Analysis of MyD88-mediated immune activation in Sjogren's syndrome pathogenesis

MyD88介导的免疫激活在干燥综合征发病机制中的分析

• 批准号: 9530733
• 负责人: Jill Marie Kramer
• 金额: $ 35.74万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9530733
• 关键词: Address; Adoptive Transfer; Affect; Animals; Antibodies; Attenuated; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Automobile Driving; B-Lymphocytes; Binding; Biological Models; Blood Cells; Bone Marrow; Cells; Chronic; Data; Dendritic Cells; Development; Diagnosis; Disease; Early Diagnosis; Etiology; Event; Exhibits; Female; Foundations; Future; Generations; Health; Hematopoietic; Immune; Immune System Diseases; Immune System and Related Disorders; Immune signaling; Immune system; Immunoglobulin G; Immunoglobulins; Inbred NOD Mice; Individual; Inflammation; Inflammation Mediators; Inflammatory; Knock-out; Knowledge; Laboratories; Ligands; Lupus; Lymphoma; Mediating; Modeling; Molecular; Mus; Myelogenous; Oral; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral; Production; Proteins; Public Health; Receptor Signaling; Reporting; Role; Saliva; Salivary; Seminal; Signal Pathway; Signal Transduction; Signaling Molecule; Sjogren' s Syndrome; Source; Specificity; Symptoms; Systemic disease; TLR2 gene; TLR4 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Work; autoreactive B cell; biglycan; curative treatments; experience; experimental study; immune activation; improved; in vivo; innovation; lacrimal; mouse model; novel; overexpression; palliative; prevent; receptor expression; reconstitution; response; salivary cell

Project Summary/ Abstract Sjögren's syndrome (SS) is an autoimmune disease in which exocrine tissue is damaged, resulting in loss of tears and saliva production. The diagnosis of SS is challenging and patients often experience symptoms for years before they are diagnosed. 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 mitigate or abrogate the progression of this debilitating disease. Even though the immune system drives SS, few mechanistic studies of the seminal factors responsible for SS are reported. Studies in lupus, a related autoimmune disease, demonstrated that Myeloid Differentiation Factor Primary Response Protein 88 (MyD88) is critical for disease development. MyD88 is an adaptor molecule that is expressed ubiquitously and is required for most Toll-like receptor (TLR) signaling. Notably, TLRs are elevated locally (in salivary tissue) and in peripheral blood cells of SS patients, suggesting TLR signaling contributes to SS pathogenesis. Surprisingly, the role of MyD88 and TLR signaling has not been evaluated in depth in SS. Our central HYPOTHESES are that MyD88 expression in salivary tissue and in immune cells is crucial for SS initiation and progression and that TLR signals via MyD88 drive SS pathogenesis. Our OBJECTIVE is to evaluate the means by which MyD88-mediated signaling contributes to SS and to identify specific factors that activate TLR signaling pathways in SS. We will use a SS mouse model (NOD.B10) and our recently developed knockout strain of NOD.B10 mice that lack MyD88. These mice provide the opportunity to examine the role of MyD88 in SS. We will test our hypotheses through the following Specific Aims: (1) To determine whether MyD88 expression by hematopoietic cells is required for SS pathogenesis. These experiments will examine autoantibody production and salivary function to determine whether hematopoietic-intrinsic MyD88 expression is crucial for specific SS disease manifestations. (2) To evaluate the role of MyD88 in the generation and pathogenicity of autoantibodies in SS. These results will identify the role of MyD88 in the development of autoantibodies in SS, and will establish whether antibodies derived from MyD88-/- NOD.B10 mice have reduced pathogenicity in vivo. (3) To investigate the role of MyD88-dependent TLR2/4 activation in SS. We will determine whether signaling via TLR2/4 in salivary tissue contributes to SS in a MyD88-dependent manner. We will also overexpress a specific damage-associated molecular pattern that activates TLR2/4 in a MyD88-dependent manner to determine whether this accelerates SS. Finally, we will assess TLR2 and TLR4 blockade in SS to determine whether these attenuate disease. This study is innovative in that it will employ a novel mouse model to evaluate the role of MyD88, a key immune signaling molecule, in SS. The proposal is significant, as it will provide new knowledge regarding the role of MyD88 and TLR2/4 signaling in SS initiation and progression. This work will lay the foundation for future studies to identify therapeutics for patients with SS and other autoimmune diseases that target TLR/MyD88-related pathways.

项目摘要/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，导致泪水丢失 和唾液的产生。SS的诊断具有挑战性，患者通常会出现数年的症状 在他们被确诊之前。一旦诊断成功，就没有针对SS的治疗方案可用； 相反，对SS的治疗是姑息性的。因此，迫切需要确定病因事件，以便 早期诊断SS，减轻或消除这种使人衰弱的疾病的进展。即使是在 虽然免疫系统是SS的驱动力，但对SS的致病因素的机制研究报道较少。 狼疮是一种相关的自身免疫性疾病，研究表明髓系分化因子是主要的 反应蛋白88(MyD88)在疾病的发生发展中起关键作用。MyD88是一种接头分子， 表达广泛，是大多数Toll样受体(TLR)信号转导所必需的。值得注意的是，TLR提高了 SS患者局部(唾液组织)和外周血细胞中，提示TLR信号参与SS 发病机制。令人惊讶的是，MyD88和TLR信号在SS中的作用还没有得到深入的评估。我们的 中心假说是，MyD88在唾液组织和免疫细胞中的表达对SS的启动至关重要 而TLR信号通过MyD88驱动SS的发病机制。我们的目标是评估 MyD88介导的信号转导对SS的贡献以及识别激活TLR的特定因素的途径 SS中的信号通路。我们将使用SS小鼠模型(NOD.B10)和我们最近开发的基因敲除品系 缺乏MyD88的NOD.B10小鼠。这些小鼠为研究MyD88在SS中的作用提供了机会。我们 我将通过以下具体目标来检验我们的假设：(1)确定MyD88的表达是否通过 SS的发病需要造血细胞。这些实验将检查自身抗体的产生和 唾液功能以确定造血内源性MyD88表达是否对特定SS疾病至关重要 表现形式。(2)探讨MyD88在SS自身抗体产生和致病中的作用。 这些结果将确定MyD88在SS自身抗体发展中的作用，并将确定 来自MyD88-/-NOD.B10小鼠的抗体在体内降低了致病性。(三)调查政府的作用 SS中MyD88依赖的TLR2/4激活。我们将确定唾液组织中是否存在通过TLR2/4的信号 以MyD88依赖的方式对SS作出贡献。我们还将过度表达与特定损害相关的 以MyD88依赖的方式激活TLR2/4以确定这是否加速SS的分子模式。 最后，我们将评估TLR2和TLR4在SS中的阻断情况，以确定它们是否能减轻疾病。本研究 它的创新之处在于，它将使用一种新的小鼠模型来评估关键免疫信号MyD88的作用 分子，在SS中。这项建议意义重大，因为它将提供关于MyD88和MyD88作用的新知识 TLR2/4信号在SS的启动和进展中的作用。这项工作将为以后的研究奠定基础 治疗针对TLR/MyD88相关通路的SS患者和其他自身免疫性疾病。