Wheat allergy (also known as immediate hypersensitivity) is a growing global public health hazard of critical significance. There is extensive evidence that such hypersensitivity reactions to wheat pose a lethal risk due to high incidence of systemic anaphylaxis. Currently existing wheat species encompass four distinct genomes (AA, DD, AABB, and AABBDD) of which exist in numerous lines and varieties. The extent of natural variation in the intrinsic allergenic potential of glutens from various wheat species remains unknown. Our research was piloted by the central hypothesis that glutens obtained from three different currently consumed wheat species [Triticum monococcum (AA genome), Triticum aestivum (AABBDD genome), and Triticum durum (AABB genome)], as well as an ancient DD genome progenitor (Aegilops tauschii) would exhibit natural variation in their respective intrinsic allergenicities in vivo in an adjuvant-free transdermal sensitization/systemic elicitation of anaphylaxis (TS/SE) mouse model of food allergy. To test this hypothesis, two aims were established: i) to validate the TS/SE mouse model for intrinsic allergenic sensitization to both alcohol and acid-soluble gluten extracts from the four above mentioned wheat species; and ii) to validate the TS/SE model for elicitation of systemic anaphylaxis by both alcohol and acid-soluble gluten extracts from the four wheat species. Our findings demonstrate that repeated skin exposures to both the alcohol and acid-soluble gluten extracts from the four different wheat species elicited significant gluten-specific IgE antibody responses. Furthermore, skin sensitized mice demonstrated clinical sensitization for life-threatening systemic anaphylaxis upon intraperitoneal challenge with the respective glutens as evidenced by significant hypothermic shock responses (HSR) and mucosal mast cell responses (MMCR). Comparative mapping analysis revealed differences in capacity to elicit sIgE among the four wheat species with T. aestivum being the most potent sensitizer for both types of gluten extracts. HSR analysis revealed that the four wheat species elicited significant largely comparable systemic anaphylactic reactions. Nevertheless, among the four wheat species, both types of gluten extracts from T. aestivum emerged as the most potent elicitors of MMCR. In summary, our study validates the TS/SE mouse model of food allergy for wheat gluten extracts from four wheat species. Furthermore, a comparative map of intrinsic allergenic potential of gluten extracts was created for the first time. This validated model serves as a cost-effective pre-clinical testing tool for assessing the intrinsic allergenic potential of glutens from novel wheats including genetically engineered wheats, various wheat lines developed by gene editing, cross-hybridization, as well as altered wheat glutens by food/industrial processing methods. This model may also be used to conduct basic research on the mechanisms underlying gluten allergy as well as developing novel methods to prevent and treat life-threatening systemic anaphylaxis elicited by glutens.
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