Innate Immunity Activation In Pathogenesis of Sjogren's Syndrome

描述（由申请人提供）：干燥综合征（SS）是一种慢性自身免疫性疾病，其特征在于唾液腺和泪腺功能障碍，表现为特征性口干和干眼症状。 腺体内炎性细胞因子的产生是重要的致病因素。 这项建议将调查先天免疫激活的作用，在SS的发展，特别强调I型干扰素（IFN）。 该建议将检验这一假设，即局部生产的I型干扰素在唾液腺内发挥关键作用的发病机制的SS。 提出了以下具体目标：目标1。 证明唾液腺内先天免疫应答的激活对于诱导腺体功能障碍至关重要。目标二。 为了证明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应答。 实验将在自身免疫易感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-/-）的小鼠中直接解决。 使用Toll样受体3激动剂poly（I：C）激活天然免疫应答。 为了确定局部炎症的影响，将使用逆行滴注技术将poly（I：C）递送到唾液腺中。 在一些实验中，腺病毒载体将用于诱导局部炎症。 将研究I型IFN对SG趋化因子产生的影响，并以相应的趋化因子受体表达为特征的早期细胞浸润。 该建议将证明I型IFN通过直接影响唾液腺功能和通过影响唾液腺上皮细胞的趋化因子产生来发挥其致病作用。 这将影响炎性细胞浸润，从而影响唾液腺内的适应性免疫应答。 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I型干扰素通路治疗SS提供理论依据。 公共卫生相关性： 目前的建议将确定干燥综合征的机制，干燥综合征的常见并发症。 拟议的研究将开发新的小鼠模型，以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.