Antigen presentation in celiac disease

Abstract

Celiac disease is caused by an inappropriate immune response to ingested gluten proteins. As a dietary antigen, gluten undergoes extensive but incomplete proteolytic digestion in the intestinal lumen. The resultant peptide fragments of gluten require deamidation, but not necessarily further intracellular processing for presentation. Recent studies reveal why the disease associated HLA-DQ2 molecule is particularly suited for binding proline-rich gluten peptides. In comparison, DQ8 exhibits different binding characteristics, which may explain the lesser risk for disease in association with this molecule.

Figure 1

HLA association in celiac disease. A vast majority of celiac patients express the HLA-DQ2 heterodimer encoded by the DQA1*05 and DQB1*02 genes. These two genes are carried either in cis on the DR3-DQ2 haplotype, or in trans in individuals who are DR5-DQ7 and DR7-DQ2 heterozygous. Most DQ2-negative patients express DQ8 encoded on the DR4-DQ8 haplotype.

Figure 2

Peptide binding signatures of DQ2 and DQ8 molecules. The DQ2-restricted γ-III epitope and the DQ8-restricted γ-I epitope recognized by lesion derived T cells of CeD patients share the same 9 amino acid core sequence. This sequence contains three glutamate residues formed by TG2-mediated deamidation in positions P1, P4 and P9. DQ2 prefers negatively charged glutamate residue in P4 (shaded) whereas DQ8 prefers glutamate in P1 and P9 (shaded).