Evidence that HLA-DQ9 confers risk to celiac disease by presence of DQ9-restricted gluten-specific T cells.

We describe the gluten T-cell response of a DR7DQ2/DR9DQ9 heterozygous celiac disease patient (CD555). Interestingly, this patient had T cells recognizing gluten in the context of human leukocyte antigen (HLA) molecules of both haplotypes. For the DR9DQ9 haplotype, DQ9 was identified as the antigen-presenting molecule. As DQ9 carries aspartate at DQ β57 but is otherwise identical to DQ8 and not considered associated with celiac disease, we aimed to characterize this DQ9-restricted T-cell response in detail. By fractionation of pepsin-trypsin digested gliadin we identified an epitope stimulatory for several T-cell clones. This epitope was identical to an epitope (DQ8-glut-1) previously identified in DQ8 patients. In CD555, this was the dominant DQ9-restricted epitope, whereas no T-cell response was found toward two other DQ8-restricted epitopes. These findings correlated with peptide binding data demonstrating that this epitope bound better to DQ9 than the two other DQ8-restricted epitopes. Although glutamine to glutamate exchange at P9 improved binding of all three epitopes to DQ8, no such effect was observed for DQ9. The differential ability of DQ8 and DQ9 to harness a negatively charged anchor at P9 may result in fewer potential gluten epitopes in DQ9 patients. Our data further indicate that DQ9 is a susceptibility factor for celiac disease.

Bodd M ，Tollefsen S ，Bergseng E ，Lundin KE ，Sollid LM ... -  《-》

Structure of celiac disease-associated HLA-DQ8 and non-associated HLA-DQ9 alleles in complex with two disease-specific epitopes.

Moustakas AK ，van de Wal Y ，Routsias J ，Kooy YM ，van Veelen P ，Drijfhout JW ，Koning F ，Papadopoulos GK ... -  《INTERNATIONAL IMMUNOLOGY》

Analysis of the binding of gluten T-cell epitopes to various human leukocyte antigen class II molecules.

Bergseng E ，Sidney J ，Sette A ，Sollid LM ... -  《HUMAN IMMUNOLOGY》

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

Celiac disease is a diet-induced, T cell-mediated enteropathy. The HLA variant DQ2.5 increases risk of the disease, and the homologous DQ2.2 confers a lower level of risk. As many as 5% of patients with celiac disease carry DQ2.2 without any other risk alleles. Epitopes commonly recognized by T cells of patients with HLA-DQ2.5 bind stably to DQ2.5 but unstably to DQ2.2. We investigated the response to gluten in patients with HLA-DQ2.2. We generated intestinal T-cell lines and clones from 7 patients with HLA-DQ2.2 (but not DQ2.5) and characterized the responses of the cells to gluten. The epitope off-rate was evaluated by gel filtration and T cell-based assays. Peptide binding to DQ2.2 was studied with peptide substitutes and DQ2 mutants. Patients with DQ2.2 and no other risk alleles had gluten-reactive T cells that did not respond to the common DQ2.5-restricted T-cell epitopes. Instead, many of the T cells responded to a distinct epitope that was not recognized by those from patients with HLA-DQ2.5. This immunodominant epitope bound stably to DQ2.2. A serine residue at P3 was required for the stable binding. The effect of this residue related to a polymorphism at DQα22 that was previously shown to determine stable binding of peptides to DQ2.5. High levels of kinetic stability of peptide-major histocompatibility complexes are required to generate T-cell responses to gluten in celiac disease; the lower risk from DQ2.2 relates to constraints imposed on gluten peptides to stably bind this HLA molecule. These observations increase our understanding of the role of the major histocompatibility complex in determining T-cell responses in patients with celiac disease and are important for peptide-based vaccination strategies.

Bodd M ，Kim CY ，Lundin KE ，Sollid LM ... -  《-》

The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease.

Hovhannisyan Z ，Weiss A ，Martin A ，Wiesner M ，Tollefsen S ，Yoshida K ，Ciszewski C ，Curran SA ，Murray JA ，David CS ，Sollid LM ，Koning F ，Teyton L ，Jabri B ... -  《-》