The Dual Face of Wheat and Cereal Reactivity: Molecular Divergence Between Soluble and Gluten-Derived Allergens.

BACKGROUND Cereal allergy comprises a heterogeneous spectrum of sensitization patterns directed toward water-soluble and gluten-derived proteins. The role of molecular cross-reactivity with homologous allergens from other cereals remains only partially understood. OBJECTIVE To investigate IgE reactivity to major wheat allergens (Tri a 14, Tri a 19, Tri a 30) and their homologs across cereals and pseudocereals, integrating bioinformatic, epidemiological, and clinical data. METHODS Sequence homology was assessed using BLAST analysis across cereal and pseudocereal proteomes. IgE reactivity was evaluated in 17,510 patients using two multiplex platforms (ImmunoCAP ISAC and ALEX2). Clinical data were available for 7201 individuals. RESULTS Tri a 14 displayed high sequence identity with multiple cereal nsLTPs, including a hitherto undefined maize-derived protein (72%), suggesting broad cross-reactivity, whereas Zea m 14 showed higher identity with Pru p 3 than with Tri a 14. Homologs of Tri a 30 and Tri a 19 were found in spelt and durum wheat. Sensitization to wheat allergens was rare (3.9%); Tri a 14 was the most frequent (64%), followed by Tri a 30 (23%) and Tri a 19 (18%). The limited cases of Tri a 14 or Tri a 19 were specifically associated with severe reactions and WDEIA. Limited co-sensitization indicated distinct IgE pathways to soluble and gluten-related proteins. CONCLUSIONS IgE profiling revealed distinct cross-reactivity patterns across cereals. Tri a 14 frequently co-sensitized with nsLTPs from both gluten-containing and gluten-free cereals, while Tri a 19 was exclusive to gluten-containing species. These findings support the need to expand molecular diagnostic panels to enhance clinical accuracy and guide dietary recommendations.