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：干燥综合征是一种人类自身免疫性疾病，其特征是由于对泪腺和唾液腺的慢性自身免疫攻击而导致外分泌功能障碍。它是唾液腺炎症和功能障碍的主要原因之一，导致眼部和口腔表面严重干燥。干燥综合征的诊断包括检测小唾液腺中白细胞浸润、类风湿因子的存在、高丙种球蛋白血症、特异性抗核自身抗体、受刺激的液体分泌丧失以及干眼和/或口干的主诉。在过去的几年中，NOD小鼠已被证明表现出许多与干燥综合征相似的疾病表现，包括受刺激的液体分泌丧失，同时出现泪腺和唾液腺白细胞浸润。对 NOD 小鼠自身免疫性外分泌病的研究表明，该疾病可分为两个阶段：第一阶段的特点是分泌腺的病理生理和生化变化，其发生与自身免疫攻击无关。第 2 期的特征是外分泌腺中出现白细胞浸润、促炎反应、针对多种腺泡细胞成分的自身抗体、腺泡细胞团损失和外分泌功能下降。使用与亲本 NOD 小鼠品系同源的特定基因敲除小鼠表明，外分泌功能的丧失首先取决于 B 细胞的存在，其次取决于白细胞介素 4 (IL-4) 细胞因子的表达。随后的研究表明，IL-4 通过调节 B 细胞中抗体同种型类型转换来发挥其活性。然而，IL-4 可以激活 B 细胞中两种不同的信号传导途径：STAT-6 和 IRS 途径。 STAT-6信号通路涉及抗体类别转换，而IRS通路涉及B细胞成熟和克隆删除。因此，当前 R21 拨款申请的目的是启动研究，检查 IL-4 在外分泌腺功能障碍和液体分泌减少中引发其效应器功能的机制。具体来说，我们计划 (t) 记录新构建的 NOD.B10.H-2b.B/c-STAT6 敲除小鼠系的自身免疫表型，并将该表型与 NOD.B10.H-2b、NOD.B10.H 进行比较-2b.lgp KO 和 NOD.B10.H-2b.IL4 KO 小鼠，以及 (2) 鉴定外分泌腺功能障碍是否依赖 IL-4 发育是由于 STAT-6、IRS 或两种信号转导途径的激活所致。这些研究的结果将有助于深入了解细胞因子 IL-4 的作用及其在调节干燥症发病机制发展中的效应机制。识别这种效应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。