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: 10457447
• 负责人: GAIL A. BISHOP
• 金额: $ 44.75万
• 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/10457447
• 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; Protein Kinase; 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 function; receptor-mediated signaling; reduce symptoms; 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说，超过2300万（约5-8%）的美国人患有慢性 炎症性疾病，其中许多涉及自身反应性B淋巴细胞的致病功能， 它们产生的自身抗体慢性炎症性疾病也容易导致随后的 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 关键的机会窗口，其中缓解自身免疫和慢性炎症也可以减少 未来的恶性肿瘤风险。然而，目前全球范围内对B细胞介导的自身免疫的许多治疗方法 耗尽B细胞，这可以缓解症状，但导致免疫抑制。因此，有一个持续的 需要开发和改进靶向自身反应性B细胞的致病功能的疗法。 衔接蛋白TNF受体相关因子3（TRAF 3）以细胞类型特异性方式起作用， 抑制导致自身免疫和恶性肿瘤的B细胞信号传导途径，以及TRAF 3的缺失 炎症诱导的降解导致B细胞中的蛋白质产生慢性B细胞TRAF 3缺乏。这 缺乏反过来又倾向于异常增强的B细胞存活和功能，导致自身免疫， 在临床前小鼠模型中的年轻成年人，以及随着年龄的增长，这些小鼠中B细胞淋巴瘤的发展。 这突出了确定TRAF 3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。 该项目的目的是解决TRAF 3如何通过B细胞调节信号的知识空白 抗原受体（BCR）和先天性Toll样受体（TLR）参与自身免疫，通过 以下具体目的：（1）鉴定TRAF 3抑制BCR信号传导的分子机制， BCR对自身免疫的贡献。(2)定义TRAF 3如何抑制B细胞信号和先天性免疫缺陷的功能 免疫Toll样受体（TLR）。(3)确定TRAF 3调节BCR和TLR信号传导的抑制作用 在B细胞特异性TRAF 3缺陷小鼠（B-Traf 3-/-）中，TRAF 3通路影响自身免疫的发展。的 这些研究的预期结果是详细了解TRAF 3的缺陷如何与 与衰老和慢性B细胞活化一起，有助于B细胞介导的自身免疫。这些知识将 在选择和开发针对自身免疫性疾病的通路靶向疗法中具有价值。