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.
