IL-4 Signaling Pathway Regulation of Sjogren's Syndrome

IL-4 信号通路对干燥综合征的调节

• 批准号: 6601460
• 负责人: AMMON B PECK
• 金额: $ 10.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6601460
• 关键词: B lymphocyte; NOD mouse; Sjogren's syndrome; acinar cell; apoptosis; autoantibody; autoimmune disorder; biological signal transduction; flow cytometry; gel electrophoresis; gene expression; histology; interleukin 4; lacrimal disorder; polymerase chain reaction; saliva; salivary glands; western blottings

DESCRIPTION: Sjogren's syndrome is a human autoimmune disease characterized by exocrine dysfunction resulting from the action of1 a chronic autoimmune attack against the lacrimal and salivary glands. It is one of the leading causes of salivary gland inflammation and dysfunction, leading to severe dryness of the ocular and oral surfaces. Diagnosis of Sjogren's syndrome includes detection of leukocytic infiltrates in the minor salivary glands, the presence of rheumatoid factor, hypergammaglobulinemia, specific anti-nuclear autoantibodies, loss of stimulated fluid secretion, and complaints of dry eyes and/or dry mouth. Over the past several years, the NOD mouse has been shown to exhibit numerous disease manifestations that parallel Sjogren's syndrome, including loss of stimulated fluid secretion concomitant with the appearance of leukocyte infiltrates in the lacrimal and salivary glands. Studies of autoimmune exocrinopathy in NOD mice have revealed that the disease can be separated into two phases: Phase 1 is characterized by pathophysiological and biochemical changes in the exude glands whose occurrence are independent of the autoimmune attack. Phase 2 is characterized by the appearance of leukocytic infiltrates in the exocrine glands, proinflammatory responses, autoantibodies to multiple acinar cell components, loss of acinar cell mass, and decline in exocrine function. The use of specific gene knockout mice congenic with the parental NOD mouse strain indicated that loss of exocrine function was dependent, first, on the presence of B cells and, second, expression of the intedeukin-4 (IL-4) cytokine. Subsequent studies suggested that IL-4 exerted its activity by regulating antibody isotypic class switching in B ceils. Nevertheless, IL-4 can activate two distinct signaling pathways in B ceils: the STAT-6 and the IRS pathways. The STAT-6 signaling pathway is involved in antibody class switching, while the IRS pathway is involved in B cell maturation and clonal deletion. Thus, the purpose of the current R21 grant application is to initiate studies examining the mechanism(s) by which IL-4 elicits its effector function in the development of exocrine gland dysfunction and decreased fluid secretion. Specifically, we plan to (t) document the autoimmune phenotype of a newly constructed NOD.B10.H-2b.B/c-STAT6 knockout mouse line and compare this phenotype to NOD.B10.H-2b, NOD.B10.H-2b.lgp KO and NOD.B10.H-2b.IL4 KO mice, and (2) identify if the IL-4 dependent development of exocrine gland dysfunction is due to activation of the STAT-6, IRS or both signal transduction pathway(s). Results from these studies will provide insight into the role of the cytokine, IL-4, and its effector mechanism in regulating development of the pathogenesis of Sjgren's syndrome. Identification of this effector mechanism could be important to the long-term goal of developing targeted preventive or early intervention strategies.

描述：Sjogren综合征是一种人类自身免疫性疾病，其特征是1慢性自身免疫性攻击对泪腺和唾液腺的慢性自身免疫性攻击引起的外分泌功能障碍。它是唾液腺炎症和功能障碍的主要原因之一，导致眼表面严重干燥。 Sjogren综合征的诊断包括检测次要唾液腺中的白细胞浸润，类风湿因子的存在，高γ-球蛋白血症，特异性抗核自身抗体，刺激性液体分泌的丧失以及眼睛干燥和/或口干的表现。在过去的几年中，已经显示出点头小鼠表现出许多疾病表现，使Sjogren综合征平行，包括刺激的液体分泌丧失与泪中和唾液腺中白细胞浸润的出现。对NOD小鼠的自身免疫性外分泌病的研究表明，该疾病可以分为两个阶段：第1阶段的特征是其发生的典型腺体生理学和生化变化的特征是其发生的独立于自身免疫性攻击。第2阶段的特征是在外分泌腺体中出现白细胞浸润，促炎反应，对多个腺泡细胞成分的自身抗体，腺泡细胞质量的损失以及外分泌功能下降。特定基因基因敲除小鼠与父母点头小鼠菌株的使用表明，外分泌功能的损失取决于B细胞的存在，其次是Intedeukin-4（IL-4）细胞因子的表达。随后的研究表明，IL-4通过调节B Ceils中的抗体同种类切换来发挥其活性。然而，IL-4可以激活B Ceils中的两个不同的信号通路：Stat-6和IRS途径。 Stat-6信号通路参与抗体类切换，而IRS途径参与B细胞成熟和克隆缺失。因此，当前R21赠款应用的目的是启动研究研究IL-4在外分泌腺功能障碍发展和液体分泌下降中引起其效应子功能的机制。具体而言，我们计划（t）记录新建的点头的自身免疫表型。功能障碍是由于Stat-6，IRS或两个信号转导途径的激活所致。这些研究的结果将洞悉细胞因子，IL-4及其效应器机制在调节SJ Gren综合征发病机理发展中的作用。鉴定这种效应器机制对于制定有针对性的预防或早期干预策略的长期目标可能很重要。