MECHANISMS OF AUTOIMMUNITY IN SLE

SLE 自身免疫机制

• 批准号: 8398955
• 负责人: DAVID STEPHEN PISETSKY
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8398955
• 关键词: Address; Antibodies; Antigen-Antibody Complex; Antinuclear Antibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Biochemical; Biological Markers; Cell Death; Cells; Cessation of life; Characteristics; Complex; DNA; Dendritic Cells; Deposition; Development; Disease; Frequencies; HMGB1 Protein; HMGB1 gene; Health; Healthcare; Histones; Immune; Immune Cell Activation; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Mediating; Membrane; Military Personnel; Modeling; Mus; Natural Immunity; Nuclear; Nuclear Antigens; Nucleic Acids; Nucleosomes; Outcome; Particulate; Pathogenesis; Phenotype; Play; Polymers; Population; Production; Property; RNA; RNA-Binding Proteins; Relative (related person); Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Tissues; Toll-like receptors; Vesicle; Veterans; Woman; abstracting; autoreactivity; base; chemical property; extracellular; improved; in vitro Model; in vivo; insight; macromolecule; macrophage; new therapeutic target; novel; public health relevance; receptor binding; research study; response; sensor; Address; Antibodies; Antigen-Antibody Complex; Antinuclear Antibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Biochemical; Biological Markers; Cell Death; Cells; Cessation of life; Characteristics; Complex; DNA; Dendritic Cells; Deposition; Development; Disease; Frequencies; HMGB1 Protein; HMGB1 gene; Health; Healthcare; Histones; Immune; Immune Cell Activation; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Mediating; Membrane; Military Personnel; Modeling; Mus; Natural Immunity; Nuclear; Nuclear Antigens; Nucleic Acids; Nucleosomes; Outcome; Particulate; Pathogenesis; Phenotype; Play; Polymers; Population; Production; Property; RNA; RNA-Binding Proteins; Relative (related person); Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Tissues; Toll-like receptors; Vesicle; Veterans; Woman; abstracting; autoreactivity; base; chemical property; extracellular; improved; in vitro Model; in vivo; insight; macromolecule; macrophage; new therapeutic target; novel; public health relevance; receptor binding; research study; response; sensor

DESCRIPTION (provided by applicant): Abstract Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of antinuclear antibodies (ANA) in association with multisystem inflammatory manifestations. These antibodies target a wide array of nuclear macromolecules and mediate disease in part by the formation of immune complexes that promote inflammation and tissue damage. While antibodies to nucleosomes and its DNA and histone components are the most characteristic of SLE, antibodies to RNA and RNA binding proteins may display similar pathogenetic properties. As shown in in vivo and in vitro experiments, nuclear antigens, including DNA, RNA and the high mobility group protein 1 (HMGB1), have activity as alarmins. Alarmins represent endogenous molecules that can be released from activated as well as dying cells and can stimulate innate immunity. Once they translocate into the extracellular milieu, nuclear antigens can stimulate toll-like receptors (TLRs), non-TLR nucleic acid sensors as well as receptors binding other components of the immune complexes. Because of their alarmin activity, nuclear molecules can play at least 3 roles in disease: 1) drive the production of antinuclear antibodies by autoantigen-specific B and T cells; 2) function as autoadjuvants to stimulate immune cell activation; and 3) form immune complexes that deposit in the tissue and incite inflammation. In view of these roles, the release or exposure of nuclear antigens in an immunologically relevant form is a key step in pathogenesis. To elucidate the release of nuclear antigens from cells, their physical-chemical properties and their signaling activity, we propose investigating these issues in in vivo and in vitro models. Specifically, we will explore the role of nuclear molecules as autoadjuvants and autoantigens in the context of microparticles. Microparticles are small membrane-bound vesicles which, like alarmins, are released from activated or dying cells and display immunostimulatory activity. Three specific aims are proposed: 1) To elucidate the in vivo and in vitro release of DNA, RNA and HMGB1 during activation and cell death, determining the relative distribution in soluble and particulate form; 2) To assess the antigenic properties of microparticles and their ability to form immune complexes in vitro and in vivo in autoimmune mice. These studies will determine whether complexes containing nucleic acids are comprised of microparticles; and 3) To define the immunological activity of microparticles, determining the contribution of DNA and RNA to their ability to stimulate macrophages and dendritic cells. These experiments will also explore novel cationic polymers to block these responses. Successful completion of these experiments will provide new insights in the pathogenic role in SLE of nuclear molecules in the form of microparticles as well as provide new biomarkers and potential targets of therapy.

描述（由申请人提供）： 抽象的全身性红斑狼疮（SLE）是一种原型自身免疫性疾病，其特征在于产生抗核抗体（ANA），与多系统炎症表现相关。这些抗体靶向各种核大分子，部分是由于促进炎症和组织损伤的免疫复合物的形成而介导了疾病。虽然对核小体及其DNA和组蛋白成分的抗体是SLE的最特征，但与RNA的抗体和RNA结合蛋白可能显示出相似的致病性能。如体内和体外实验所示，包括DNA，RNA和高迁移率蛋白1（HMGB1）在内的核抗原具有震撼力。警报代表可从激活和垂死的细胞中释放的内源分子，可以刺激先天免疫。一旦将它们转移到细胞外环境中，核抗原就可以刺激类似收费的受体（TLR），非TLR核酸传感器以及结合免疫复合物其他成分的受体。 由于其警报活性，核分子可以在疾病中至少发挥3个作用：1）驱动自身抗原特异性B和T细胞的抗核抗体产生； 2）充当自身助理，以刺激免疫细胞激活； 3）形成沉积在组织中的免疫复合物并引起炎症。鉴于这些作用，以免疫学相关的形式释放或暴露核抗原是发病机理的关键步骤。为了阐明细胞中核抗原的释放，它们的物理化学特性及其信号传导活性，我们建议在体内和体外模型中研究这些问题。具体而言，我们将探讨核分子作为自动助剂和自动抗原在微粒的背景下的作用。微粒是膜结合的小囊泡，如警报蛋白，是从活化或垂死的细胞中释放出来的，并显示出免疫刺激活性。 提出了三个具体目的：1）阐明激活和细胞死亡期间DNA，RNA和HMGB1的体内和体外释放，确定可溶性和颗粒形式的相对分布； 2）评估微粒的抗原特性及其在自身免疫小鼠中体外和体内形成免疫复合物的能力。这些研究将确定含有核酸的复合物是否由微粒组成。 3）定义微粒的免疫学活性，确定DNA和RNA对刺激巨噬细胞和树突状细胞的能力的贡献。这些实验还将探索新型的阳离子聚合物以阻止这些反应。这些实验的成功完成将为微粒形式的核分子SLE提供新的见解，并提供新的生物标志物和潜在的治疗靶标。