Tracking Extracellular Vesicles Derived From B Cells in Autoimmunity

追踪自身免疫中 B 细胞衍生的细胞外囊泡

• 批准号: 10450549
• 负责人: Loren D Erickson
• 金额: $ 24.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-12 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450549
• 关键词: Adaptive Immune System; Address; Affect; Anatomy; Animal Model; Antibodies; Antibody titer measurement; Antigen-Antibody Complex; Antigens; Antinuclear Antibodies; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological; Biological Markers; Blood; Blood Circulation; Cells; Complement Receptor; Complex; Data; Deposition; Disease; Fc Receptor; Flow Cytometry; Functional disorder; Genetic; Goals; Hand; IgG autoantibodies; Immune Tolerance; Immune response; Immunization; Immunize; Immunoglobulin Class Switching; Immunoglobulin G; Individual; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Investigation; Keyhole Limpet Hemocyanin; Kidney; Knock-in; Knowledge; Label; Lead; Link; Lipids; Lupus; Measures; Mediating; Memory B-Lymphocyte; Methodology; Molecular; Mononuclear; Mouse Strains; Mus; Mutant Strains Mice; Neutrophil Activation; Nuclear; Nuclear Antigens; Nucleic Acids; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phagocytes; Phenotype; Plasma; Plasma Cells; Production; Property; Proteins; Reporter; Research Project Grants; Role; Series; Serum; Signal Transduction; Site; Source; Spatial Distribution; Structure of germinal center of lymph node; Surface; System; Systemic Lupus Erythematosus; T-Lymphocyte; Technology; Testing; Tissues; Vesicle; antigen binding; autoreactivity; base; biophysical properties; cell type; chronic autoimmune disease; conditional mutant; congenic; experimental study; extracellular vesicles; in vivo; intercellular communication; lupus prone mice; mouse model; nanoparticle; neutrophil; novel; novel strategies; novel therapeutic intervention; response; tissue injury; tool; uptake; vesicular release

PROJECT ABSTRACT Immune complexes (ICs) cause inflammation and are critical for the damage of multiple organs in systemic lupus erythematosus (SLE). Despite clear evidence linking ICs to the pathogenesis of SLE, identification of how ICs form and the factors that influence IC localization and pathogenicity in tissues has remained elusive. Our preliminary studies demonstrate that activated B cells secrete extracellular vesicles (EVs) that express antigen- specific surface IgG and bind antigen. Moreover, we have identified circulating IgG+ EVs from lupus-prone mice that bind nuclear antigens, are taken up by neutrophils, and localize to the kidney. Recent studies of SLE patients have also identified circulating EVs that co-express IgG and nuclear antigens on their surface which correlate with increased antinuclear antibody titers in whole plasma. Based on these data, we propose a novel hypothesis that IgG-expressing EVs released by activated B cells upregulate inflammatory pathways either directly (i.e., as an IC), or indirectly by interacting with a variety of cells of the innate immune system that then contribute to the pathogenesis of lupus. We will test this hypothesis using a novel reporter mouse strain that allows for the in vivo tracking, isolation, and functional interrogation of EVs derived from class-switched IgG+ B cells. Since little is known about how ICs form in vivo and how they promote inflammatory immune responses in autoimmunity, we propose a series of exploratory experiments to evaluate the intrinsic biophysical properties of B cell-derived EVs, and the effect of B cell-derived EVs on the formation of ICs and on the control of inflammatory responses of innate immune cells (mononuclear phagocytes; neutrophils) in healthy and autoimmune disease states. We will use cutting-edge technologies to rigorously analyze individual B cell-derived EVs and to molecularly define the B cell subsets that produce IgG-expressing EVs. These experiments will provide an important framework for determining the function and disease-related dysfunction of this potentially novel mode of IC formation. Our long- term goal is to investigate B cell-derived EVs in mediating intercellular communication, regulating deleterious host immune responses in SLE, which may provide new therapeutic strategies to reduce inflammation and tissue injury.

项目摘要 免疫复合体(IC)可引起炎症，并在系统性红斑狼疮的多器官损害中起关键作用 红斑狼疮(SLE)。尽管有明确的证据表明ICs与SLE的发病机制有关，但确定ICs是如何 IC的形态和影响IC在组织中的定位和致病性的因素仍然是未知的。我们的 初步研究表明，激活的B细胞分泌细胞外小泡(EVS)，表达抗原- 特异性表面免疫球蛋白和结合抗原。此外，我们还从狼疮易感小鼠中鉴定出循环中的igg+ev。 结合核抗原，被中性粒细胞摄取，并定位于肾脏。系统性红斑狼疮患者的最新研究进展 还发现了循环中的肠道病毒，它们在表面共同表达免疫球蛋白和核抗原，这些抗原与 全血浆中抗核抗体效价升高。基于这些数据，我们提出了一个新的假设 由活化的B细胞释放的表达免疫球蛋白的EV直接上调炎症途径(即，AS IC)，或间接通过与先天免疫系统的各种细胞相互作用，这些细胞随后有助于 狼疮的发病机制。我们将使用一种新的报告小鼠品系来验证这一假设，这种品系允许在体内 追踪、分离和功能询问来源于类别转换的免疫球蛋白G+B细胞的EV。因为很少是 我们知道IC是如何在体内形成的，以及它们是如何在自身免疫中促进炎症免疫反应的 提出了一系列探索性实验来评估B细胞来源的电动汽车的内在生物物理性质， B细胞来源的EVS在ICs形成和控制炎症反应中的作用 健康和自身免疫性疾病状态下的天然免疫细胞(单核巨噬细胞；中性粒细胞)。我们会 使用尖端技术严格分析单个B细胞来源的EV，并从分子上定义 产生表达免疫球蛋白的EVS的B细胞亚群。这些实验将提供一个重要的框架 确定这种潜在的新的IC形成模式的功能和疾病相关的功能障碍。我们的长- 学期目标是研究B细胞来源的EVS在调节细胞间通讯、调节有害物质方面的作用 SLE的宿主免疫反应，可能为减轻炎症和组织提供新的治疗策略 受伤。