An Evolutionary Perspective on Human Cross-sensitivity to Tree Nut and Seed Allergens

Tree nut allergies are some of the most common and serious allergies in the United States. Patients who are sensitive to nuts or to seeds commonly called nuts are advised to avoid consuming a variety of different species, even though these may be distantly related in terms of their evolutionary history. This is because studies in the literature report that patients often display sensitivity to multiple nut species (crosssensitivity) if they have an existing nut allergy. These reports suggest that cross-sensitivity in patients with nut allergies may be caused by an IgE antibody reacting with epitopes present in the seed proteins of different species (cross-reactivity), for example, if IgE isolated from the serum of a patient were able to bind to both almond and peanut allergens. We hypothesize that allergenic proteins in seeds may have similar amino acid sequences that cause the observed cross-sensitivity. Here, we test the hypothesis that similarity in the protein sequences of allergenic nuts drives cross-sensitivity and cross-reactivity by reconstructing the gene trees of three allergenic seed-storage proteins (vicilin, legumin, and 2S albumin) from species sampled across vascular plants. We generate estimates of their phylogenetic relationships and compare these to the allergen cross-sensitivity and cross-reactivity data that is reported in the literature. In general, evolutionary relationships of the three proteins are congruent with the current understanding of plant species relationships. However, we find little evidence that distantly related nut species reported to be crossreactive share similar vicilin, legumin, or 2S albumin amino acid sequences. Our data thus suggests that features of the proteins other than their amino acid sequences may be driving the cross-reactivity observed during in vitro tests and skin tests. Our results support current treatment guidelines to limit nut and seed consumption if allergies are present in a patient. More studies are necessary to better understand the characteristics of allergenic proteins and patterns of cross-sensitivity in patients who suffer from nut allergies.