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

 描述(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，其特征是循环自身抗体的存在，泪腺和唾液腺(SG)的炎症，以及令人衰弱的眼睛和口腔干燥。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：针对细胞内蛋白的自身抗体如何在SS中发挥致病作用？该提案将重点放在Ro52反应性自身抗体上。近70%的SS患者抗Ro52抗体阳性，他们的存在与较高的疾病严重程度有关。然而，Ro52反应性自身抗体在SS发病机制中的确切作用仍不清楚。通过使用俄克拉荷马州Sjögren综合征转化研究中心提供的独特患者材料和我们实验室开发的新型实验小鼠模型系统，该建议将研究抗Ro52自身抗体在SS中的致病作用。我们实验室的工作已经确定，系统的天然免疫激活直接参与SS发病的不同方面。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了SG功能障碍。基于我们大量已发表的和初步的数据，这一建议将检验激活的先天免疫和抗Ro52自身抗体之间的相互作用在SS发病中起关键作用的总体假设。在目标1中，我们将评估导致SG中自身抗体沉积的先天免疫机制。我们将检验这样一种假设，即在体内，天然免疫的激活上调了SGS中Ro52的表达，并影响了抗Ro52抗体在组织中的沉积。在目的2中，我们将验证SS患者SGS中的免疫球蛋白沉积与SS发病相关的假说。使用我们新的Ro52免疫模型，我们还将检验抗体沉积和腺体功能障碍代表SS早期阶段的假设，随后是唾液腺中的淋巴细胞渗透。在目的3中，我们将探讨抗Ro52抗体调节SS中I型干扰素应答的机制。基于我们的初步数据，我们将检验一种假设，即细胞穿透抗Ro52抗体干扰Ro52的细胞功能，并在唾液腺和浆细胞样树突状细胞中引起失调的I型干扰素反应。这项建议汇集了不同的专家团队，包括免疫学家、遗传学家、分子生物学家、生物统计学家和临床研究人员，以解决这种最普遍的自身免疫性疾病之一的致病机制。通过综合多种专业知识、一种新颖的小鼠模型系统和独特的SS患者材料，该建议将确定SS的先天免疫和自身抗体介导的SG病理机制(S)。

 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.