Bruton's Tyrosine Kinase and Immune Tolerance in Type 1 Diabetes

布鲁顿酪氨酸激酶和 1 型糖尿病的免疫耐受

• 批准号: 8042106
• 负责人: Peggy L Kendall
• 金额: $ 37.94万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-27 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8042106
• 关键词: Address; Adoptive Transfer; Agammaglobulinaemia tyrosine kinase; Amino Acids; Antigen Presentation; Antigens; Autoantibodies; Autoantigens; Autoimmune Diabetes; B cell repertoire; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Assay; Cell physiology; Cells; Clinical; Complement 3d Receptors; Complex; Dependence; Development; Diabetes Mellitus; Disease; Disease Progression; Effectiveness; Employee Strikes; Event; Goals; Immune Tolerance; Immunoglobulin G; Inbred NOD Mice; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Knock-out; Lead; Link; Mature B-Lymphocyte; Mediating; Modeling; Molecular; Mus; Outcome; Phosphotransferases; Play; Process; Property; Receptor Signaling; Receptors, Antigen, B-Cell; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Staging; System; T-Lymphocyte; Testing; Therapeutic Intervention; Transgenic Mice; Transgenic Model; Transgenic Organisms; Tyrosine Kinase Domain; Tyrosine Kinase Inhibitor; adapter protein; antigen binding; autoreactive B cell; autoreactivity; base; islet; mouse model; novel; prevent; reconstitution; research study; response; small molecule; tool

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) results from a complex cascade of events that breaks immune tolerance and culminates in the destruction of islet 2 cells. B lymphocytes (B cells) play a critical role in disease development, probably via antigen-presentation to pathogenic T cells. B cell contribution to the development of diabetes depends upon multiple factors, including loss of tolerance to self antigen. This tolerance is mediated by cellular responses to antigen-binding via the B cell receptor (BCR). Bruton's tyrosine kinase (BTK) is a central component of the BCR-triggered signaling pathway. Understanding cell signaling components underlying B cell-driven diabetes development will advance the field toward specific targeting of pathogenic B cells. We have introgressed btk-deficiency onto the nonobese diabetic (NOD) mouse model of T1D, and found that this results in significant protection against the development of diabetes. In addition, btk-deficiency interferes with B cell related breaches of immune tolerance, as evidenced by the loss of insulin-specific IgG autoantibodies in wild type NOD mice, and reduction of insulin-binding B cells in a transgenic anti-insulin BCR model. The specific hypothesis underlying this proposal is that BTK-mediated propagation of BCR signals contributes to 1) selection and survival of autoreactive B lymphocytes, and 2) disease- promoting functional properties of these B cells. To understand the mechanisms of action of BTK in breaking B lymphocyte tolerance and promoting disease in autoimmune diabetes, we propose to: 1) discover how BTK participates in the selection and retention of autoreactive B lymphocytes, using use new tools that include a conditional, B cell-specific BTK knockout model and small molecule BTK- inhibitors, 2) determine which domains of the BTK molecule are responsible for autoreactive B lymphocyte selection and function, by systematically restoring independent components responsible for the kinase and linking functions, and 3) investigate the mechanisms of btk-deficiency in preventing T1D by examining effects on B cell subsets, antigen-presenting outcomes, and regulatory parameters. This project has direct clinical importance in understanding how BCR-signaling supports the selection, survival and function of autoreactive B cells in T1D, as a necessary step in developing therapeutic interventions. PUBLIC HEALTH RELEVANCE: Autoreactive B lymphocytes are essential to the development of type 1 diabetes. The goal of this project is to understand how B cell signaling, mediated by Bruton's tyrosine kinase, supports the breach of immunologic tolerance that occurs in this disease. These discoveries will provide new avenues of intervention for the specific targeting of autoreactive, pathogenic B cells.

描述（由申请人提供）：1型糖尿病（T1D）是由一系列复杂的事件引起的，这些事件破坏了免疫耐受，最终导致胰岛2细胞的破坏。B淋巴细胞（B细胞）在疾病发展中发挥关键作用，可能通过抗原呈递到致病性T细胞。B细胞对糖尿病发展的贡献取决于多种因素，包括对自身抗原耐受性的丧失。这种耐受性是通过B细胞受体（BCR）对抗原结合的细胞反应介导的。布鲁顿酪氨酸激酶（BTK）是bcr触发信号通路的核心组成部分。了解B细胞驱动糖尿病发展的细胞信号传导成分将推动致病B细胞特异性靶向领域的发展。我们将btk缺乏症渗透到非肥胖糖尿病（NOD） T1D小鼠模型中，发现这对糖尿病的发展有显著的保护作用。此外，在野生型NOD小鼠中胰岛素特异性IgG自身抗体的缺失，以及在转基因抗胰岛素BCR模型中胰岛素结合B细胞的减少，都证明了btk缺乏症会干扰B细胞相关的免疫耐受破坏。这一提议的具体假设是，btk介导的BCR信号的传播有助于1)自身反应性B淋巴细胞的选择和存活，以及2)这些B细胞促进疾病的功能特性。为了了解BTK在自身免疫性糖尿病中破坏B淋巴细胞耐受性和促进疾病的作用机制，我们提出：1)发现BTK如何参与自身反应性B淋巴细胞的选择和保留，使用新的工具，包括有条件的，B细胞特异性BTK敲除模型和小分子BTK抑制剂；2)通过系统地恢复负责激酶和连接功能的独立成分，确定BTK分子的哪些结构域负责自身反应性B淋巴细胞的选择和功能；3)通过检测btk缺乏对B细胞亚群、抗原呈递结果和调节参数的影响，研究btk缺乏预防T1D的机制。该项目在了解bcr信号如何支持T1D中自身反应性B细胞的选择、生存和功能方面具有直接的临床意义，是开发治疗干预措施的必要步骤。