International Immunology, Vol. 12, No. 8, 1157-1166,
August 2000
© 2000 Japanese Society for Immunology
Structure of celiac disease-associated HLA-DQ8 and non-associated HLA-DQ9 alleles in complex with two disease-specific epitopes
Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, 47100 Arta, Greece
1 Department of Immunohematology and Blood Bank, Leiden University Medical Center, RC 2300 Leiden, The Netherlands
2 Laboratory of Immunology, Department of Internal Medicine, University of Ioannina Medical School, 45110 Ioannina, Greece
Correspondence to: G. K. Papadopoulos
The association of celiac disease (CD) with HLA-DQ2 and HLA-DQ8 is indicative of preferential mucosal T cell recognition of gluten fragments bound to either DQ allele. We have recently identified two gluten-derived, HLA-DQ8-restricted T cell stimulatory peptides, one each from gliadin and glutenin, recognized by specific T cell clones derived from the small intestine of CD patients. We have now performed molecular modeling and examined the fine specificity of these peptides in complex with HLA-DQ8. There is only one binding register for both peptides, with glutamine residues at the p1 and p9 anchor positions. Both T cell clones recognize substituted peptides at p1 and p9, but poorly so at p2–p8, especially the gliadin-specific clone. Contrasting patterns of recognition of p9Gln 
Glu peptide variants (both predicted as better DQ8 binders by modeling) were observed: enhancement of recognition for the gliadin peptide, yet complete absence thereof for the glutenin peptide. The double-substituted gliadin peptide variant p1/9Gln Glu, which can also arise by pepsin/acid/transglutaminase treatment, shows a considerable increase in sensitivity of recognition, consistent with better binding of this peptide to DQ8, as predicted by energy minimization. Surprisingly, the two native peptides are also recognized by their respective T cell clones in the context of the related molecule HLA-DQ9 (ß57Asp+). The p1/9Gln Glu gliadin peptide variant is likewise recognized, albeit with a 10-fold lower sensitivity, the first reported p9Glu binding in a ß57Asp+ MHC II allele. Our results have important implications for the pathogenesis of autoimmune disease and the possible manipulation of aberrant responses thereof.
Keywords: antigens/peptides, autoimmunity, HLA-DQ, MHC, T cells
3 Present address: Laboratory of Pathophysiology, The Medical School, University of Athens, Athens 11527, Greece
Transmitting editor: J.-F. Bach
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