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

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由应用程序提供）：原发性Sjögren综合征（SS）是一种系统性自身免疫性疾病，其特征是存在循环自身抗体，泪和唾液网格的炎症（SG）以及眼睛和嘴巴的干燥性。我们研究的长期目标是了解SS发病机理中的一个关键问题：针对细胞内蛋白的自身抗体如何在SS中发挥致病作用？提案将集中于RO52反应性自身抗体。几乎70％的SS患者的抗RO52阳性，其存在与较高的疾病严重程度有关。但是，RO52反应性自身抗体在SS发病机理中的确切作用仍然未知。通过使用俄克拉荷马州Sjögren综合征转化研究中心和新型实验小鼠模型系统在我们的实验室中开发的新型患者材料，该建议将研究SS抗RO52自身抗体的致病作用。我们实验室的工作首先确定，先天免疫的系统性激活直接参与SS发病机理的不同方面。我们最近发表的工作首次证明了RO52产生的抗体反应直接参与SG功能障碍。基于我们的大量发布和初步数据，该提案将检验一个总体假设，即活化的先天免疫学和抗RO52自身抗体之间的相互作用在SS发病机理中起着至关重要的作用。在AIM 1中，我们将评估负责SG自身抗体沉积的先天免疫学机制。我们将检验以下假设：先天免疫学的体内激活上调SGS内的RO52表达，并影响组织内抗RO52抗体的沉积。在AIM 2中，我们将检验以下假设：SS患者SS的IgG沉积与SS发病机理有关。使用我们的新型RO52免疫模型，我们还将检验以下假设：抗体沉积和腺功能障碍代表SS的早期阶段，随后是唾液腺中的淋巴细胞浸润。在AIM 3中，我们将评估SS中I型IFN响应的抗RO52抗体介导的调节的机制。基于我们的初步数据，我们将检验以下假设：渗透抗RO52抗体会干扰RO52的细胞功能，并在唾液腺和铂类树突状细胞中引起I型IFN反应失调。该提案汇集了一群专家团队。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解决了最普遍的自身免疫性疾病之一的致病机制。通过整合多个专业知识，一种新型的小鼠模型系统和独特的SS患者材料，该建议将定义负责SS中先天免疫学和自身抗体介导的SG病理学的机制。