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: 8064723
• 负责人: Umesh S Deshmukh
• 金额: $ 19.06万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064723
• 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 Glands; Sialadenitis; Sjogren' s Syndrome; Submandibular gland; Symptoms; Syndrome; T-Lymphocyte; 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（由申请人提供）：SJ“ Gren's综合征（SS）是一种慢性自身免疫性疾病，其特征是唾液和泪腺功能障碍，表现为特征性的口腔和干眼症状。在腺体内的炎症性细胞系的产生特征是腺体内的炎症性因素是一种重要的病原因素。干扰素（IFN）将测试唾液腺内I型IFN的定位，在SS的发病机理中起关键的作用。因此，SG会影响SG内的局部自适应反应。 i：c确定局部炎症的影响，在某些实验中，将使用逆行灌输量将其诱导I ifn的炎症症状，以供应对早期的融合。 I型IFN通过直接影响唾液腺功能以及通过唾液腺上皮细胞的趋化因子产生而发挥其致病作用，这将影响炎症细胞浸润。 SS中的IFN路径。 公共卫生相关性：当前的提案将确定口腔综合征的机制，这是SJ“ Gren's综合征的常见并发症。拟议的研究将开发新的小鼠模型，以研究负责唾液腺损害和功能丧失的病理机制。