身抗体。肯德尔实验室致力于了解B细胞 支持关节炎的发展。我们最初使用的是缺乏B细胞信号蛋白的小鼠 Bruton‘s酪氨酸激酶(BTK)在自发性自身免疫K/BxN模型中的作用 关节炎。研究表明，有显著的疾病保护作用，伴随着 自身抗体，总免疫球蛋白相对较少。在这项工作中，我们制作了新的 发现BTK还会影响肠道微生物群，即被认为是 在包括类风湿性关节炎在内的自身免疫性疾病的发展中起着重要作用。我们发现 肠道中的特殊免疫器官，称为佩尔氏斑，非常小，它们 制造低水平的IgA抗体，而不是像应该的那样很好地结合肠道细菌。此外， 微生物群的失调可能对自身免疫有保护作用。 关节炎。这一提议背后的假设是BTK介导的信号 支持粘膜免疫并调节影响自身免疫的微生物，以 测试的目的是：1)定义BTK缺陷与K/BxN不足小鼠的IgA谱系， 包括选择、克隆和体细胞高突变证据等特征，2) 确定BTK在调节微生物群中的细胞特异性作用，区分B细胞 细胞和髓系细胞的功能，以及3)决定BTK的表达和功能 类风湿关节炎患者与对照组髓系细胞和B细胞的不同，以及IgA是否与共生体结合 细菌被改变了。该项目对于了解异常的B细胞是如何 自身免疫患者的细胞可能会引起微生物群的变化，从而调节疾病。

Rheumatoid arthritis (RA) results from a complex cascade of events that breaks immune tolerance and culminates in the destruction of synovial tissue. Both genetic and environmental factors contribute to disease. B lymphocytes (B cells) play a critical role, producing the autoantibodies that trigger arthritis. The Kendall lab works toward understanding B cells that support arthritis development. We originally used mice deficient in the B cell signaling protein Bruton’s tyrosine kinase (BTK) to test its role in the K/BxN model of spontaneous autoimmune arthritis. The studies indicated significant disease protection, accompanied by loss of autoantibodies, with relative sparing of total IgG. In the course of this work, we made the new discovery that BTK also affects the gut microbiome, commensal organisms that are thought to play an important role in the development of autoimmune diseases, including RA. We found that specialized immune organs in the gut, called Peyer’s patches, are very small, and that they make low levels of IgA antibody that does not bind gut bacteria as well as it should. Further, there is dysregulation of the microbiome that may have a protective effect against autoimmune arthritis. The hypothesis underlying this proposal is that BTK-mediated signaling supports mucosal immunity and regulates microbes that influence autoimmunity, to be tested in Aims which: 1) define the IgA repertoire in Btk-deficient versus –sufficient K/BxN mice, including features such as selection, clonality and evidence of somatic hypermutation, 2) determine the cell-specific role of BTK in regulating the microbiome, differentiating between B cell and myeloid cell functions, and 3) determine whether BTK expression and function in myeloid and B cells differ in RA patients and controls, and whether IgA binding of commensal bacteria are altered. This project has direct clinical importance in understanding how aberrant B cells in autoimmune patients may cause microbiome shifts that modulate disease.