HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease.
Tollefsen, Stig 1; Arentz-Hansen, Helene 1; Fleckenstein, Burkhard 1; Molberg, Oyvind 1,2; Raki, Melinda 1; Kwok, William W. 3; Jung, Gunther 4; Lundin, Knut E.A. 1,5; Sollid, Ludvig M. 1
[Article]
Journal of Clinical Investigation.
116(8):2226-2236, August 2006.
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Celiac disease is associated with HLA-DQ2 and, to a lesser extent, HLA-DQ8. Type 1 diabetes is associated with the same DQ molecules in the opposite order and with possible involvement of trans-encoded DQ heterodimers. T cells that are reactive with gluten peptides deamidated by transglutaminase 2 and invariably restricted by DQ2 or DQ8 can be isolated from celiac lesions. We used intestinal T cells from celiac patients to map DQ2 and DQ8 epitopes within 2 representative gluten proteins, [alpha]-gliadin AJ133612 and [gamma]-gliadin M36999. For [alpha]-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of 2 separate regions. For [gamma]-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of the same region. Some [gamma]-gliadin peptides were recognized by T cells in the context of DQ2 or DQ8 when bound in exactly the same registers, but with different requirements for deamidation; deamidation at peptide position 4 (P4) was important for DQ2-restricted T cells, whereas deamidation at P1 and/or P9 was important for DQ8-restricted T cells. Peptides combining the DQ2 and DQ8 signatures could be presented by DQ2, DQ8, and trans-encoded DQ heterodimers. Our findings shed light on the basis for the HLA associations in celiac disease and type 1 diabetes.
Copyright (C) 2006 The American Society for Clinical Investigation, Inc.