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

基本信息

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
项目类别：
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&apos 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

项目摘要

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 Sjögren综合征（SS）是一种自身免疫性疾病，外分泌组织受损，导致流泪和唾液的流失。初级SS（PSS）影响唾液和泪组织，并导致许多严重全身性疾病表现。一旦实现诊断，就不会可用的;相反，SS治疗是姑息治疗的。这是肯定需要确定将会的病因事件促进SS的早期诊断和治疗剂的发展，以减轻这种衰弱的进展疾病。我们实验室的研究表明，髓样分化因子一级反应蛋白88 （MYD88）对于PSS开发至关重要。 MyD88是一个衔接子分子，无处不在，是大多数Toll样受体（TLR）和IL-1受体（IL-1R）家族成员信号所需。值得注意的是，TLR和 IL-1R家族成员在局部（唾液组织）和SS患者的外周血细胞中升高，建议这些受体有助于SS。介导的特定配体和受体尚未深入评估PSS中MyD88依赖性途径。 TLR7是MyD88依赖性的在许多自身免疫性疾病中实施的内体TLR，尽管其在PSS中的作用仍然很大未知。我们的中心假设是B细胞中心TLR7依赖性信号网络驱动PSS 发病。我们的目的是确定B细胞的TLR7激活如何控制PSS疾病发病机理。我们将采用PSS鼠标模型（NOD.B10）和我们实验室中开发的点头小鼠的敲除菌株缺乏TLR7的表达。这些小鼠提供了一个独特的模型系统来检查TLR7在PSS中的作用直接地。该提案的理由取决于以下事实：在狼疮中，相关的自身免疫性疾病TLR7 B细胞的激活对于疾病发展至关重要。我们的初步数据表明TLR7激动剂加速PSS的开发并促进与年龄相关的B细胞（ABC）的扩展，A B细胞子集在小鼠和人类的自身免疫性中实施，但在PSS中仍然很少了解。我们将测试我们的通过完成两个特定目的的假设：（1）在体外评估PSS小鼠中TLR7依赖性B细胞激活（2）在体内以TLR7依赖性方式鉴定特定的B细胞子集，这些特定的B细胞子集以PSS介导PSS。这研究具有创新性，因为它将发现与MyD88依赖性信号的作用相关的新机制 PSS中的网络，将确定B细胞中TLR7激活如何控制特定疾病表现。这提案很重要，因为它将揭示主要控制PSS慢性炎症的新机制。见解从拟议的研究中获得的将揭示可针对的新型途径和特定细胞类型治疗PSS和其他自身免疫性疾病。奖学金培训计划详细介绍了全面的教育 PI的培训经验，包括研究经验，发展科学写作和演讲技能和参加国家会议。布法罗大学的环境非常出色，因为口腔生物学系有悠久的历史，为在口腔科学领域的成功职业做准备。