MOLECULAR BASIC OF PARANEOPLASTIC RETINOPATHY

大多数，如果不是所有的话，副肿瘤性视网膜病变或癌症- 迄今报道的相关性视网膜病变(CAR)有免疫学上的 基础。在疾病过程中发生的免疫事件， 在这种情况下，视网膜中的视觉细胞会因癌症逐渐死亡， 人们对此了解甚少。我们建议检验这样一种假设 视网膜病变的发生是对常见疾病的免疫反应的结果 肿瘤组织和视网膜中的抗原。肿瘤的生长会导致 蛋白质抗原的生产。这些抗原是由于细胞释放的 周转和坏死，并刺激宿主免疫系统登上 免疫反应。抗体和免疫活性T细胞 针对肿瘤抗原的主要抗原决定簇产生的。 一些抗体或细胞可以穿过血-视网膜屏障， 与相似的抗原结合或在视网膜中共享表位。我们建议 研究两种视网膜蛋白，这两种蛋白与先前的研究有关 副肿瘤性视网膜病变：23 kDa蛋白或恢复素和46 kDa 蛋白质或烯醇化酶。我们的长期目标是阐明分子 副肿瘤性视网膜病变的基础将为我们提供 了解疾病的过程，但也可能导致设计一种 合理有效的治疗。为了更好地理解 这种疾病的发病机制，获得患者血清是很重要的 用于研究并将这些结果与从动物身上获得的数据进行比较 学习。动物研究提供了检验假说的机会 自身免疫参与疾病的诱发和建立 表位在发病机制中的重要性。为了实现我们的目标 为了确定这种自身免疫性疾病的分子基础，我们建议 具体目标如下：1.免疫反应的特征 在副肿瘤性视网膜病变中：a)确定哪些主要蛋白质 副肿瘤患者血清中的抗体可识别整个视网膜 视网膜病变综合征患者和年龄匹配的对照组，以及b)确定 视网膜中的哪些细胞类型与抗体发生免疫细胞化学反应 在副肿瘤视网膜病变综合征患者血清中。2.人物塑造 人外周血淋巴细胞的细胞免疫反应 副肿瘤性视网膜病变患者和对照组。3.对 利用表位研究候选视网膜蛋白的免疫原性 映射。4.确定抗体在副肿瘤中的作用 视网膜病变：a)确定抗体是否与 视网膜损伤，以及b)确定视网膜损伤的致病决定因素 候选抗原。

The majority, if not all, cases of paraneoplastic retinopathy or cancer- associated retinopathy (CAR) thus far reported have an immunological basis. Immunological events which occur during the course of the disease, in which visual cells in the retina gradually die as a result of cancer, are poorly understood. We propose to test the hypothesis that such retinopathies occur as the result of the immune response against common antigens in tumor tissue and retina. Growth of a tumor leads to production of protein antigens. These antigens are released due to cell turnover and necrosis, and stimulate the host immune system to mount an immunological response. Antibodies and immunocompetent T cells are produced against the major antigenic determinants of the tumor antigens. Some of the antibodies or cells can cross the blood-retina barrier and bind to similar antigens or share epitopes in the retina. We propose to study two retinal proteins that have been implicated in prior studies of paraneoplastic retinopathy: 23 kDa protein or recoverin, and 46 kDa protein or enolase. Our long-term goal is to elucidate the molecular basis for paraneoplastic retinopathies which will provide us with an understanding of the disease process but may also lead to the design of a rational and effective therapy. In order to better understand the mechanism of this disease entity, it is important to obtain patient sera for study and to compare those results with the data obtained from animal studies. Animal studies provide the opportunity to test the hypothesis of the autoimmune involvement in the disease induction and establish the importance of epitopes in the pathogenesis. To accomplish our goal of determining the molecular basis for this autoimmune disease, we propose the following specific aims: 1. Characterization of the immune responses in paraneoplastic retinopathy by: a) determining which major proteins in whole retina are recognized by antibodies in sera from paraneoplastic retinopathy syndrome patients and age-matched controls, and b) determining what cell types in the retina react immunocytochemically with antibodies in paraneoplastic retinopathy syndrome patient sera. 2. Characterization of cellular responses of peripheral lymphocytes from blood of paraneoplastic retinopathy patients and controls. 3. Characterization of immunogenic properties of the candidate retinal proteins by epitope mapping. 4. Define the role of antibodies in the paraneoplastic retinopathy by: a) determining whether the antibodies are responsible for the retinal damage, and b) determining the pathogenic determinants of the candidate antigens.