Role of TLR7-mediated B cell activation in primary Sjogren’s syndrome

项目摘要 干燥综合征(SS)是一种自身免疫性疾病，外分泌组织受损，导致 流眼泪和流口水。原发性SS(PSS)影响唾液和泪腺组织，导致许多严重的 全身性疾病表现。一旦获得诊断，就没有SS特异性的治疗选择 更确切地说，SS的治疗是姑息性的。因此，迫切需要确定将导致 促进SS的早期诊断和治疗方法的发展，以减缓这种衰弱的进展 疾病。我们实验室的研究表明，髓系分化因子初级反应蛋白88 (MyD88)对于PSS开发是必不可少的。MyD88是一种普遍表达的接头分子， 大多数Toll样受体(TLR)和IL-1受体(IL-1R)家族成员信号转导所必需的。值得注意的是，TLR和 SS患者局部(唾液组织)和外周血细胞IL-1R家族成员升高， 提示这些受体参与了SS的形成。介导细胞活化的特定配体和受体 PSS中依赖MyD88的通路还没有得到深入的评估。TLR7是依赖于MyD88的 内体TLR与许多自身免疫性疾病有关，尽管其在PSS中的作用仍很大 未知。我们的中心假设是B细胞固有的TLR7依赖的信号网络驱动PSS 发病机制。我们的目标是确定B细胞的TLR7激活如何调控PSS疾病的发病机制。我们 将采用我们实验室开发的PSS小鼠模型(NOD.B10)和NOD.B10基因敲除小鼠 缺乏TLR7的表达。这些小鼠提供了一个独特的模型系统来检测TLR7在PSS中的作用 直接去吧。这一建议的理由是，在狼疮中，一种相关的自身免疫性疾病，TLR7 B细胞的激活对疾病的发展至关重要。我们的初步数据显示TLR7激动剂 加速PSS的发展并促进与年龄相关的B细胞(一种B细胞亚群)的扩张 与小鼠和人类的自身免疫有关，但在PSS中仍知之甚少。我们将测试我们的 两个特定目的的完成提出假说：(1)评估PSS小鼠体外依赖TLR7的B细胞活化 以及(2)在体内以TLR7依赖的方式确定介导PSS病理的特异性B细胞亚群。这 这项研究具有创新性，因为它将揭示与MyD88依赖的信号转导作用相关的新机制 并将确定B细胞中TLR7激活如何管理特定的疾病表现。这 这项提议意义重大，因为它将揭示治理PSS慢性炎症的新机制。真知灼见 从拟议的研究中获得的信息将揭示新的途径和特定的细胞类型，可以作为靶点 治疗PSS和其他自身免疫性疾病。团契培训计划详细说明了一项全面的教育 PI的培训经验，包括研究经验、科学写作和演示的发展 技能，以及参加国家会议。布法罗大学的环境非常好，因为 口腔生物学系在帮助学员在口腔科学领域取得成功方面有着悠久的历史。

Project Summary Sjögren’s syndrome (SS) is an autoimmune disease in which exocrine tissue is damaged, resulting in loss of tears and saliva. Primary SS (pSS) affects salivary and lacrimal tissue and results in many serious systemic disease manifestations. Once diagnosis is achieved, no SS-specific curative treatment options are available; rather treatments for SS are palliative. Thus, there is a critical need to identify etiologic events that will facilitate earlier diagnosis of SS and development of therapeutics that mitigate the progression of this debilitating disease. Studies in our laboratory revealed that Myeloid Differentiation Factor Primary Response Protein 88 (MyD88) is essential for pSS development. MyD88 is an adaptor molecule that is expressed ubiquitously and is required for most Toll-like receptor (TLR) and IL-1 receptor (IL-1R) family member signaling. Notably, TLRs and IL-1R family members are elevated locally (in salivary tissue) and in peripheral blood cells of SS patients, suggesting these receptors contribute to SS. The specific ligands and receptors that mediate activation of Myd88-dependent pathways in pSS have not, as yet, been evaluated in depth. TLR7 is a MyD88-dependent endosomal TLR that is implicated in many autoimmune diseases, although its role in pSS remains largely unknown. Our central hypothesis is that B cell-intrinsic TLR7-dependent signaling networks drive pSS pathogenesis. Our objective is to identify how TLR7 activation of B cells governs pSS disease pathogenesis. We will employ a pSS mouse model (NOD.B10) and a knockout strain of NOD.B10 mice developed in our laboratory that lacks expression of TLR7. These mice provide a unique model system to examine the role of TLR7 in pSS directly. The rationale for this proposal rests on the fact that in lupus, a related autoimmune disease, TLR7 activation of B cells is critical for disease development. Our preliminary data reveal that TLR7 agonism accelerates pSS development and promotes expansion of age-associated B cells (ABCs), a B cell subset implicated in autoimmunity in mice and humans, but one that remains poorly understood in pSS. We will test our hypothesis by completion of two specific aims: (1) Assess TLR7-dependent B cell activation in pSS mice in vitro and (2) Identify specific B cell subsets that mediate pathology in pSS in a TLR7-dependent manner in vivo. This study is innovative because it will uncover new mechanisms related to the role of MyD88-dependent signaling networks in pSS and will identify how TLR7 activation in B cells governs specific disease manifestations. This proposal is significant because it will reveal new mechanisms that govern chronic inflammation in pSS. Insights obtained from the proposed studies will reveal novel pathways and specific cell types that can be targeted to treat pSS and other autoimmune diseases. The fellowship training plan details a comprehensive educational training experience for the PI, including research experience, development of scientific writing and presentation skills, and participation in national meetings. The environment at the University of Buffalo is outstanding, as the Department of Oral Biology has a long history of preparing mentees for successful careers in the oral sciences.