The long-term objective of the proposed research is to understand the role of autoimmunity in initiating or exacerbating degenerative retinal disorders in humans. The proposal focuses primarily on cancer-associated retinopathy (CAR), a paraneoplastic syndrome, as an experimental model for studying the involvement of autoimmunity in photoreceptor cell degeneration. The working hypothesis proposes that CAR stems from an autoimmune response which is directed towards antigens or epitopes found in both the tumor and photoreceptor cells. Molecular mimicry of this sort is thought to underlie several autoimmune diseases, including some ocular inflammatory diseases in humans. The experiments described here will use autoantibodies obtained from patients with defined retinal diseases in order to detect retinal autoantigens. Once the antigens have been characterized, it should be possible a) to determine the immunogenic source that initiated the autoimmune response, b) to provide diagnostic information about patients, if findings support the correlation between a retinal disorder and the presence of specific autoantibodies, and c) to investigate mechanisms by which autoantibodies influence retinal degeneration. The results obtained from these experiments may prove to be an important part in the diagnosis of CAR and the early detection of some cancers. The finding that different paraneoplastic syndromes may share a common initiation event will help focus studies on early tumor development. Finally, more experimental models are needed if we hope to understand and eventually develop treatments for photoreceptor degeneration, the leading cause of blindness in this country. The identification of retinal autoantigens which can elicit an experimental autoimmune condition in animals would be an important step in the development of additional models.
