Innate Immunity Activation In Pathogenesis of Sjogren's Syndrome

描述（申请人提供）：干燥综合征（SS）是一种以唾液腺和泪腺功能障碍为特征的慢性自身免疫性疾病，表现为特征性口干和眼干症状。腺体内炎性细胞因子的产生是重要的致病因素。本提案将研究先天免疫激活在SS发生中的作用，特别关注I型干扰素（IFN）。本提案将检验I型干扰素局部产生的假设提出了以下具体目标： 目标 1. 证明唾液腺内先天免疫反应的激活对于诱导腺体功能障碍至关重要。 目标 2. 证明 I 型 IFN 决定淋巴细胞浸润到 SG 中，从而影响 SG 内的局部适应性免疫反应。使用 Toll 样受体 3 激动剂聚 (I:C) 直接在缺乏干扰素（α 和 β）受体 1 (IFNAR-/-) 的小鼠中激活先天免疫反应。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。将研究趋化因子的产生，并表征相应趋化因子受体表达的早期细胞浸润，该提案将证明 I 型干扰素通过直接影响唾液腺功能并影响唾液腺上皮细胞的趋化因子产生来发挥其致病作用，这将影响炎症细胞浸润，从而影响唾液腺内的适应性免疫反应。该提案的结果将阐明 I 型干扰素在 SS 发病机制中的作用。治疗 SS 中 I 型 IFN 通路的逻辑基础。 公共健康相关性：当前提案将确定口干综合征的机制，口干综合征是干燥综合征的常见并发症。 拟议的研究将开发新型小鼠模型来研究导致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.