Innate Immunity Activation In Pathogenesis of Sjogren's Syndrome

描述（申请人提供）：Sj"gren's syndrome （SS）是一种以唾液和泪腺功能障碍为特征的慢性自身免疫性疾病，表现为特征性的口干和眼干症状。腺体内炎性细胞因子的产生是一个重要的致病因素。本研究将探讨先天免疫激活在SS发展中的作用，特别强调I型干扰素（IFN）。本研究将验证唾液腺内I型ifn的局部产生在SS发病机制中起关键作用的假设。提出以下具体目标：证明唾液腺内先天免疫反应的激活是诱导腺体功能障碍的关键。目标2。证明I型IFN指示淋巴细胞浸润到SG，从而影响SG内的局部适应性免疫反应。该实验将在自身免疫易感性的NZB/W F1小鼠中进行。I型ifn的作用将在缺乏干扰素（α和β）受体1 （IFNAR-/-）的小鼠中直接得到解决。使用toll样受体3激动剂poly（I:C）可以激活先天免疫反应。为了确定局部炎症的影响，poly（I:C）将通过逆行滴注技术进入唾液腺。在一些实验中，腺病毒载体将用于诱导局部炎症。I型IFN对SG趋化因子产生的影响将被研究，并以相应的趋化因子受体表达为特征的早期细胞浸润。本提案将证明I型ifn通过直接影响唾液腺功能和影响唾液腺上皮细胞的趋化因子产生来发挥其致病作用。这将影响炎症细胞的浸润，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IFN在SS发病机制中的作用，并为治疗SS中的I型IFN通路提供逻辑依据。

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.