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Identification of Immunodominant Epitopes of -Gliadin in HLA-DQ8 Transgenic Mice following Oral Immunization¹

Stefania Senger^*, Francesco Maurano^*, Maria F. Mazzeo^*, Marcello Gaita^*, Olga Fierro^*, Chella S. David, Riccardo Troncone, Salvatore Auricchio, Rosa A. Siciliano^* and Mauro Rossi^2,*

^* Istituto di Scienze dell’Alimentazione, Consiglio Nazionale delle Ricerche, Avellino, Italy; Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905; and European Laboratory for Food Induced Diseases and Department of Pediatrics, University "Federico II" of Naples, Naples, Italy

Celiac disease, triggered by wheat gliadin and related prolamins from barley and rye, is characterized by a strong association with HLA-DQ2 and HLA-DQ8 genes. Gliadin is a mixture of many proteins that makes difficult the identification of major immunodominant epitopes. To address this issue, we expressed in Escherichia coli a recombinant -gliadin (r--gliadin) showing the most conserved sequence among the fraction of -gliadins. HLA-DQ8 mice, on a gluten-free diet, were intragastrically immunized with a chymotryptic digest of r--gliadin along with cholera toxin as adjuvant. Spleen and mesenteric lymph node T cell responses were analyzed for in vitro proliferative assay using a panel of synthetic peptides encompassing the entire sequence of r--gliadin. Two immunodominant epitopes corresponding to peptide p13 (aa 120–139) and p23 (aa 220–239) were identified. The response was restricted to DQ and mediated by CD4⁺ T cells. In vitro tissue transglutaminase deamidation of both peptides did not increase the response; furthermore, tissue transglutaminase catalyzed extensive deamidation in vitro along the entire r--gliadin molecule, but failed to elicit new immunogenic determinants. Surprisingly, the analysis of the cytokine profile showed that both deamidated and native peptides induced preferentially IFN- secretion, despite the use of cholera toxin, a mucosal adjuvant that normally induces a Th2 response to bystander Ags. Taken together, these data suggest that, in this model of gluten hypersensitivity, deamidation is not a prerequisite for the initiation of gluten responses.

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