Beta-B1 Crystallin - a New Candidate Uveitis Autoantigen

描述：（申请人？s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， 一种影响超过一百万人的重要临床疾病 并导致高达11%的视力丧失。该项目的健康相关性是 它特别试图定义候选抗原， 眼内源性人类炎性疾病，导致改善 诊断测试、新的治疗干预或识别 继发性疾病高风险的患者亚群。 尽管许多免疫介导的炎症性疾病被认为是由 预期活化的CD 4 T细胞、B细胞活化和克隆扩增， 同时发生。这些选择的B细胞具有相同的抗原特异性， 致病性T细胞及其抗体提供了一种重要工具， 表征驱动免疫应答的靶抗原。的主题 这项建议是评估一个令人兴奋的候选葡萄膜炎抗原，β B1 晶状体蛋白，通过与葡萄膜炎标记抗体Fab 5-3的反应性鉴定 ANCA，因为其在前葡萄膜炎中的相关性和其晶状体外 表情这项建议的一个优点是得到了热情的支持， 一群合作者的合作，他们是透镜晶体的领导者 研究，研究β B1晶体蛋白，并在人类葡萄膜炎的临床研究 帮助采购实验材料和试剂。 第一个具体目的是表征眼内和眼外组织中的β B1晶状体蛋白表达， 非眼组织的免疫组织化学和分子生物学 工具.这些研究将证实初步结果，并加强我们的 关于这种蛋白质的知识，以前没有被证明 在透镜的外面。第二个具体目标是探索 β B1晶体蛋白血清反应性与 眼内炎症或白内障的发展。在第三个具体目标中， β B1晶状体蛋白被用作抗原以开发人类的啮齿动物模型， 前葡萄膜炎经典的动物葡萄膜炎模型模拟后部，而不是后部。 前葡萄膜炎;因此开发了前葡萄膜炎动物模型 将大大扩展我们研究这种疾病发病机制的能力， 视觉疾病的重要原因。 因此，这一提议提出了两个新颖而重要的预测： 晶状体蛋白存在于晶状体外分布，并且特异性 针对该蛋白质免疫反应性与葡萄膜炎或 葡萄膜炎相关的白内障

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.