Microparticles as a Source of Nuclear Antigens in Systemic Lupus Erythematosus

微粒作为系统性红斑狼疮核抗原的来源

• 批准号: 7847568
• 负责人: DAVID STEPHEN PISETSKY
• 金额: $ 19.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-22 至 2012-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847568
• 关键词: Address; Antibodies; Antigen Targeting; Antigen-Antibody Complex; Antinuclear Antibodies; Atherosclerosis; Autoimmune Diseases; Binding; Biological Markers; Biological Models; Blood; Blood Cells; Cell Communication; Cell Line; Cell surface; Cells; Cessation of life; Clinical; DNA; Deposition; Development; Disease; Flow Cytometry; Goals; Immune; Immune Complex Diseases; Immune system; Immunoglobulin G; In Vitro; Indium; Inflammation; Interferons; Investigation; Kidney Diseases; Lupus; Membrane; Monitor; Morbidity - disease rate; Mus; Nature; Nuclear Antigens; Nucleic Acids; Nucleosomes; Organ; Pathogenesis; Pathogenicity; Patients; Plasma; Production; Property; Public Health; RNA; Role; Serum; Signal Transduction; Source; Structure; System; Systemic Lupus Erythematosus; Tissues; Vasculitis; body system; cytokine; extracellular; in vivo; in vivo Model; kidney vascular structure; macrophage; mortality; novel; novel strategies; nuclease; particle; public health relevance; research study; Address; Antibodies; Antigen Targeting; Antigen-Antibody Complex; Antinuclear Antibodies; Atherosclerosis; Autoimmune Diseases; Binding; Biological Markers; Biological Models; Blood; Blood Cells; Cell Communication; Cell Line; Cell surface; Cells; Cessation of life; Clinical; DNA; Deposition; Development; Disease; Flow Cytometry; Goals; Immune; Immune Complex Diseases; Immune system; Immunoglobulin G; In Vitro; Indium; Inflammation; Interferons; Investigation; Kidney Diseases; Lupus; Membrane; Monitor; Morbidity - disease rate; Mus; Nature; Nuclear Antigens; Nucleic Acids; Nucleosomes; Organ; Pathogenesis; Pathogenicity; Patients; Plasma; Production; Property; Public Health; RNA; Role; Serum; Signal Transduction; Source; Structure; System; Systemic Lupus Erythematosus; Tissues; Vasculitis; body system; cytokine; extracellular; in vivo; in vivo Model; kidney vascular structure; macrophage; mortality; novel; novel strategies; nuclease; particle; public health relevance; research study

DESCRIPTION (provided by applicant): The goal of these investigations is to elucidate the role of microparticles (MPs) as a key source of nuclear antigens in systemic lupus erythematosus (SLE) and characterize these structures as components of pathogenic immune complexes (ICs). MPs are small membrane-structures that are released from cells during cell activation or death. These particles contain DNA and RNA in a form that is protected from extracellular nucleases and allows binding of antinuclear antibodies (ANAs). As such, MPs may form immune complexes that can either deposit in the tissue or promote cytokine production including interferon- 1 (IFN). Because of the value of assessing MPs as target antigens in SLE and their effector function, we are proposing studies to address fundamental questions concerning the nature of ANA binding to MPs and their immunological effects. Three specific aims are proposed: 1) To analyze the binding of antinuclear antibodies to MPs generated in in vitro and in vivo model systems as well as those circulating in patient blood. The MPs in patient blood will be analyzed for binding to a panel of monoclonal anti-DNA and anti- nucleosome antibodies; 2) To analyze the expression of MPs in the blood of patients with SLE, focusing on particles with bound antibody, and determine the relationship to clinical manifestations and disease activity. Using plasma from lupus patients, circulating MPs will be quantified by flow cytometry in terms of cell surface markers, including bound Ig. The number and properties of MPs will be related to disease activity and organ-specific manifestations. Sera of patients with SLE will also be screened for binding to the in vitro-generated particles; and 3) To investigate the effects of ANAs on the immunological activities of microparticles in in vitro systems. The immunological effects of MPs on cytokine production by macrophage cell lines and peripheral blood cells will be assessed in vitro, characterizing effects of monoclonal ANA as well as IgG purified by patient sera. Together, these experiments will provide important new information on a novel group of subcellular signaling structures relevant to the pathogenesis of SLE as well as the development of novel biomarkers and new therapies. PUBLIC HEALTH RELEVANCE: These studies will focus on the role of microparticles in systemic lupus erythematosus (SLE), a prototypic autoimmune disease characterized by inflammation and damage of multiple organ systems. An important mechanism of this disease concerns the formation and deposition of immune complexes that contain nucleic acids. In these studies, we will explore the role of cellular microparticles as a source of this nucleic acid. Understanding the role of microparticles in the immune complex disease will provide information to allow the development of new treatments as well as markers to assess the course of SLE and its renal and vascular complications.

描述（由申请人提供）：这些研究的目的是阐明微粒（MPS）作为全身性红斑狼疮（SLE）（SLE）中核抗原的关键来源，并将这些结构作为致病免疫复合物（ICS）的组成部分。 MPS是小膜结构，在细胞激活或死亡过程中从细胞中释放出来。这些颗粒包含以保护不受细胞外核酸酶的形式的DNA和RNA，并允许抗核抗体（ANAS）结合。因此，MP可能形成可以沉积在组织中或促进包括干扰素1（IFN）的细胞因子产生的免疫复合物。由于评估MP作为SLE中的靶抗原及其效应子功能的价值，因此我们提出研究以解决有关ANA与MPS结合的性质及其免疫学效应的基本问题。提出了三个具体目的：1）分析抗核抗体与体外和体内模型系统中产生的MP的结合，以及患者血液中循环的抗体抗体。将分析患者血液中的MP与单克隆抗DNA和抗核小体抗体的结合。 2）分析SLE患者血液中MPS的表达，重点放在具有结合抗体的颗粒上，并确定与临床表现和疾病活性的关系。使用狼疮患者的血浆，将通过流式细胞仪（包括结合Ig）来定量流式细胞仪。 MP的数量和特性将与疾病活动和器官特异性表现有关。还将筛选患有SLE患者的血清与体外生成的颗粒结合； 3）研究ANA对体外系统中微粒免疫活性的影响。将在体外评估MPS对巨噬细胞系和外周血细胞细胞因子产生的免疫学影响，表征单克隆ANA的作用以及由患者血清纯化的IgG。总之，这些实验将提供有关与SLE发病机理以及新型生物标志物和新疗法相关的新型亚细胞信号结构的重要新信息。公共卫生相关性：这些研究将侧重于微粒在全身性红斑狼疮（SLE）中的作用，这是一种原型自身免疫性疾病，其特征在于多个器官系统的炎症和损害。这种疾病的重要机制是含有核酸的免疫复合物的形成和沉积。在这些研究中，我们将探讨细胞微粒作为该核酸的来源的作用。了解微粒在免疫复杂疾病中的作用将提供信息，以开发新的治疗方法，并评估SLE及其肾脏和血管并发症的过程。