MECHANISMS OF AUTOIMMUNITY IN SLE

SLE 自身免疫机制

• 批准号: 8044328
• 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/8044328
• 关键词: 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; Disease; HMGB1 Protein; HMGB1 gene; Histones; Immune Cell Activation; In Vitro; Inflammation; Inflammatory; Mediating; Membrane; Modeling; Mus; Natural Immunity; Nuclear; Nuclear Antigens; Nucleic Acids; Nucleosomes; Particulate; Pathogenesis; Play; Polymers; Production; Property; RNA; RNA-Binding Proteins; Relative (related person); Research; Research Personnel; Role; Signal Transduction; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Tissues; Toll-like receptors; Vesicle; abstracting; base; chemical property; extracellular; in vitro Model; in vivo; insight; macromolecule; macrophage; new therapeutic target; novel; 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. PUBLIC HEALTH RELEVANCE: Project Narrative These studies are relevant to the health of veterans by addressing key issues in the pathogenesis of autoimmune disease. Like other autoimmune diseases, SLE is growing in frequency as the number of women in the military increases. By elucidating the role of extracellular nuclear molecules in forming pathogenic immune complexes, these studies will provide new insights into the mechanisms of inflammation and autoreactivity in SLE. These studies could suggest new biomarkers for autoimmune diseases based on assessing microparticle number and phenotype. Finally, our studies on the immune properties of microparticles could identify new signaling pathways operating in autoimmunity, allowing the development of more effective immunosuppressive agents to improve outcomes and reduce the burden of health care in the veteran population.

描述（由申请人提供）： 摘要系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病，其特征是产生抗核抗体（ANA）并伴有多系统炎症反应。这些抗体靶向广泛的核大分子，并通过形成促进炎症和组织损伤的免疫复合物来介导疾病。虽然核小体及其DNA和组蛋白成分的抗体是SLE最具特征的，但RNA和RNA结合蛋白的抗体可能显示出相似的致病特性。如在体内和体外实验中所示，核抗原，包括DNA、RNA和高迁移率族蛋白1（HMGB 1），具有作为警报素的活性。Alarmins代表内源性分子，其可以从激活的以及垂死的细胞释放，并且可以刺激先天免疫。一旦它们易位到细胞外环境中，核抗原可以刺激Toll样受体（TLR）、非TLR核酸传感器以及结合免疫复合物的其他组分的受体。 由于其alarmin活性，核分子可在疾病中发挥至少3种作用：1）驱动自身抗原特异性B和T细胞产生抗核抗体; 2）作为自身佐剂刺激免疫细胞活化; 3）形成免疫复合物，其存款在组织中并引发炎症。鉴于这些作用，以免疫相关形式释放或暴露核抗原是发病机制中的关键步骤。为了阐明从细胞中释放的核抗原，它们的物理化学性质和它们的信号传导活性，我们建议在体内和体外模型中研究这些问题。具体来说，我们将探讨核分子作为自身佐剂和自身抗原的微粒的上下文中的作用。微粒是小的膜结合囊泡，其像警报素一样，从活化或垂死的细胞释放并显示免疫刺激活性。 提出了三个具体目标：1）阐明在活化和细胞死亡期间DNA、RNA和HMGB 1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;和3）为了定义微粒的免疫活性，确定DNA和RNA对其刺激巨噬细胞和树突细胞的能力的贡献。这些实验还将探索新的阳离子聚合物来阻断这些反应。这些实验的成功完成将为以微粒形式存在的核分子在SLE中的致病作用提供新的见解，并提供新的生物标志物和潜在的治疗靶点。 公共卫生关系： 这些研究通过解决自身免疫性疾病发病机制中的关键问题与退伍军人的健康相关。像其他自身免疫性疾病一样，SLE的发病率随着军队中女性人数的增加而增加。通过阐明细胞外核分子在形成致病性免疫复合物中的作用，这些研究将为SLE的炎症和自身反应机制提供新的见解。这些研究可以基于评估微粒数量和表型为自身免疫性疾病提出新的生物标志物。最后，我们对微粒免疫特性的研究可以识别在自身免疫中发挥作用的新信号通路，从而开发出更有效的免疫抑制剂，以改善结果并减轻退伍军人群体的医疗保健负担。