MECHANISM OF RETINAL DAMAGE IN AUTOIMMUNE RETINOPATHY

视网膜变性是世界上导致视力丧失的主要原因之一。不同形式视网膜变性的视网膜细胞死亡机制尚不完全清楚。有证据表明，视网膜病变患者的一个子集可能有自身免疫成分的疾病。一种可能性是与视网膜功能障碍和视网膜变性相关的自身抗体可能导致视网膜损伤。基于临床和体外观察，我们提出自身抗体可能参与视网膜功能障碍患者某些形式视网膜病变的发展的假设。某些类型的人获得性视网膜病变可能是由自身抗体的作用引起的，在长期暴露于视网膜蛋白特异性自身抗体后，通过激活细胞凋亡反应起作用。当抗体通过血液-视网膜屏障进入视网膜并穿透视网膜细胞时，它们通过凋亡引发光感受器死亡。视网膜细胞的大量死亡可能导致严重的组织损伤，视力丧失，最终失明。抗体渗透到活的视网膜细胞将构成免疫介导的视网膜变性的新机制。由于缺乏直接证明患者视网膜细胞凋亡的组织，使用体外模型和动物模型的研究可以更好地了解免疫球蛋白诱导的细胞死亡机制。我们建议利用培养的视网膜细胞和动物模型来研究自身抗体在视网膜损伤中的作用。我们的长期目标是明确自身免疫性视网膜病变的诱导和视网膜损伤机制，并建立新的体外模型来分析抗体作用对视网膜的影响。为了实现我们的目标，我们提出以下具体目标：(1)通过研究特异性、抗体细胞渗透和细胞毒性之间的关系，确定与视网膜功能障碍和变性相关的自身抗体是否对视网膜细胞具有细胞毒性；(2)通过细胞进入机制和自身抗体对细胞功能的影响，明确抗视网膜自身抗体在视网膜损伤中的作用；(3)通过明确抗体诱导视网膜细胞凋亡导致视网膜损伤的机制，研究不同视网膜细胞对抗体诱导凋亡的敏感性，探讨抗体诱导视网膜损伤中细胞死亡的机制。

Retinal degeneration is one of the leading causes of visual loss in the world. The mechanism of retinal cell death in different forms of retinal degenerations is not fully understood. There is evidence that a subset of patients with retinopathy may have an autoimmune component to the disease. One possibility is that autoantibodies associated with retinal dysfunction and retinal degeneration could cause retinal damage. Based on clinical and in vitro observations, we propose the hypothesis that autoantibodies may participate in the development of some forms of retinopathies in patients with retinal dysfunction. Some types of human acquired retinopathy may be caused by the action of autoantibodies, functioning through the activation of cell apoptotic responses after prolonged exposure to autoantibodies specific to retinal proteins. When antibodies gain access to the retina through the blood-retinal barrier and penetrate retinal cells, they initiate photoreceptor death by apoptosis. A massive death of retinal cells may lead to significant tissue damage, to visual loss, and finally, to blindness. Antibody penetration into living retinal cells will then constitute a new mechanism of immunologically mediated retinal degeneration. Because the lack of availability of tissue for a direct demonstration of apoptotic cell death in affected retinas of patients, studies using an in vitro model and animal models provide better understanding of the mechanism of cell death induced by immunoglobulins. We propose to use cultured retinal cells and an animal model to study the involvement of autoantibodies in retinal damage. Our long-term goal is to define the mechanism of induction and retinal damage in those autoimmune retinopathies and develop a new in vitro model to analyze the effect of antibody action on retinas. To achieve our goals we propose the following specific aims: (1) Determine whether autoantibodies associated with retinal dysfunction and degeneration are cytotoxic for retinal cells by investigating the relationship between specificity, antibody cell penetration, and cytotoxicity; (2) Define the role of anti-retinal autoantibodies in retinal damage by examining the mechanism of cell entry and the effect of autoantibodies on cell function; (3) Examine the mechanism of cell death in antibody-induced retinal damage by defining the mechanism of antibody-induced apoptosis in retinal cells leading to retinal damage and studying the sensitivity of different retinal cells to antibody-induced apoptosis.