Innate Immunity Activation In Pathogenesis of Sjogren's Syndrome

描述(申请人提供)：SJ“格伦综合征(SS)是一种慢性自身免疫性疾病，以唾液和泪腺功能障碍为特征，表现为典型的口干和眼干症状。腺体内产生的炎性细胞因子是一个重要的致病因素。这项建议将研究先天免疫激活在SS的发展中的作用，特别是I型干扰素(干扰素)。这一建议将检验这一假说，即唾液腺中I型IFN的局部产生在SS的发病机制中发挥关键作用。具体目标如下：目的1.证明唾液腺内天然免疫反应的激活是导致腺体功能障碍的关键。目的2.证明I型干扰素支配淋巴细胞渗入SG，从而影响SG内的局部获得性免疫反应。实验将在倾向于自身免疫的NZB/W F1小鼠身上进行。I型IFN的作用将直接在缺乏干扰素(α和β)受体1(IFNAR-/-)的小鼠中得到解决。先天免疫反应将使用Toll样受体3激动剂Poly(I：C)来激活。为了确定局部炎症的影响，将使用逆行滴注技术将聚(I：C)输送到唾液腺中。在一些实验中，腺病毒载体将被用来诱导局部炎症。I型干扰素对SG趋化因子产生的影响将被研究，早期细胞浸润物的特征是相应的趋化因子受体的表达。这项建议将证明I型IFN通过直接影响唾液腺功能和影响唾液腺上皮细胞产生趋化因子来发挥其致病作用。这将影响炎症细胞的渗透，从而影响唾液腺内的适应性免疫反应。本研究结果将阐明I型干扰素在SS发病机制中的作用，并为针对SS的I型干扰素途径的治疗提供逻辑依据。 公共卫生相关性：目前的建议将确定口干综合征的机制，这是干燥综合征的一种常见并发症。拟议的研究将开发新的小鼠模型，以研究唾液腺损伤和功能丧失的病理机制。

DESCRIPTION (provided by applicant): Sj"gren's syndrome (SS) is a chronic autoimmune disorder characterized by salivary and lacrimal gland dysfunction, which manifests as the characteristic dry mouth and dry eye symptoms. Production of inflammatory cytokines within the glands is an important pathogenic factor. This proposal will investigate the role of innate immunity activation in the development of SS, with special emphasis on type I interferons (IFN). This proposal will test the hypothesis that localized production of type I IFNs within the salivary glands play a critical role in the pathogenesis of SS. Following specific aims are proposed: Aim 1. To demonstrate that activation of innate immune responses within the salivary glands is critical for inducing gland dysfunction. Aim 2. To demonstrate that type I IFN dictates lymphocytic infiltration into the SG and thereby influences localized adaptive immune responses within the SG. The experiments will be carried out in autoimmune prone NZB/W F1 mice. The role of type I IFNs will be directly addressed in mice lacking the interferon (alpha and beta) receptor 1 (IFNAR-/-). Innate immune responses will be activated using Toll-like receptor 3 agonist poly(I:C). To determine the effects of localized inflammation, poly(I:C) will be delivered into the salivary glands using retrograde instillation technique. In some experiments adenoviral vectors will be used to induce localized inflammation. The effects of type I IFN on SG chemokine production will be investigated and early cellular infiltrates characterized for corresponding chemokine-receptor expression. This proposal will demonstrate that type I IFNs exert their pathogenic effects by directly affecting the salivary gland function and by influencing the chemokine production by salivary gland epithelial cells. This will influence the inflammatory cell infiltration and thereby the adaptive immune responses within the salivary glands. The findings from this proposal will clarify the role of type I IFNs in the pathogenesis of SS and provide logical basis to therapeutically target the type I IFN pathway in SS. PUBLIC HEALTH RELEVANCE: The current proposal will identify the mechanisms for dry mouth syndrome, a common complication of Sj"gren's syndrome. The proposed studies will develop novel mouse models to study pathological mechanisms responsible for salivary gland damage and loss of function.