T-cell response to gluten in patients with HLA-DQ2.2 reveals requirement of peptide-MHC stability in celiac disease

10.1053/j.gastro.2011.11.021Gastroenterology1423552-561GAST

Design of new high-affinity peptide ligands for human leukocyte antigen-DQ2 using a positional scanning peptide library

Human leukocyte antigen (HLA)-DQ2 (DQA1 x 0501/DQB1 x 0201) is associated with several immune disorders, including celiac disease, which is caused by an inappropriate T-cell response to gluten. Interference with peptide presentation by HLA-DQ2, for example, by the use of peptide blockers, is a possible treatment strategy for such HLA-associated disorders. A successful implementation of this strategy will depend on the identification of ligands that bind much better to HLA-DQ2 than the disease related epitopes. We have used a positional scanning nonapeptide library to determine the optimal amino acids for each position of the HLA-DQ2 binding frame. By combining the optimal residues in each position, we were able to design high affinity binders to HLA-DQ2. Interestingly, the decapeptide with highest affinity was composed of the most favorable residues in each position. This sequence bound 50-fold better than the immunodominant gluten epitope DQ2-alpha-1-gliadin, which makes it an interesting lead compound for the development of blockers. For some natural HLA-DQ2 ligands, the correlation between measured and predicted affinities was poorer, but notably these peptides did not have optimal amino acids at all positions. Our approach represents a straightforward strategy for developing high-affinity binders to HLA class II molecules. (C) 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.Transplantation and autoimmunit

Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease

10.1016/j.bmc.2007.07.001Bioorganic and Medicinal Chemistry15206565-6573BMEC

Structural and functional studies of trans-encoded HLA-DQ2.3 (DQA1*03:01/DQB1*02:01) protein molecule

10.1074/jbc.M111.320374Journal of Biological Chemistry2871713611-13619JBCH