Innate immunity and autoantibodies in the pathogenesis of Sjogren's Syndrome

干燥综合征发病机制中的先天免疫和自身抗体

• 批准号: 9340332
• 负责人: Umesh S Deshmukh
• 金额: $ 10万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-07 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340332
• 关键词: Address; Affect; Antibodies; Antibody Response; Autoantibodies; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Biological Models; Biopsy; Cell Culture Techniques; Cell Line; Cell physiology; Cells; Center for Translational Science Activities; Chronic; Classification; Clinical; Data; Dendritic Cells; Deposition; Development; Diagnosis; Diagnostic tests; Disease; Ductal Epithelial Cell; Epithelial Cells; Functional disorder; Genetic; Goals; Health; Human; IRF1 gene; IRF3 gene; Immune; Immune Sera; Immunization; Immunoglobulin G; Immunologist; In Situ; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Interferons; Interleukin-1; Knowledge; Labial Salivary Gland; Laboratories; Lacrimal gland structure; Lead; Link; Lymphocyte; Mediating; Modeling; Molecular; Monitor; Mus; Natural Immunity; New Zealand; Oklahoma; Oral cavity; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Play; Poly I-C; Production; Proteins; Publishing; Research; Research Personnel; Resources; Role; Saliva; Salivary Glands; Severity of illness; Sialadenitis; Sjogren' s Syndrome; Staging; Stimulus; Symptoms; Testing; Time; Tissues; Ubiquitin; Ubiquitination; Work; Xerostomia; aluminum sulfate; base; cytokine; eye dryness; genetic signature; in vivo; inhibiting antibody; mouse model; novel; novel diagnostics; overexpression; response; systemic autoimmune disease

 DESCRIPTION (provided by applicant): Primary Sjögren's syndrome (SS) is a systemic autoimmune disorder characterized by the presence of circulating autoantibodies, inflammation of lacrimal and salivary glands (SG), and a debilitating dryness of the eyes and mouth. The long term goal of our research is to understand a critical question in SS pathogenesis: how do autoantibodies targeting intracellular proteins exert pathogenic effects in SS? This proposal will focus on Ro52-reactive autoantibodies. Almost 70% of SS patients are positive for anti-Ro52 and their presence is associated with higher disease severity. However, the precise role of Ro52-reactive autoantibodies in SS pathogenesis remains unknown. By using unique patient material available to us in the Oklahoma Sjögren's Syndrome Center of Translational Research and novel experimental mouse model systems developed in our laboratory this proposal will investigate the pathogenic role of anti-Ro52 autoantibodies in SS. Work from our laboratory has firmly established that systemic activation of innate immunity is directly involved in different facets of SS pathogenesis. Our recently published work demonstrates for the first time that Ro52- generated antibody responses are directly involved in SG dysfunction. Based on our substantial published and preliminary data, this proposal will test the overall hypothesis that interactions between activated innate immunity and anti-Ro52 autoantibodies play a critical role in SS pathogenesis. In Aim 1, we will assess innate immune mechanisms responsible for autoantibody deposition in SG. We will test the hypothesis that in vivo activation of innate immunity upregulates Ro52 expression within the SGs, and influences deposition of anti-Ro52 antibodies within the tissue. In Aim 2, we will test the hypothesis that IgG deposition in SGs of SS patients is associated with SS pathogenesis. Using our novel Ro52-immunization model we will also test the hypothesis that antibody deposition and glandular dysfunction represent the early stage of SS, which is followed by lymphocytic infiltration in salivary glands. In Aim 3, we will evaluate the mechanisms of anti-Ro52 antibody mediated modulation of type I IFN response in SS. Based on our preliminary data we will test the hypothesis that cell penetrating anti-Ro52 antibodies interfere with the cellular functions of Ro52 and cause a dysregulated type I IFN response in salivary gland and plasmacytoid dendritic cells. This proposal brings together a diverse team of experts; immunologists, geneticists, molecular biologist, biostatisticians and clinical researchers to address the pathogenic mechanisms of one of the most prevalent autoimmune disorder. By integrating multiple expertise, a novel mouse model system and unique SS patient material, this proposal will define the mechanism(s) responsible for innate immunity and autoantibody-mediated SG pathology in SS.

 描述（由申请人提供）：原发性干燥综合征（SS）是一种全身性自身免疫性疾病，其特征为存在循环自身抗体、泪腺和唾液腺（SG）炎症以及使人虚弱的眼和口干燥。我们研究的长期目标是了解SS发病机制中的一个关键问题：靶向细胞内蛋白的自身抗体如何在SS中发挥致病作用？该提案将集中于Ro 52反应性自身抗体。几乎70%的SS患者抗Ro 52阳性，其存在与较高的疾病严重程度相关。然而，Ro 52反应性自身抗体在SS发病机制中的确切作用仍然未知。通过使用独特的患者材料提供给我们在俄克拉荷马州Sjögren综合征转化研究中心和新的实验小鼠模型系统在我们的实验室中开发的这个建议将调查抗Ro 52自身抗体在SS的致病作用。我们实验室的工作已经确定先天免疫的系统激活直接参与SS发病机制的不同方面。我们最近发表的工作首次证明Ro 52产生的抗体反应直接参与SG功能障碍。基于我们大量的已发表和初步数据，该提案将测试激活的先天免疫和抗Ro 52自身抗体之间的相互作用在SS发病机制中起关键作用的总体假设。在目标1中，我们将评估先天免疫机制负责自身抗体沉积在SG。我们将检验先天免疫的体内激活上调SG内Ro 52表达并影响组织内抗Ro 52抗体沉积的假设。在目的2中，我们将检验SS患者SG中IgG沉积与SS发病机制相关的假设。使用我们的新的Ro 52免疫模型，我们还将测试的假设，抗体沉积和腺体功能障碍代表SS的早期阶段，其次是淋巴细胞浸润唾液腺。在目的3中，我们将评估抗Ro 52抗体介导的SS中I型IFN应答的调节机制。基于我们的初步数据，我们将测试的假设，即细胞穿透性抗Ro 52抗体干扰Ro 52的细胞功能，并导致I型干扰素反应失调的唾液腺和浆细胞样树突状细胞。该提案汇集了不同的专家团队;免疫学家，遗传学家，分子生物学家，生物统计学家和临床研究人员，以解决最普遍的自身免疫性疾病之一的致病机制。通过整合多种专业知识，一种新的小鼠模型系统和独特的SS患者材料，该提案将定义SS中先天免疫和自身抗体介导的SG病理学的机制。