title: Intestinal T cell responses to gluten peptides are largely heterogeneous: implications for a peptide-based therapy in celiac disease.
abstract: The identification of gluten peptides eliciting intestinal T cell responses is crucial for the design of a peptide-based immunotherapy in celiac disease (CD). To date, several gluten peptides have been identified to be active in CD. In the present study, we investigated the recognition profile of gluten immunogenic peptides in adult HLA-DQ2(+) celiac patients. Polyclonal, gliadin-reactive T cell lines were generated from jejunal mucosa and assayed for both proliferation and IFN-gamma production in response to 21 peptides from wheat glutenins and alpha-, gamma-, and omega-gliadins. A magnitude analysis of the IFN-gamma responses was performed to assess the hierarchy of peptide potency. Remarkably, 12 of the 14 patients recognized a different array of peptides. All alpha-gliadin stimulatory peptides mapped the 57-89 N-terminal region, thus confirming the relevance of the known polyepitope 33-mer, although it was recognized by only 50% of the patients. By contrast, gamma-gliadin peptides were collectively recognized by the great majority (11 of 14, 78%) of CD volunteers. A 17-mer variant of 33-mer, QLQPFPQPQLPYPQPQP, containing only one copy of DQ2-alpha-I and DQ2-alpha-II epitopes, was as potent as 33-mer in stimulating intestinal T cell responses. A peptide from omega-gliadin, QPQQPFPQPQQPFPWQP, although structurally related to the alpha-gliadin 17-mer, is a distinct epitope and was active in 5 out of 14 patients. In conclusion, these results showed that there is a substantial heterogeneity in intestinal T cell responses to gluten and highlighted the relevance of gamma- and omega-gliadin peptides for CD pathogenesis. Our findings indicated that alpha-gliadin (57-73), gamma-gliadin (139-153), and omega-gliadin (102-118) are the most active gluten peptides in DQ2(+) celiac patients.
authors.affiliation: Institute of Food Sciences-National Research Council, Avellino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Camarca
authors.forename: Robert P
authors.initials: RP
authors.lastname: Anderson
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Mamone
authors.forename: Olga
authors.initials: O
authors.lastname: Fierro
authors.forename: Angelo
authors.initials: A
authors.lastname: Facchiano
authors.forename: Susan
authors.initials: S
authors.lastname: Costantini
authors.forename: Delia
authors.initials: D
authors.lastname: Zanzi
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Salvatore
authors.initials: S
authors.lastname: Auricchio
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Riccardo
authors.initials: R
authors.lastname: Troncone
authors.forename: Carmen
authors.initials: C
authors.lastname: Gianfrani
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000276:immunology*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005903:Gliadin / Q000235:genetics / Q000276:immunology*; D005983:Glutens / Q000276:immunology; D006683:HLA-DQ Antigens; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D010446:Peptide Fragments; D005983:Glutens; D007371:Interferon-gamma; D005903:Gliadin