Cancer Associated Retinopathies (CAR) occur most commonly in patients with small cell carcinoma of the lung (SCCL), although this phenomenon has also been encountered in patients with retinopathies associated with breast, colon, prostate and cervical carcinomas. CAR degenerations progress rapidly and are reported to manifest prior to the recognition of the causal cancer. Serum samples obtained from CAR patients have consistently demonstrated a specific antibody reaction with a 23 kDa retina protein which is now referred to as the retinal CAR antigen. The cloning of the cDNA corresponding to this antigen and its recognition as the photoreceptor molecule 'Recoverin' has identified an important link in the biological processes involved in these retinopathies. The molecular cloning of a cDNA of the same nucleic acid sequence from a cDNA library prepared from mRNA derived from a culture of SCCL identifies an immunological 'Cancer Connection' which could be responsible for initiating an autoimmune retinopathy. These finding introduce the hypothesis that, in some cancer associated retinopathies, 'Molecular Mimicry' is the cause of the collective indications of retinal hypersensitivity. The long term goals of this proposal are to investigate the pathogenesis of CAR. To ascertain the significance of the 23 kDa retinal CAR antigen/antibody reaction to vision loss in CAR patients and determine if this immunological response is directly involved in the retinopathic events that occur in CAR or is it simply a marker which identifies the presence of a SCCL aberrantly expressing a distinctive retinal protein.
The specific aims are to (a) evaluate the incidence of expression of the retinal CAR antigen in cultures of SCCL deposited in the ATCC as well as in primary cultures of SCCL originated from CAR patients, (b) investigate the immunological response of experimental animals to sensitization to the potentially uveitogenic retinal CAR antigen and specific peptide components of the molecule and (c) characterize the nature of the genes expressing the retinal CAR antigen and the corresponding antigenic component identified in the culture of small cell carcinoma of the lung. The study will use a combination of immunological and molecular biology techniques to determine if the indications of retinal hypersensitivity associated with CAR represent an example of immune-mediated vision loss resulting from antigenic cross-reactions.
