Innate Immunity Activation In Pathogenesis of Sjogren's Syndrome

干燥综合征发病机制中的先天免疫激活

• 批准号: 7896758
• 负责人: Umesh S Deshmukh
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896758
• 关键词: Address; Adenovirus Vector; Adenoviruses; Affect; Agonist; Area; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Biological Models; Cells; Characteristics; Chronic; Complication; Data; Development; Disease; Epithelial Cells; Functional disorder; Gene Expression; Genes; Gland; Human; IFNAR1 gene; Immune response; Infiltration; Inflammation; Inflammatory; Interferon Type I; Interferons; Investigation; Lacrimal gland structure; Leucocytic infiltrate; Link; Lymphocyte; Modeling; Mus; Natural Immunity; Pathogenesis; Pathway interactions; Patients; Play; Poly I-C; Production; Recombinants; Research; Role; Salivary; Salivary Glands; Sialadenitis; Sjogren' s Syndrome; Submandibular gland; Symptoms; Syndrome; TLR2 gene; Techniques; Testing; Time; Up-Regulation; Virus Diseases; Work; Xerostomia; adaptive immunity; base; cell type; chemokine; chemokine receptor; clinically relevant; cytokine; eye dryness; human TLR3 protein; immune activation; interferon alpha receptor; interferon alpha-beta receptor; lipoteichoic acid; loss of function; mouse model; novel; novel strategies; public health relevance; receptor expression; research study

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.

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，表现为特征性的口干和眼干症状。腺体内炎症细胞因子的产生是重要的致病因素该提案将研究先天免疫激活在 SS 发展中的作用，特别强调 I 型干扰素 (IFN)。该提案将检验 I 型 IFN 局部产生的假设。唾液腺内的免疫应答在 SS 的发病机制中发挥着关键作用，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。 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。该实验将在具有自身免疫倾向的 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 激动剂聚 (I:C) 可以激活先天免疫反应。 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。 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，并表征早期细胞浸润的相应趋化因子受体表达。 该提案将证明 I 型干扰素通过直接影响唾液腺功能和影响唾液腺上皮细胞趋化因子的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 型干扰素通路治疗提供逻辑基础。 公共健康相关性：当前的提案将确定口干综合症的机制，这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唾液腺损伤和功能丧失的病理机制。