In relation to the prediction of allergenicity three aspects have to be discussed: IgE immunogenicity, IgE cross-reactivity, and T-cell cross-reactivity. IgE immunogenicity depends largely on factors other than the protein itself: the context and dose and "history" of the protein by the time it reaches the immune system. It is, therefore, not fully predictable from structural information. In contrast, IgE cross-reactivity can be much more reliably assessed by in-silico homology searches in combination with in vitro IgE antibody assays. The in-silico homology search is unlikely to miss potential cross-reactivity with sequenced allergens. So far, no biologically relevant cross-reactivity at the antibody level has been demonstrated between proteins without easily demonstrable homology. T-cell cross-reactivity is much more difficult to predict than B-cell cross-reactivity. Moreover, its effects are more diverse. Yet, pre-existing cross-reactive T-cell activity is likely to influence the outcome not only of the immune response, but also of the effect phase of the allergic reaction. The question of whether any antigen can be allergenic is still a matter of debate.
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