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：
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
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/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

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

展开

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，对于全身性狼疮的多个器官的损害至关重要红斑（SLE）。尽管有明确的证据将IC与SLE的发病机理联系起来，但鉴定了ICS 形式以及影响组织中IC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细胞分泌表达抗原的细胞外囊泡（EV）特定表面IgG并结合抗原。此外，我们已经确定了富有狼疮的小鼠的循环IgG+ evs 结合核抗原，被嗜中性粒细胞吸收，并定位在肾脏上。 SLE患者的最新研究还确定了循环中的电动汽车，即在其表面上共表达IgG和核抗原随着整个血浆中抗核抗体滴度的增加。基于这些数据，我们提出了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（即一个IC），或通过与先天免疫系统的多种细胞相互作用，然后间接有助于狼疮的发病机理。我们将使用新型的记者小鼠菌株检验该假设，该假设允许体内从类别开关的IgG+ B细胞得出的EV的跟踪，隔离和功能询问。因为很少了解IC在体内如何形成以及它们如何促进自身免疫性中的炎症免疫反应，我们提出了一系列探索性实验，以评估B细胞衍生的EV的固有生物物理特性，以及B细胞衍生的电动汽车对IC形成以及控制炎症反应的影响在健康和自身免疫性疾病状态下，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并分子定义 B细胞子集产生表达IgG的EV。这些实验将为确定这种潜在的IC形成模式的功能和与疾病相关的功能障碍。我们的长期术语目标是调查B细胞衍生的电动汽车，以调节细胞间通信，调节有害 SLE中的宿主免疫反应，这可能提供新的治疗策略来减少炎症和组织受伤。