AGE RELATED CATARACT--ANTIBODY MEDIATED AUTOIMMUNE DISEA

年龄相关性白内障--抗体介导的自身免疫性疾病

• 批准号: 2608666
• 负责人: TOSHIMICHI SHINOHARA
• 金额: $ 19.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-12-04 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2608666
• 关键词: aging; animal tissue; antigen antibody reaction; autoantibody; autoimmune disorder; autoimmunity; autoradiography; cataract; cell membrane; cellular pathology; complement deficiency; crystallins; cytolysis; electron microscopy; enzyme linked immunosorbent assay; epithelioma; histopathology; laboratory mouse; lens; microorganism antigen; monoclonal antibody; organ culture; pathologic process; surface antigens; vision disorders

Cataract is a major cause of visual impairment in the world and more than 60% of the elderly population suffers from this disorder. Age related cataracts have been thought to be a consequence of the aging process, yet the etiology of age related cataract continues to remain elusive. One of the causes may be due to loss of lens epithelial cells. Although lens epithelial cells remain capable of proliferation throughout life, with increasing age, epithelial cell density is known to decrease. Interestingly, in cataract involving the lens cortex, a significantly lower cell density was reported. Epithelial cells are involved in maintaining the physiology of the lens including transparency. Thus, lens homeostasis might be disturbed by a decrease in the epithelial cell density in older lenses resulting in cataract formation. We would like to find a specific etiology which causes damage to the lens epithelial cells. Interestingly, more than 40% of healthy humans and more than 80% of cataractous patients exhibit elevated antibody titers against crystallins suggesting that autoantigens are generated. Those antibodies might damage the lens epithelial cells. Specific lens epithelial cell damage (LECD) was observed in mice injected with lens antigens possibly by an autoimmune insult induced by the antibodies against crystallins. The autoantibodies might be raised by either endogenous autoantigens or cross-reacting antigens present in infectious microbes. Infection by microbes having homologous antigens to the lens proteins can induce the autoantibodies at higher levels which may result in death of the lens epithelial cells and development of lens opacification. Thus, we hypothesize that autoantibodies against crystallins can induce trauma to the lens epithelial cells, resulting in death of the epithelial cells which lead to cataract formation. To test this hypothesis we propose the following aims. 1) Test the hypothesis that autoantibodies against lens antigens can cause LECD in mice and in cultured lens epithelial cell; 2) To determine the basic mechanism whereby autoantibodies damage lens epithelial cell, whether complement- or cell-mediated, and whether directed against cell surface or basement membrane components; 3) To determine whether leaking indigenous lens crystallins or homologous epitopes in microbial antigens are responsible for autoantibodies; 4) Design interventions to prevent autoimmune response in laboratory animals. These studies could lead to the development of interventions to prevent age related cataract in human.

白内障是世界上视觉障碍的主要原因，而不是 60％的老年人口患有这种疾病。与年龄有关 白内障被认为是衰老过程的结果 与年龄相关的白内障的病因仍然难以捉摸。之一 原因可能是由于晶状体上皮细胞的丧失所致。虽然镜头 上皮细胞在一生中仍然能够增殖， 年龄增加，已知上皮细胞密度会降低。 有趣的是，在涉及镜头皮质的白内障中 报道了较低的细胞密度。上皮细胞参与 维持包括透明度在内的镜头的生理学。因此，镜头 稳态可能会因上皮细胞的减少而感到困扰 旧镜头的密度导致白内障形成。我们想 找到对晶状体上皮损害的特定病因 细胞。有趣的是，超过40％的健康人和80％以上 白内障患者表现出较高的抗体滴度 结晶蛋白表明是生成自身抗原的。那些抗体 可能会损害晶状体上皮细胞。 在注射的小鼠中观察到了特定的透镜上皮细胞损伤（LECD） 与晶状体抗原可能受到自身免疫性侮辱 抗晶蛋白的抗体。自身抗体可能由 内源性自身抗原或交叉反应抗原存在于 传染性微生物。具有同源抗原的微生物感染 晶状体蛋白可以在较高级别诱导自身抗体 可能会导致晶状体上皮细胞的死亡和晶状体的发展 无情。因此，我们假设自动抗体反对 结晶蛋白可以诱导晶状体上皮细胞创伤，从而导致 上皮细胞的死亡，导致白内障形成。测试 我们提出以下目标。 1）检验假设 针对晶状体抗原的自身抗体可能导致小鼠和 培养的透镜上皮细胞； 2）确定基本机制 从而自身抗体会损害透镜上皮细胞，是否补体 - 或细胞介导的，以及针对细胞表面还是基底的指向 膜成分； 3）确定是否泄漏土著镜头 微生物抗原中的结晶蛋白或同源表位是负责的 用于自身抗体； 4）设计干预措施以防止自身免疫 实验动物的反应。这些研究可能导致 开发干预措施以防止人类与年龄相关的白内障。