Journal of Experimental Medicine, Vol 180, 133-140, Copyright © 1994 by Rockefeller University Press

ARTICLES

A pathogenic autoimmune process targeted at a surrogate epitope

AT Kozhich, Y Kawano, CE Egwuagu, RR Caspi, RK Maturi, JA Berzofsky and I Gery
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892.

Immunization with the retinal interphotoreceptor retinoid-binding protein (IRBP) induces in a variety of animals an inflammatory eye disease, experimental autoimmune uveoretinitis (EAU). We have previously shown that sequence 1181-1191 of bovine IRBP (BOV 1181-1191) is immunodominant and highly uveitogenic and immunogenic in Lewis rats. Sequence 1181-1191 of the rat IRBP (RAT 1181-1191) differs from BOV 1181-1191 by two residues, at positions 1188 and 1190, that are pivotal for the immunological activity of the bovine epitope. Here we show that, unlike its bovine homologue, RAT 1181-1191 did not induce EAU or an immune response in Lewis rats. The immunological inactivity of RAT 1181-1191 in Lewis rats is due at least in part to its poor affinity toward the antigen-presenting cells of these rats, as shown by its failure to compete with binding of BOV 1181-1191 to Lewis adherent spleen cells. Moreover, unlike all other known autologous homologues of immunopathogenic epitopes, RAT 1181-1191 was not recognized by lymphocytes sensitized against BOV 1181-1191 and failed to stimulate proliferation, uveitogenic capacity or signal transduction in these cells. These findings thus suggest that RAT 1181-1191 is not a likely target for lymphocytes sensitized against BOV 1181-1191 in the process in which these cells recognize IRBP in the rat eye and trigger the inflammatory reaction of EAU. Our data further suggest that the target for the disease-inducing lymphocytes is sequence 273-283 of the rat IRBP: (a) sequence 273-283 is highly conserved and is identical in the bovine and rat proteins; (b) determinant 273-283 is a "repeat" of 1181- 1191 in the fourfold structure of IRBP and shares seven residues with BOV 1181-1191; (c) rat peptide 273-283 is recognized by lymphocytes sensitized against BOV 1181-1191 and stimulates them for proliferation and for acquisition of uveitogenicity; and (d) moreover, sequence 273- 283 is superior to BOV 1181-1191 in its capacity to generate uveitogenicity in lymphocytes sensitized against this bovine peptide. The present study thus describes for the first time a system in which an autologous homologue of an immunopathogenic epitope is inactive and a "surrogate" determinant apparently serves as the target for lymphocytes sensitized against the immunopathogenic peptide.
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This article has been cited by other articles:

• Shao, H., Lei, S., Sun, S. L., Xiang, J., Kaplan, H. J., Sun, D. (2003). CpG-Containing Oligodeoxynucleotide 1826 Converts the Weak Uveitogenic Rat Interphotoreceptor Retinoid-Binding Protein Peptide 1181-1191 into a Strong Uveitogen. J. Immunol. 171: 4780-4785 [Abstract] [Full Text]  
• Moudgil, K. D., Kim, E., Yun, O. J., Chi, H. H., Brahn, E., Sercarz, E. E. (2001). Environmental Modulation of Autoimmune Arthritis Involves the Spontaneous Microbial Induction of T Cell Responses to Regulatory Determinants Within Heat Shock Protein 65. J. Immunol. 166: 4237-4243 [Abstract] [Full Text]  

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