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: 8583319
• 负责人: Peggy L Kendall
• 金额: $ 32.3万
• 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/8583319
• 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; Islet Cell; 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; public health relevance; 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.

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。