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

基本信息

批准号：
10549373
负责人：
Loren D Erickson
金额：
$ 20.19万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/10549373
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 Breeding Cell secretion Cells Circulation 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 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 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

项目摘要

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.

项目摘要免疫复合物 (IC) 会引起炎症，并且对于系统性狼疮中多个器官的损伤至关重要红斑狼疮（SLE）。尽管有明确的证据将 IC 与 SLE 的发病机制联系起来，但仍无法确定 IC 与 SLE 的发病机制之间的关系。 IC 的形式以及影响 IC 在组织中定位和致病性的因素仍然难以捉摸。我们的初步研究表明，活化的 B 细胞会分泌表达抗原的细胞外囊泡 (EV) 特异性表面 IgG 并结合抗原。此外，我们还从易患狼疮的小鼠中鉴定出循环 IgG+ EV 结合核抗原，被中性粒细胞摄取，并定位于肾脏。 SLE 患者的最新研究还发现了在其表面共表达 IgG 和核抗原的循环 EV，这与全血浆中抗核抗体滴度增加。根据这些数据，我们提出一个新的假设激活的 B 细胞释放的表达 IgG 的 EV 可以直接上调炎症途径（即， IC），或间接通过与先天免疫系统的多种细胞相互作用，从而促进狼疮的发病机制。我们将使用一种新的报告小鼠品系来测试这一假设，该品系允许在体内对源自类别转换 IgG+ B 细胞的 EV 进行跟踪、分离和功能询问。由于很少是了解 IC 在体内如何形成以及它们如何促进自身免疫中的炎症免疫反应，我们提出了一系列探索性实验来评估 B 细胞衍生的 EV 的内在生物物理特性，以及 B 细胞来源的 EV 对 IC 形成和炎症反应控制的影响健康和自身免疫性疾病状态下的先天免疫细胞（单核吞噬细胞；中性粒细胞）。我们将使用尖端技术严格分析单个 B 细胞衍生的 EV，并从分子角度定义产生表达 IgG 的 EV 的 B 细胞亚群。这些实验将为确定这种潜在的新型 IC 形成模式的功能和疾病相关功能障碍。我们的长期长期目标是研究 B 细胞衍生的 EV 在介导细胞间通讯、调节有害物质方面的作用。 SLE 中的宿主免疫反应，可能提供减少炎症和组织的新治疗策略受伤。