Beta-B1 Crystallin - a New Candidate Uveitis Autoantigen

Beta-B1 Crystallin——一种新的候选葡萄膜炎自身抗原

• 批准号: 6415564
• 负责人: Lynn K Gordon
• 金额: $ 15.29万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-03 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6415564
• 关键词: autoantigens; cataract; clinical research; crystallins; enzyme linked immunosorbent assay; gene expression; human subject; immunocytochemistry; inflammation; iridocyclitis; laboratory mouse; laboratory rat; northern blottings; pathologic process; polymerase chain reaction; posttranslational modifications; western blottings

DESCRIPTION: (Applicant?s Abstract) The long-term objectives of this work are to enhance the understanding of the pathogenic mechanisms of anterior uveitis, an important clinical disease that affects more than one million individuals and causes vision loss in up to 11%. The health-relatedness of the project is that it specifically attempts to define candidate antigens that drive certain endogenous human inflammatory diseases of the eye, resulting in improved diagnostic testing, novel therapeutic interventions, or identification of patient subsets at high risk for secondary disease. Although many immune-mediated inflammatory diseases are thought to result from activated CD4 T cells, B cell activation and clonal expansion is expected to occur in tandem. These selected B cells have the same antigenic specificity of the pathogenic T cell, and their antibodies offer an important tool to characterize the target antigen driving the immune response. The subject of this proposal is to evaluate an exciting candidate uveitis antigen, betaB1 crystallin, identified by reactivity with a uveitis marker antibody, Fab 5-3 ANCA, for its relevance in anterior uveitis and for its extra-lenticular expression. A strength of this proposal is the enthusiastic support and cooperation of a group of collaborators have who are leaders in lens crystallin research, studies of betaB1 crystallin, and in human uveitis clinical research to help with the acquisition of experimental materials and reagents. The first specific aim characterizes betaB1 crystallin expression in ocular and non-ocular tissues using immunohistochemical studies and molecular biology tools. These studies will confirm the preliminary findings and enhance our knowledge about this protein, which has not previously been demonstrated outside of the lens. The second specific aim is designed to explore the relationship between seroreactivity against betaB1 crystallin and the development of intraocular inflammation or cataract. In the third specific aim, betaB1 crystallin is used as an antigen to develop a rodent model of human anterior uveitis. The classic animal uveitis models mimic posterior, not anterior uveitis; therefore development of an anterior uveitis animal model would significantly expand our ability to study the pathogenesis of this important cause of visual morbidity. This proposal thus addresses two novel and important predictions: that betaB1 crystallin is present in an extralenticular distribution, and that specific immune reactivity against this protein is relevant in uveitis or uveitis-associated cataract.

描述：（申请人的摘要）这项工作的长期目标是 为了增强对前葡萄膜炎的致病机制的理解， 一个重要的临床疾病，影响超过一百万个人 并导致高达11％的视力丧失。该项目的健康相关性是 它专门试图定义驱动一定的候选抗原 眼睛内源性人类炎症性疾病，导致改善 诊断测试，新型治疗干预措施或鉴定 患者子集患有继发性疾病的高风险。 尽管许多免疫介导的炎症性疾病被认为是由 活化的CD4 T细胞，B细胞激活和克隆膨胀有望 同时出现。这些选定的B细胞具有相同的抗原特异性 致病性T细胞及其抗体为 表征驱动免疫反应的靶抗原。主题 该建议是评估令人兴奋的候选葡萄膜抗原，betab1 结晶蛋白，通过葡萄膜炎标记抗体的反应性鉴定，Fab 5-3 ANCA，因为它与前葡萄膜炎及其垂直外炎的相关性 表达。该建议的优势是热情的支持和 一群合作者的合作是镜头结晶的领导者 研究，BETAB1结晶蛋白的研究和人类葡萄膜炎临床研究 帮助获取实验材料和试剂。 第一个特定目的是特定的，是betab1结晶蛋白在眼和 非眼组织使用免疫组织化学研究和分子生物学 工具。这些研究将确认初步发现并增强我们的 关于这种蛋白质的知识，以前尚未证明 在镜头外。第二个特定目标旨在探索 针对BETAB1结晶蛋白的血清反应性与 眼内炎症或白内障的发展。在第三个特定目标中， betab1晶体用作发展人类啮齿动物模型的抗原 前葡萄膜炎。经典动物葡萄膜炎模型模仿后部，而不是 前葡萄膜炎；因此开发动物前葡萄膜炎模型 将大大扩大我们研究此发病机理的能力 视觉发病率的重要原因。 因此，该提案解决了两个新颖而重要的预测：BETAB1 结晶蛋白存在于脑外分布中，该特异性 针对该蛋白质的免疫反应性与葡萄膜炎或 葡萄膜炎相关性白内障。