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M. J. Mattapallil, P. Silver, J. Mattapallil, Z. Karabekian, H. McDowell, C.-C. Chan, E. James, W. Kwok, C. David, R. R. Caspi; HLA Class II Specific Epitopes of Retinal Arrestin Are Uveitogenic in the ‘Humanized’ Mouse Model of EAU. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5163.
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© ARVO (1962-2015); The Authors (2016-present)
Autoimmune uveitis affects 150,000 Americans annually and is a leading cause of blindness. Pathogenesis is thought to involve T cell mediated responses to retinal proteins, such as retinal arrestin (S-Ag). Susceptibility to autoimmune uveitis is strongly associated with HLA class I and class II alleles. The objective of this study was to define the epitopes that might be pathogenic in the context of different HLA class II molecules.
Experimental autoimmune uveitis (EAU) was induced in the ‘humanized’ mouse model, transgenic for different HLA class II alleles, using S-Ag. Synthetic peptides based on the amino acid sequence of S-Ag protein were used to identify immunodominant and pathogenic epitopes specific to each HLA class II alleles. HLA class II tetramer loaded with allele specific uveitogenic epitopes of S-Ag was used to identify and isolate pathogenic CD4 positive T cells.
We have identified permissive and non-permissive alleles of the HLA-DR and -DQ genes and characterized allele-specific uveitogenic epitopes. The sequences of these epitopes overlap with some of the previously identified peptides of S-Ag (M and N), which elicit memory responses in lymphocytes of uveitis patients. HLA-DR restricted S-Ag specific CD4+ T cells could be detected in blood and draining lymph nodes of immunized mice using HLA class II tetramers.
Our results demonstrate that HLA class II tetramers can be used to detect and isolate antigen specific T cells in uveitis patients. Our data provide new insights into the pathogenesis of human uveitis, and may help in the development of antigen specific therapies.
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