Prediction of IgE-binding epitopes by means of allergen surface comparison and correlation to cross-reactivity.

The experimental determination of conformational allergen epitopes recognized by IgE is a difficult task because they often involve discontinuous amino acid residues, being separated in the primary allergen sequence, and require the correct allergen fold.We sought to develop a computational tool for the localization of conformational IgE epitopes by using a structure-based comparison of allergen surfaces and IgE cross-reactivity data.Our approach involves the quantitative analysis of geometric and physicochemical surface parameters and the subsequent correlation of surface similarity scores to immunologic data. The software tool Surface comparison-based Prediction of Allergenic Discontinuous Epitopes (SPADE) is able to predict the IgE epitopes of an allergen given the availability of at least 2 structural models and IgE reactivity data.We report on the application of our tool to 3 allergen families: the lipocalins, the group 10 pathogenesis-related proteins, and the group 2/3 grass pollen allergens. First, we succeeded in the partial relocalization of IgE epitopes of bovine β-lactoglobulin and grass pollen Phl p 2 as known from the x-ray structures of their antibody complexes. Second, we measured the relative binding of anti-Bet v 1 IgE to 10 homologous proteins and correlated these data to surface comparison results involving Bet v 1, 5 of the homologs, and 2 hypoallergenic Bet v 1 isoforms. Thereby we predicted IgE-reactive surface portions in agreement with IgE epitope-mapping studies.Our approach is the first for the prediction of IgE epitopes by combining structural and IgE cross-reactivity data. It should be useful for the development of point-mutated or structurally disrupted allergen derivatives for allergen-specific immunotherapy.