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.

白内障是世界范围内视力损害的主要原因， 60%的老年人患有这种疾病。年龄相关 白内障被认为是衰老过程的结果，然而， 年龄相关性白内障的病因仍然是难以捉摸的。之一 其原因可能是由于透镜上皮细胞的损失。虽然透镜 上皮细胞在整个生命过程中仍然能够增殖， 随着年龄的增长，上皮细胞密度降低。 有趣的是，在涉及透镜皮质的白内障中， 据报道细胞密度较低。上皮细胞参与了 保持包括透明度在内的透镜的生理特性。因此，透镜 上皮细胞的减少可能会扰乱体内平衡 老年人晶状体密度增加，导致白内障形成。我们想 寻找导致透镜上皮损伤的特定病因 细胞有趣的是，超过40%的健康人和超过80%的 的白内障患者表现出针对 晶体蛋白表明产生了自身抗原。那些抗体 可能会损伤透镜上皮细胞。 在小鼠中观察到特异性透镜上皮细胞损伤（LECD） 与透镜抗原接触，可能是由于 抗晶体蛋白抗体。自身抗体可能是由 内源性自身抗原或交叉反应抗原存在于 传染性微生物抗原同源的微生物感染 透镜蛋白可以诱导更高水平的自身抗体 可能导致透镜上皮细胞死亡和透镜发育 不透明化因此，我们假设， 晶状体蛋白可诱导透镜上皮细胞的损伤， 导致白内障形成的上皮细胞死亡。测试 根据这一假设，我们提出以下目标。1)检验这一假设 针对透镜抗原的自身抗体可以在小鼠和小鼠中引起LECD。 体外培养的透镜上皮细胞; 2）初步探讨其作用机制 由此自身抗体损伤透镜上皮细胞，无论是补体- 或细胞介导的，以及是否针对细胞表面或基底 膜组件; 3）确定是否泄漏土著透镜 晶体蛋白或微生物抗原中的同源表位负责 4）设计干预措施，以防止自身免疫性 实验室动物的反应。这些研究可能会导致 制定干预措施，预防人类年龄相关性白内障。