Regulation of B cell signaling in autoimmunity by TRAF3

TRAF3 对自身免疫中 B 细胞信号传导的调节

• 批准号: 10728904
• 负责人: GAIL A. BISHOP
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728904
• 关键词: Adaptor Signaling Protein; Address; Affect; Age; Aging; American; Animals; Antibody-Producing Cells; Appearance; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; Blood Cells; Cell Compartmentation; Cell Line; Cell Survival; Cell physiology; Cells; Chronic; Complex; Data; Development; Disease; Event; Future; Genetic; Goals; Hematopoietic Neoplasms; Human; Immunologic Receptors; Immunosuppression; In Vitro; Individual; Inflammation; Inflammatory; Interruption; Knowledge; Lead; Leukocytes; Life; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediating; Modeling; Molecular; Multiple Sclerosis; Mus; Outcome Study; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phosphotransferases; Post-Translational Protein Processing; Process; Proteins; Receptor Signaling; Regulation; Reporting; Rheumatoid Arthritis; Risk; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Systemic Lupus Erythematosus; TNF receptor-associated factor 3; TNFRSF5 gene; Tissues; Toll-like receptors; United States National Institutes of Health; Virulence Factors; Work; aged; autoreactive B cell; autoreactivity; cancer cell; cell type; chronic inflammatory disease; effective therapy; in vivo; innate immune function; mouse model; pre-clinical; prevent; protein kinase D; receptor; receptor binding; receptor-mediated signaling; reduce symptoms; restraint; stress disorder; targeted treatment; young adult

The National Institutes of Health reports that > 23 million (~5-8%) of Americans suffer from chronic inflammatory conditions, many of which involve the pathogenic functions of autoreactive B lymphocytes and the autoantibodies they produce. Chronic inflammatory conditions also predispose to the subsequent development of malignancies, such as B cell lymphoma, in the affected cells and tissues. There is thus a critical window of opportunity in which alleviation of autoimmunity and chronic inflammation can also reduce future risk of malignancies. However, many of the current treatments for B cell-mediated autoimmunity globally deplete B cells, which can alleviate symptoms but result in immunosuppression. There is thus an ongoing need for development and refinement of therapies that target the pathogenic function of autoreactive B cells. The adapter protein TNF Receptor Associated Factor 3 (TRAF3) acts in a cell-type-specific manner to suppress B cell signaling pathways contributing to both autoimmunity and malignancy, and loss of TRAF3 protein in B cells by inflammation-induced degradation creates chronic B cell TRAF3 deficiency. This deficiency in turn predisposes to abnormally enhanced B cell survival and function, leading to autoimmunity in young adults in a preclinical mouse model, and development of B cell lymphoma in these mice as they age. This highlights a critical need to define how TRAF3 regulates B cell functions, the long-term goal of this work. The objective of this project is to address the knowledge gap of how TRAF3 regulates signals via the B cell antigen receptor (BCR) and the innate Toll-like Receptors (TLR) that are involved in autoimmunity, via the following Specific Aims: (1) Identify the molecular mechanisms by which TRAF3 restrains BCR signaling and BCR contributions to autoimmunity. (2) Define how TRAF3 inhibits B cell signals and functions of innate immune Toll-like receptors (TLRs). (3) Determine how inhibition of TRAF3-regulated BCR and TLR signaling pathways impacts development of autoimmunity in B cell-specific TRAF3-deficient mice (B-Traf3-/-). The expected outcome of these studies is a detailed knowledge of how a deficiency in TRAF3, which is associated with both aging and chronic B cell activation, contributes to B cell-mediated autoimmunity. This knowledge will be valuable in selection and development of pathway-targeted therapies for autoimmune conditions.

美国国立卫生研究院报告称，2300万(约5%-8%)的美国人患有慢性病。 炎症状态，其中许多涉及自身反应B淋巴细胞的致病功能和 它们产生的自身抗体。慢性炎症状况也容易导致随后的 在受影响的细胞和组织中发生恶性肿瘤，如B细胞淋巴瘤。因此，有一个 缓解自身免疫和慢性炎症的关键机会之窗也可以减少 未来患上恶性肿瘤的风险。然而，目前全球许多针对B细胞介导的自身免疫的治疗方法 消耗B细胞，这可以缓解症状，但会导致免疫抑制。因此，有一个正在进行的 需要开发和改进针对自身反应性B细胞致病功能的治疗方法。 适配器蛋白肿瘤坏死因子受体相关因子3(TRAF3)以细胞类型特异性的方式作用于 抑制导致自身免疫和恶性肿瘤的B细胞信号通路以及TRAF3的丢失 炎症诱导的B细胞中的蛋白质降解导致慢性B细胞TRAF3缺乏症。这 缺陷反过来易导致B细胞存活和功能异常增强，从而导致自身免疫。 临床前小鼠模型中的年轻成年人，以及这些小鼠随着年龄的增长而发生B细胞淋巴瘤的情况。 这突显了确定TRAF3如何调节B细胞功能的迫切需要，这是这项工作的长期目标。 这个项目的目标是解决TRAF3如何通过B细胞调节信号的知识差距 参与自身免疫的抗原受体(BCR)和先天Toll样受体(TLR)，通过 具体目标如下：(1)确定TRAF3抑制BCR信号转导的分子机制。 BCR对自身免疫的贡献。(2)明确TRAF3如何抑制B细胞信号和先天功能 免疫Toll样受体(TLRs)。(3)确定TRAF3对BCR和TLR信号的抑制作用 途径影响B细胞特异性TRAF3缺陷小鼠自身免疫的发展(B-TRAF3-/-)。这个 这些研究的预期结果是详细了解TRAF3的缺陷如何与 随着年龄的增长和慢性B细胞的激活，有助于B细胞介导的自身免疫。这一知识将会 在选择和开发针对自身免疫性疾病的途径靶向治疗方法方面具有价值。