Diversification of the celiac disease -gliadin complex in wheat: a 33-mer peptide with six overlapping epitopes, evolved following polyploidization

The gluten proteins from wheat, barley and rye are responsible both for celiac disease (CD) and for non-celiac gluten sensitivity, two pathologies affecting up to 6-8% of the human population worldwide. The wheat -gliadin proteins contain three major CD immunogenic peptides: p31-43, which induces the innate immune response; the 33-mer, formed by six overlapping copies of three highly stimulatory epitopes; and an additional DQ2.5-glia-3 epitope which partially overlaps with the 33-mer. Next-generation sequencing (NGS) and Sanger sequencing of -gliadin genes from diploid and polyploid wheat provided six types of -gliadins (named 1-6) with strong differences in their frequencies in diploid and polyploid wheat, and in the presence and abundance of these CD immunogenic peptides. Immunogenic variants of the p31-43 peptide were found in most of the -gliadins. Variants of the DQ2.5-glia-3 epitope were associated with specific types of -gliadins. Remarkably, only type 1 -gliadins contained 33-mer epitopes. Moreover, the full immunodominant 33-mer fragment was only present in hexaploid wheat at low abundance, probably as the result of allohexaploidization events from subtype 1.2 -gliadins found only in Aegilops tauschii, the D-genome donor of hexaploid wheat. Type 3 -gliadins seem to be the ancestral type as they are found in most of the -gliadin-expressing Triticeae species. These findings are important for reducing the incidence of CD by the breeding/selection of wheat varieties with low stimulatory capacity of T cells. Moreover, advanced genome-editing techniques (TALENs, CRISPR) will be easier to implement on the small group of -gliadins containing only immunogenic peptides.