Peptide binding to HLA-DQ2 and development of blocking agents for the treatment of celiac disease
Appears in the following Collection
AbstractCeliac disease is a chronic inflammatory disorder of the small intestine with a strong association to HLA-DQ2. This thesis focused on peptide binding to HLA-DQ2 and the development of peptide blockers for the treatment of celiac disease. We have investigated the relative contribution of each hydrogen bond interaction between the peptide main chain and MHC residues in DQ2 and our results demonstrated that hydrogen bonds at positions P4 and P2 are most important for peptide binding. In addition, no evidence of a hydrogen bond in position P1 was found. Detailed characterization of gluten T cell epitopes gave knowledge on the importance of proline spacing for the binding to DQ2. Cyclic and dimeric peptides were investigated as peptide blockers, and we demonstrated proof-of principle for inhibition of DQ2 mediated presentation of gluten T cell epitopes. Finally, a study was performed to elucidate peptide determinant selection by HLA-DQ2 as a factor to explain the strong HLA association in celiac disease. The results demonstrated that the gluten T cell epitopes mainly bind to HLA-DQ2 and not to other HLA class II molecules.
Publications included in PhD thesis:
1. Bergseng E, Xia J, Kim CY, Khosla C, Sollid LM 2005. Main chain hydrogen bond interactions in the binding of proline-rich gluten peptides to the celiac disease associated HLA-DQ2 molecule. J Biol Chem 280:21791-21796.
2. Qiao SW, Bergseng E, Molberg O, Jung G, Fleckenstein B, Sollid LM 2005. Refining the rules of gliadin T cell epitope binding to the disease associated DQ2 molecule in celiac disease; importance of proline spacing and glutamine deamidation. J Immunol 175:254-261
3. Xia J, Bergseng E, Fleckenstein B, Siegel M, Kim C-Y, Khosla C, Sollid LM,2005. Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease.Bioorg Med Chem 15(20):6565-73
4. Bergseng E, Sidney J, Sette A, Sollid LM 2008. Analysis of the binding of gluten T-cell epitopes to various human leukocyte antigen class II molecules. Hum Immunol 69(2):94-100