B Lymphocytes in Autoimmune Disease

自身免疫性疾病中的 B 淋巴细胞

基本信息

批准号：
10640819
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
项目类别：
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/10640819
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 Myelogenous Myeloid Cell Activation Myeloid Cells Organ Organism Outcome Patients Peyer&apos s Patches Phagocytes Play Process Production Receptor Signaling Rheumatoid Arthritis Role Signal Transduction Signaling Protein Sorting 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 humoral immunity deficiency immunoregulation microbiome monocyte novel peripheral blood prevent protective effect

项目摘要

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.

类风湿关节炎（RA）是由一系列复杂的事件造成的，这些事件破坏了免疫耐受性和最终导致滑膜组织的破坏。遗传和环境因素导致疾病。 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。我们最初使用了缺乏B细胞信号蛋白的小鼠布鲁顿的酪氨酸激酶（BTK）测试其在赞助自动免疫的K/BXN模型中的作用关节炎。研究表明，通过丢失而实现了明显的疾病保护自身抗体，总IgG相对保留。在这项工作的过程中，我们制作了新的发现BTK还会影响肠道微生物组，共生生物，被认为是在包括RA在内的自身免疫性疾病的发展中起着重要作用。我们发现肠道中的专门免疫器官，称为佩耶的斑块，很小，它们制作低水平的IgA抗体，该抗体不会尽其所能结合肠道细菌。此外，微生物组的失调可能对自身免疫有保护作用关节炎。该提案的基础假设是BTK介导的信号传导支持粘膜免疫学并调节影响自身免疫性的微生物在目的中测试的目的：1）定义BTK缺陷与k/bxn小鼠的IgA曲目，包括选择，克隆性和躯体过度突击的证据等特征，2）确定BTK在调节微生物组中的细胞特异性作用，并区分B 细胞和髓样细胞功能，3）确定BTK表达和功能是否在 RA患者和对照组的髓样和B细胞不同，以及IgA的结合是否存在细菌改变。该项目在理解异常b中的直接临床重要性自身免疫性患者的细胞可能会导致调节疾病的微生物组转移。