B Lymphocytes in Autoimmune Disease

自身免疫性疾病中的 B 淋巴细胞

• 批准号: 10370125
• 负责人: Peggy L Kendall
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370125
• 关键词: Affect; Affinity; Agammaglobulinaemia tyrosine kinase; Antibiotics; Antibodies; Antigens; Arthritis; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Cell Antigen Receptor; B-Lymphocytes; Bacteria; Binding; Biological Assay; Cell physiology; Cells; Clinical; Clonality; Complex; Cytometry; Development; Disease; Disease Outcome; Environmental Risk Factor; Event; Failure; Fc Receptor; Funding; Genetic; Human; Immune; Immune Tolerance; Immune system; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; In Vitro; Individual; Infection; Inflammatory; Intestines; K/BxN model; Lead; Link; Malignant Neoplasms; Mediating; Microbe; Modeling; Molecular; Mucosal Immunity; Mucous Membrane; Mus; Myeloid Cell Activation; Myeloid Cells; Organ; Organism; Outcome; Patients; Peyer' s Patches; Phagocytes; Play; Process; Production; Receptor Signaling; Rheumatoid Arthritis; Role; Signal Transduction; Signaling Protein; Structure of germinal center of lymph node; Supporting Cell; System; T-Lymphocyte; Testing; Time; Tissues; Toll-like receptors; Tyrosine Kinase Inhibitor; Veterans; Woman; Work; adaptive immunity; arm; autoimmune arthritis; autoimmune pathogenesis; autoreactivity; commensal bacteria; commensal microbes; cytokine; experimental study; fighting; functional disability; gut bacteria; gut microbes; gut microbiome; immunoregulation; microbiome; monocyte; novel; peripheral blood; prevent; protective effect

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.

风湿性关节炎（RA）是由一系列复杂的事件引起的， 耐受性，并最终破坏滑膜组织。遗传和环境 因素导致疾病。B淋巴细胞（B细胞）发挥关键作用，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， 支持关节炎发展。我们最初使用缺乏B细胞信号蛋白的小鼠 布鲁顿酪氨酸激酶（BTK），以测试其在自发性自身免疫性K/BxN模型中的作用 关节炎研究表明，显著的疾病保护，伴随着损失， 自身抗体，总IgG相对较少。在这项工作的过程中，我们制作了新的 发现BTK也影响肠道微生物组，肠道微生物被认为 在自身免疫性疾病的发展中起重要作用，包括RA。我们发现 肠道中专门的免疫器官，称为派伊尔氏淋巴结，非常小，而且它们 产生低水平的IgA抗体，不能很好地结合肠道细菌。此外，本发明还 微生物群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介导的信号传导 支持粘膜免疫并调节影响自身免疫的微生物， 测试的目的是：1）确定Btk缺陷与充足K/BxN小鼠中的IgA库， 包括诸如选择、克隆性和体细胞超突变的证据等特征，2） 确定BTK在调节微生物组中的细胞特异性作用，区分B 细胞和骨髓细胞功能，以及3）确定BTK表达和功能是否在 RA患者和对照组的骨髓和B细胞不同， 细菌被改变了。该项目具有直接的临床意义，在了解如何异常B 自身免疫性患者的细胞可能导致调节疾病的微生物组变化。