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

基本信息

批准号：
10533971
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
项目类别：
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/10533971
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&apos 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

项目摘要

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，大于2300万（约5-8％）的美国人患有慢性炎症条件，其中许多涉及自动反应性B淋巴细胞的致病功能和它们产生的自身抗体。慢性炎症条件也容易发生受影响的细胞和组织中恶性肿瘤的发展，例如B细胞淋巴瘤。因此有一个减轻自身免疫和慢性炎症的关键机会窗口也可以减少未来的恶性肿瘤风险。但是，全球B细胞介导的自身免疫的当前许多治疗方法耗尽B细胞，可以减轻症状，但会导致免疫抑制。因此有一个正在进行的针对自动反应性B细胞致病功能的疗法的开发和细化的需求。衔接蛋白TNF受体相关因子3（TRAF3）以细胞类型的方式作用于抑制B细胞信号传导途径，导致自身免疫和恶性肿瘤以及TRAF3的丧失通过炎症诱导的降解在B细胞中的蛋白质会导致慢性B细胞TRAF3缺乏症。这反过来，缺乏易于异常增强的B细胞存活和功能，导致自身免疫性临床前小鼠模型中的年轻人以及这些小鼠年龄的B细胞淋巴瘤的发展。这强调了定义TRAF3如何调节B细胞功能的迫切需求，这是这项工作的长期目标。该项目的目的是解决TRAF3如何通过B单元调节信号的知识差距通过自身免疫性涉及的抗原受体（BCR）和先天性收费受体（TLR）以下特定目的：（1）确定TRAF3限制BCR信号传导和 BCR对自身免疫的贡献。（2）定义TRAF3如何抑制B细胞信号和先天的功能免疫电话样受体（TLR）。（3）确定如何抑制TRAF3调节的BCR和TLR信号传导途径会影响B细胞特异性TRAF3缺陷型小鼠自身免疫的发展（B-TRAF3 - / - ）。这这些研究的预期结果是详细了解TRAF3中的缺陷是如何相关的随着衰老和慢性B细胞活化，有助于B细胞介导的自身免疫。这些知识会在选择和开发靶向自身免疫性疾病的途径疗法方面有价值。