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：
9353179
负责人：
Peggy L Kendall
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353179
关键词：
Adverse effects Affect Affinity Agammaglobulinaemia tyrosine kinase American Antibodies Antigen Presentation Antigens Arthritis Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving B-Cell Development B-Lymphocytes Binding Biological Preservation Bone Marrow Cell Communication Cells Clinical Complement Complex Dangerousness Data Dendritic Cells Development Disease Dose Drug Design Drug Targeting Event FDA approved Future Genetic Goals Histology Human Immune Tolerance Immune system Immunoglobulin G Immunologic Deficiency Syndromes Immunosuppression Infection Inflammatory Arthritis Innate Immune System Joints K/BxN model Kinetics Knock-out Lymphoma Maintenance Malignant Neoplasms Mediating Memory Modeling Mus Normal Cell Pathogenicity Pharmaceutical Preparations Pharmacology Phosphotransferases Play Process Production Proteins Receptor Signaling Receptors, Antigen, B-Cell Rheumatoid Arthritis Role Secondary to Signal Pathway Signal Transduction Signaling Protein Specificity Structure of germinal center of lymph node System T-Lymphocyte Testing Therapeutic Therapeutic Intervention Time Tissues Veterans Woman Work antigen binding autoimmune arthritis autoreactive B cell autoreactivity comparative efficacy design drug efficacy fighting immune function improved inhibitor/antagonist joint destruction joint injury kinase inhibitor middle age mouse model novel novel drug class novel therapeutics pre-clinical trial prevent public health relevance response rituximab small molecule tool

项目摘要

DESCRIPTION (provided by applicant): Rheumatoid arthritis results from a complex cascade of events that breaks immune tolerance and culminates in the destruction of synovial tissue. B lymphocytes (B cells) play a critical role n disease development, producing the autoantibodies that trigger this disease. B cell contributions to arthritis depend upon multiple factors, beginning with loss of B cell tolerance to self-antigen, which occurs at immature stages of B cell development in the bone marrow, prior to T cell interactions. This tolerance is mediated by B cell signaling 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. This protein is not present in T cells, so offers the opportunity to study B cell contributions to lost tolerance in this disease. Understanding B cell signaling components that support arthritis development will advance the field toward specific targeting of pathogenic B cells. We used btk-deficiency to test the role of BTK in the K/BxN model of spontaneous autoimmune arthritis, and found significant disease protection, accompanied by loss of autoantibodies, with relative sparing of total IgG. These findings complement our previous work showing that autoreactive B cells are more sensitive to loss of BTK than normal cells are. Therefore, unlike global B cell immunosuppression offered by general B cell-targeting drugs such as rituximab, these findings suggest that it is possible to target B cell signaling in a way that would preferentially eliminate autoreactive cells without inducing generalized B cell immunodeficiency. The specific hypothesis underlying this proposal is that autoreactive B cells are more dependent on BTK-mediated signal amplification than normal B cells. To understand the mechanisms of action of BTK in promoting autoimmune arthritis, we will use our newly developed mouse models that include 1) an inducible model that allows timed deletion of BTK, to simulate pharmacologic inhibition without the confounding effect of off-target binding, 2) conditional, B cell-specific and dendritic cell-specific BTK knockout models to test cell-specific contributions of BTK, and 3) btk-deficent models as controls for testing of small molecule BTK inhibitors to determine how drug specificity and dosing compare with genetic deficiency, to enhance future drug design. This project has direct clinical importance in understanding how BCR-signaling supports the function of autoreactive B cells in autoimmune arthritis, as a necessary step in developing therapeutic interventions.

描述（由申请人提供）：类风湿关节炎是由一系列复杂的事件引起的，这些事件破坏了免疫耐受性，并在滑膜组织的破坏中达到顶峰。 B淋巴细胞（B细胞）起着至关重要的作用N疾病发展，产生触发该疾病的自身抗体。 B细胞对关节炎的贡献取决于多种因素，首先是B细胞对自我抗原的耐受性丧失， B细胞信号传导对通过B细胞受体（BCR）对抗原结合的反应介导的耐受性。 Bruton的酪氨酸激酶（BTK）是BCR触发信号通路的中心成分。该蛋白质不存在于T细胞中，因此提供了研究B细胞贡献以丧失该疾病的耐受性的机会。了解支持关节炎发育的B细胞信号传导成分将使该领域朝着病原B细胞的特定靶向。我们使用BTK缺乏症来测试BTK在赞助自身免疫性关节炎的K/BXN模型中的作用，并发现通过自身抗体的丧失而实现了重要的疾病保护，并且总IgG相对保留。这些发现完成了我们以前的工作，表明自动反应性B细胞比正常细胞对BTK的损失更敏感。因此，与一般B细胞靶向药物（如利妥昔单抗）提供的全局B细胞免疫抑制不同，这些发现表明可以靶向A中的B细胞信号如果不引起广泛的B细胞免疫缺陷，可以优先消除自动反应性细胞。该建议的基本假设是自动反应性B细胞比正常B细胞更依赖BTK介导的信号扩增。 To understand the mechanisms of action of BTK in promoting autoimmune arthritis, we will use our newly developed mouse models that include 1) an induced model that allows timed deletion of BTK, to simulate pharmaceutical inhibition without the confounding effect of off-target binding, 2) conditional, B cell-specific and dendritic cell-specific BTK knockout models to test cell-specific contributions of BTK, and 3) BTK茶模型作为测试小分子BTK抑制剂的对照，以确定药物特异性和给药的方式与遗传缺乏症相比，以增强未来的药物设计。该项目在理解BCR信号如何支持自身免疫性关节炎中自动反应性B细胞的功能方面具有直接的临床重要性，这是开发治疗性干预措施的必要步骤。