TNF deficiency induces breach of B cell tolerance via altering B cell regulatory signals

TNF 缺乏通过改变 B 细胞调节信号诱导 B 细胞耐受性的破坏

基本信息

批准号：
10432124
负责人：
Tam D Quach
金额：
$ 8.38万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
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：
2021-06-16 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432124
关键词：
Address Affect Affinity Agonist Anti-Inflammatory Agents Antibodies Antibody Formation Antigen-Antibody Complex Antigens Antinuclear Antibodies Autoantibodies Autoimmune Autoimmunity B-Cell Activation B-Lymphocytes Binding Biological CD22 gene Cells Clinical Clonal Expansion DNA Data Defect Demyelinating Diseases Development Disease Drug usage Enzymes Follicular Dendritic Cells Homeostasis Human Immune response Immune system Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Individual Interleukin-17 Knowledge Ligands Lupus Mediating Memory Memory B-Lymphocyte Mus Mutate Opportunistic Infections PTPN6 gene PTPRC gene Pathogenicity Pathway interactions Patient Selection Patients Peripheral Pharmaceutical Preparations Plasma Plasma Cells Play Pristane Production Psoriasis RNA Reaction Reagent Regulation Reporting Rheumatoid Arthritis Risk Role SLEB1 gene Self Tolerance Signal Transduction Signaling Molecule Stimulus Structure Structure of germinal center of lymph node Systemic Lupus Erythematosus T-Lymphocyte TLR2 gene TLR7 gene TNF gene TNFRSF1A gene TNFRSF1B gene Testing Tumor Necrosis Factor-Beta United States Vasculitis arm autoreactive B cell autoreactivity chronic autoimmune disease cohort drug development ds-DNA effective therapy effector T cell glycosylation improved individual patient inhibitor long term memory male mouse model novel overexpression prevent response restoration safe patient side effect

项目摘要

PROJECT SUMMARY 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 small focused study proposes that TNF deficiency, together with a second inducing stimulus, compromises B cell selection via reduction of negative B cell signaling and enhancement of T effector cell activities. To test this hypothesis, the first aim utilizes: 1) TNF deficient mice of 2 different backgrounds, autoreactive Sle1.TNF-/- mice induced with a TLR9 agonist and NZM2328.TNFR1/2 double deficient mice, and 2) Sle1.TNF-/-.Yaa, in which male mice over express TLR7, to determine the mechanism for the signaling defect of activated B cells that alters B cell selection via either GC and/or extrafollicular pathway. The second aim will address similar questions in TNFi treated patients by identifying changes in CD22 binding dynamics which thereby affect BCR signaling in autoreactive B cells. This aim is made possible due to the development of the novel ANA reagent that identify enriched autoreactive B cells in both humans and mice. 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 in GC and extrafollicular pathways.

项目概要众所周知，接受 TNF 抑制剂 (TNFi) 治疗的患者会产生自身抗体和自身免疫。然而，TNFi 诱导 B 细胞耐受破坏的机制尚未确定。在人类中， TNFi 通过破坏生发中心 (GC) 的形成来影响 B 细胞和 T 细胞的稳态，而生发中心 (GC) 的形成对于高血糖至关重要。亲和抗原特异性抗体的产生和自身反应性 B 细胞的阴性选择。同样，在小鼠中， TNF 信号传导缺陷可阻止 GC 形成，诱导 TFH 和 CD4+IL-17 产生细胞扩增，并且改变自身抗体谱。这项小型重点研究提出，TNF 缺乏以及第二种诱导刺激，通过减少负 B 细胞信号传导和增强 B 细胞选择来损害 B 细胞选择 T 效应细胞活性。为了检验这一假设，第一个目标利用：1) 2 种不同的 TNF 缺陷小鼠背景，用 TLR9 激动剂和 NZM2328.TNFR1/2 双诱导的自身反应性 Sle1.TNF-/- 小鼠缺陷小鼠，以及 2) Sle1.TNF-/-.Yaa，其中雄性小鼠过度表达 TLR7，以确定活化 B 细胞的信号传导缺陷，通过 GC 和/或滤泡外途径改变 B 细胞选择。第二个目标将通过识别 CD22 结合的变化来解决 TNFi 治疗患者中的类似问题从而影响自身反应性 B 细胞中的 BCR 信号传导。这一目标之所以成为可能，是因为开发新型 ANA 试剂，可识别人类和小鼠体内富集的自身反应性 B 细胞。这这项研究的结果将阐明 TNFi 对调节 B 细胞耐受性的影响，并改善我们的了解免疫系统如何调节 GC 和滤泡外途径中的 B 细胞耐受性。