The Role of TNF in Breaking B Cell Tolerance

TNF 在破坏 B 细胞耐受性中的作用

• 批准号: 10188437
• 负责人: Tam D Quach
• 金额: $ 12.77万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10188437
• 关键词: Address; Affect; Affinity; Age; Agonist; Amyloid fibers; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Antibody-Producing Cells; Antigen-Antibody Complex; Antigens; Antinuclear Antibodies; Autoantibodies; Autoimmune; Autoimmunity; B cell differentiation; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological; CD22 gene; Cells; Chromatin; Clinical; Clinical Research; Computational Biology; Computer Models; Data; Defect; Demyelinating Diseases; Development; Development Plans; Disease; Drug usage; Education; Educational workshop; Environment; Escherichia coli; Faculty; Follicular Dendritic Cells; Foundations; Future; Generations; Goals; Grant; Homeostasis; Human; IL17 gene; Immune response; Immune system; Immunologist; In Vitro; Individual; Institutes; Interleukin-17; Knowledge; Ligands; Lupus; Mediating; Medical Research; Mentors; Methodology; Modeling; Mus; Opportunistic Infections; Pathogenicity; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Phenotype; Play; Postdoctoral Fellow; Pristane; Process; Production; Psoriasis; RNA; Reagent; Regulation; Research; Research Activity; Research Personnel; Research Project Grants; Resources; Rheumatoid Arthritis; Role; SLEB1 gene; Sampling; Self Tolerance; Signal Transduction; Source; Stimulus; Structure; Structure of germinal center of lymph node; System; Systemic Lupus Erythematosus; T-Lymphocyte; TLR2 gene; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Technology; Testing; Training; Training Activity; United States; Vasculitis; Work; attenuation; autoreactive B cell; autoreactivity; career development; chronic autoimmune disease; cohort; cytokine; design; drug development; effective therapy; effector T cell; experience; immunoregulation; improved; individual patient; inhibitor/antagonist; insight; instructor; interleukin-21; member; mouse model; mutational status; next generation sequencing; novel; personalized medicine; predictive modeling; prevent; response; restoration; safe patient; side effect; skills

Dr. Quach's central goal is to acquire new skills that will establish her as a systems immunologist. The proposed research combines murine and human studies to identify mechanisms by which TNF deficiency breaks tolerance. The gained knowledge will guide future efforts in designing personalized medicine for autoimmune patients. Candidate: Dr. Quach is an instructor at the Feinstein Institute for Medical Research (FIMR). Through her Ph.D and post-doctoral work, she focused on the development and regulation of B cells in humans. The proposed career development plan will build upon her previous experience with four training goals to enhance her trajectory toward becoming an independent investigator: 1) gain expertise in utilizing mouse models; 2) become proficient in computational biology; 3) gain insights into conducting clinically oriented research projects, and 4) build a foundation of data and methodologies to generate predictive models. Mentors/Environment: Dr. Quach and her mentor, Dr. Anne Davidson, have assembled a strong team of advisors and collaborators to guide her through the proposed training and research activities. The proposed project utilizes the intellectual, research and clinical facilities available at the FIMR and the resources available through her external advisors and collaborators, Dr. Steven Kleinstein and Dr. Inaki Sanz. FIMR is committed to support junior faculty members through internal grants and opportunities for networking and education. Dr. Quach will attend national seminars/workshops when optimal training is not available locally. Research: The induction of autoantibody and autoimmunity in patients treated with TNF inhibitors (TNFi) is well- known; however, the mechanism by which TNFi induce breach of B cell tolerance is yet to be determined. In humans, TNFi affect B and T cell homeostasis via disruption of germinal center (GC) formation which is pivotal for high affinity antigen-specific antibody production and negative selection of autoreactive B cells. Similarly, in mice, TNF signaling deficiency prevents GC formation, induces TFH and CD4+IL-17 producing cell expansion, and alters autoantibody profiles. This study proposes that TNF deficiency, together with a second inducing stimulus, compromises GC B cell selection via reduction of negative GC B cell signaling and enhancement of T effector cell activities. To test this hypothesis, the first aim utilizes TNF deficient mice of 2 different backgrounds, autoreactive Sle1.TNF-/- mice induced with a TLR9 agonist and NZM2328.TNFR1/2 double deficient mice, to determine the mechanism for the signaling defect in GC B cells that alters B cell selection, and how T cells help to enhance this process. The second aim will address similar questions in TNFi treated patients using a novel fluorescent reagent to detect and isolate ANA reactive B cells combined with next generation sequencing technology. A combination of phenotyping and functional studies is used to determine T cells' influences. The results from this study will elucidate the effects of TNFi on regulating B cell tolerance and improve our understanding of how the immune system regulates B cell tolerance when GC formation is abnormal.

Quach 博士的中心目标是获得新技能，使她成为一名系统免疫学家。拟议的 研究结合了小鼠和人类研究，以确定 TNF 缺乏破坏耐受性的机制。 所获得的知识将指导未来为自身免疫患者设计个性化医疗的努力。 候选人：Quach 博士是范斯坦医学研究所 (FIMR) 的讲师。通过她的博士学位 在博士后工作中，她专注于人类 B 细胞的发育和调节。拟议的 职业发展计划将以她之前的经验为基础，通过四个培训目标来提升她的发展轨迹 成为一名独立研究者：1）获得利用小鼠模型的专业知识； 2）变得熟练 计算生物学； 3) 深入了解开展临床导向的研究项目，以及 4) 建立 生成预测模型的数据和方法的基础。 导师/环境：Quach 博士和她的导师 Anne Davidson 博士组建了一支强大的团队 顾问和合作者指导她完成拟议的培训和研究活动。拟议的 项目利用 FIMR 的知识、研究和临床设施以及可用资源 通过她的外部顾问和合作者 Steven Kleinstein 博士和 Inaki Sanz 博士。 FIMR 致力于 通过内部拨款以及网络和教育机会来支持初级教员。博士。 当当地无法提供最佳培训时，Quach 将参加国家研讨会/讲习班。 研究：使用 TNF 抑制剂 (TNFi) 治疗的患者可很好地诱导自身抗体和自身免疫。 已知；然而，TNFi 诱导 B 细胞耐受破坏的机制尚未确定。在 在人类中，TNFi 通过破坏至关重要的生发中心 (GC) 形成来影响 B 和 T 细胞稳态 用于高亲和力抗原特异性抗体生产和自身反应性 B 细胞的阴性选择。同样，在 小鼠中，TNF 信号传导缺陷阻止 GC 形成，诱导 TFH 和 CD4+IL-17 产生细胞扩增， 并改变自身抗体谱。这项研究提出，TNF 缺乏以及第二种诱导因素 刺激，通过减少阴性 GC B 细胞信号传导和增强 T 来损害 GC B 细胞选择 效应细胞活动。为了检验这一假设，第一个目标是利用 2 种不同背景的 TNF 缺陷小鼠， 用 TLR9 激动剂和 NZM2328.TNFR1/2 双缺陷小鼠诱导自身反应性 Sle1.TNF-/- 小鼠， 确定 GC B 细胞信号传导缺陷改变 B 细胞选择的机制，以及 T 细胞如何提供帮助 来加强这个过程。第二个目标将使用一种新颖的方法解决接受 TNFi 治疗的患者中的类似问题。 荧光试剂结合下一代测序检测和分离 ANA 反应性 B 细胞 技术。结合表型分析和功能研究来确定 T 细胞的影响。这 这项研究的结果将阐明 TNFi 对调节 B 细胞耐受性的影响，并改善我们的 了解当 GC 形成异常时免疫系统如何调节 B 细胞耐受性。