Analysis of MyD88-mediated immune activation in Sjogrens syndrome pathogenesis

项目摘要 舍格伦综合征（SS）是一种自身免疫性疾病，其外分泌组织受损， 眼泪和唾液。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。 疾病表现。一旦确诊，没有SS特异性治愈性治疗选择;相反， SS的治疗是姑息性的。因此，迫切需要识别病因事件，以促进早期诊断 SS的诊断和缓解这种使人衰弱的疾病的进展的疗法的开发。研究 在我们的实验室中发现，髓样分化因子主要反应蛋白88（MyD 88）是必需的， pSS开发。MyD 88是一种无处不在表达的衔接分子，是大多数Toll样细胞所需的 受体（TLR）和IL-1受体（IL-1 R）家族成员信号传导。值得注意的是，TLR和IL-1 R家族成员是 升高局部（唾液组织）和SS患者的外周血细胞，表明这些受体有助于 到SS。我们的中心假设是（i）组织特异性MyD 88表达决定了不同的pSS疾病 研究表明，（ii）MyD 88依赖性信号网络的激活驱动pSS发病机制。我们 目的是鉴定MyD 88的组织特异性贡献，并确定MyD 88介导的信号传导。 控制pSS疾病发病机制的网络。我们将采用pSS小鼠模型（NOD.B10）和条件性的 在我们的实验室中开发的NOD.B10小鼠的敲除品系在造血细胞中缺乏MyD 88的表达， 免疫细胞（Immune Cells）这些小鼠提供了一个独特的模型系统来检查MyD 88的作用 直接在pSS中。该提议的基本原理在于MyD 88介导的信号通路的激活 导致了许多自身免疫性疾病唾液组织和免疫细胞都表达受体， 炎症通过MyD 88，如TLR和IL-1 R家族成员。我们在MyD 88缺陷的pSS小鼠中的研究 表明MyD 88是pSS发病机制的关键;然而，表达MyD 88的特定细胞类型， 疾病和MyD 88依赖的信号通路，激活pSS是不完全理解。我们 将通过完成三个具体目标来检验我们的假设：（1）鉴定MyD 88的免疫细胞特异性贡献 pSS发病机制，（2）评估pSS中MyD 88依赖性IL-36相关细胞因子，和（3）评估 pSS中的MyD 88依赖性内体TLR，TLR 7和TLR 9。这项研究是创新的，因为它将揭示新的 与MyD 88依赖性信号网络在pSS中的作用相关的机制，并将识别特定的细胞类型 介导不同的pSS疾病表现。MyD 88依赖性TLR和IL-1 R家族的靶向阻断 成员信号通路代表了治疗pSS的创新治疗方法。这项建议 是重要的，因为它将揭示新的机制，管理慢性炎症的pSS。从以下方面获得的见解 这项研究将揭示新的途径，可以有针对性地治疗pSS和其他自身免疫疾病。

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. Our central hypotheses are that (i) tissue-specific MyD88 expression dictates distinct pSS disease manifestations and that (ii) activation of MyD88-dependent signaling networks drives pSS pathogenesis. Our objectives are to identify the tissue-specific contributions of MyD88 and to determine the MyD88-mediated signaling networks that govern pSS disease pathogenesis. We will employ a pSS mouse model (NOD.B10) and a conditional knockout strain of NOD.B10 mice developed in our laboratory that lacks expression of MyD88 in the hematopoietic compartment (immune cells) specifically. These mice provide a unique model system to examine the role of MyD88 in pSS directly. The rationale for this proposal rests on the fact that activation of MyD88-mediated signaling pathways contributes to many autoimmune diseases. Both salivary tissue and immune cells express receptors that promote inflammation via MyD88, such as TLRs and IL-1R family members. Our studies in pSS mice deficient in MyD88 demonstrate that MyD88 is crucial for pSS pathogenesis; however, the specific cell types that express MyD88 in disease and the MyD88-dependent signaling pathways that are activated in pSS are incompletely understood. We will test our hypotheses by completion of three specific aims: (1) Identify immune cell-specific contributions of MyD88 to pSS pathogenesis, (2) Evaluate MyD88-dependent IL-36-related cytokines in pSS, and (3) Assess the role of the MyD88-dependent endosomal TLRs, TLR7 and TLR9, in pSS. This study is innovative because it will uncover new mechanisms related to the role of MyD88-dependent signaling networks in pSS and will identify specific cell types that mediate distinct pSS disease manifestations. Targeted blockade of MyD88-dependent TLR and IL-1R family member signaling pathways represents an innovative therapeutic approach for the treatment of pSS. 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 that can be targeted to treat pSS and other autoimmune diseases.