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

TLR7 介导的 B 细胞激活在原发性干燥综合征中的作用

• 批准号: 10676443
• 负责人: Achamaporn Punnanitinont
• 金额: $ 3.45万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676443
• 关键词: Acceleration; Address; Adoptive Transfer; Affect; Age; Agonist; American; Animals; Antigen Presentation; Autoantibodies; Autoimmune Diseases; Autoimmunity; Automobile Driving; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Biological Models; Biological Response Modifiers; Blood Cells; Cell Compartmentation; Cells; Characteristics; Chronic; Data; Development; Diagnosis; Disease; Early Diagnosis; Endosomes; Environment; Etiology; Event; Exhibits; Exocrine Glands; Family member; Fellowship; Health; Human; Immune; Immune System Diseases; Immune system; In Vitro; Individual; Inflammation; Inflammatory; Interleukin-1 Receptors; Kidney; Knock-out; Laboratories; Ligands; Lung; Lupus; Mediating; Modeling; Mus; Myelogenous; Oral; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Production; Proteins; Public Health; Recording of previous events; Reporting; Research; Rest; Role; Saliva; Salivary; Science; Seminal; Signal Transduction; Sjogren' s Syndrome; Sorting; Symptoms; Systemic disease; T-Lymphocyte; TLR7 gene; Testing; Tissues; Toll-like receptors; Training; Training and Education; Universities; Writing; autoreactivity; burden of illness; career; cell type; curative treatments; cytokine; experience; experimental study; immune activation; improved; in vivo; innovation; insight; lacrimal; meetings; morphogens; mouse model; novel; oral biology; palliate; palliative; peripheral blood; polarized cell; receptor; response; skills; systemic autoimmune disease; targeted treatment; therapeutic development

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.

项目摘要 舍格伦综合征（SS）是一种自身免疫性疾病，其中外分泌组织受损，导致 眼泪和唾液的流失。原发性SS（pSS）影响唾液和泪腺组织，并导致许多严重的 全身性疾病表现。一旦确诊，没有SS特异性治愈性治疗选择， 可用;而SS的治疗是姑息性的。因此，迫切需要确定病因学事件， 促进SS的早期诊断和缓解这种衰弱性疾病进展的治疗方法的开发 疾病我们实验室的研究表明，髓样分化因子初级反应蛋白88 （MyD 88）是pSS发育所必需的。MyD 88是一种普遍表达的衔接分子， 大多数Toll样受体（TLR）和IL-1受体（IL-1 R）家族成员信号传导所需。值得注意的是，TLR和 IL-1 R家族成员在SS患者的局部（唾液组织）和外周血细胞中升高， 提示这些受体参与SS。介导细胞活化的特异性配体和受体 pSS中的Myd 88依赖性通路尚未进行深入评价。TLR 7是一种MyD 88依赖性蛋白。 内体TLR与许多自身免疫性疾病有关，尽管其在pSS中的作用仍然很大程度上 未知我们的中心假设是B细胞内在的TLR 7依赖性信号网络驱动pSS 发病机制我们的目的是确定B细胞的TLR 7活化如何控制pSS疾病的发病机制。我们 将使用我们实验室开发的pSS小鼠模型（NOD.B10）和NOD.B10小鼠的敲除品系 缺乏TLR 7表达的细胞。这些小鼠提供了一个独特的模型系统，以检查TLR 7在pSS中的作用 直接.这一提议的基本原理是基于这样一个事实，即在狼疮（一种相关的自身免疫性疾病）中，TLR 7 B细胞的活化对于疾病的发展是至关重要的。我们的初步数据显示，TLR 7激动 加速pSS发育并促进与年龄相关的B细胞（ABC）（一种B细胞亚群）的扩增 与小鼠和人类的自身免疫有关，但在pSS中仍然知之甚少。我们将测试我们的 通过完成两个具体目标来假设：（1）体外评估pSS小鼠中TLR 7依赖性B细胞活化 和（2）鉴定在体内以TLR 7依赖性方式介导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MyD 88依赖性信号作用相关的新机制 pSS中的网络，并将确定B细胞中的TLR 7激活如何控制特定的疾病表现。这 这项提议意义重大，因为它将揭示pSS中控制慢性炎症的新机制。见解 从拟议的研究中获得的结果将揭示新的途径和特定的细胞类型，可以靶向 治疗pSS和其他自身免疫性疾病。研究金培训计划详细介绍了一个全面的教育 PI的培训经验，包括研究经验、科学写作和演示的发展 技能和参加国家会议。布法罗大学的环境非常出色， 口腔生物学系有着悠久的历史，为口腔科学的成功事业做好准备。