The development of an IgE response to an allergen involves a series of interactions between T cells and B cells. B cells bearing appropriate antigen-specific surface immunoglobulins interact with proliferating allergen-specific T cells, leading to isotype switching and the generation of antigen-specific IgE. The antigen-specific IgE then binds to the Fc(ε)RI receptors of mast cells and basophils. Because antigen-specific IgE plays such a critical role in the pathogenesis of allergic disease, determination of allergen-specific, IgE-binding epitopes is an important first step toward a better understanding of this complex disease process. Studies defining the peanut allergens should now allow more specific research to be done on improved diagnostic methods for peanut hypersensitivity, new immunotherapeutic approaches for this chronic and often severe disease, and development of hypoallergenic or less sensitizing plants. Immediate hypersensivity reactions to foods are mediated through the interaction of IgE with a specific food protein. While specific IgE-binding epitopes from the major allergens of cow's milk (25), codfish (26), hazelnut (27), soybeans (28), and shrimp (29) have been elucidated, there have been few, if any, common characteristics found in these binding sites. Our work on the IgE- binding sites of Ara h 1, 2, and 3 indicates that there are no common amino- acid sequence motifs shared by these epitopes. However, we have determined that in the IgE-binding epitopes of these allergens the hydrophobic amino- acid residues appear to play a critical role in IgE binding. The observation that alteration of a single amino acid leads to the loss of IgE binding in a population of peanut-sensitive individuals is significant because it suggests that while each patient may display a polyclonal IgE reaction to a particular allergen (16, 17), IgE from different patients recognize the same epitope and must interact with that epitope in a similar fashion. Besides after the finding that many epitopes in each of the different peanut allergens contained more than one residue critical for IgE binding, it was also determined that more than on residue type (ala or met) could be substituted at certain positions in an epitope with similar results. This information may allow the design of a hypoallergenic protein that would be effective in blunting allergic reactions for a population of peanut-sensitive individuals. Furthermore, a peanut from which the IgE-binding epitopes of the major allergens have been removed may prevent the development of peanut hypersensitivity in individuals genetically predisposed. The characteristics that have been attributed to allergenic proteins include their abundance in the food source, their resistance to food processing, and their stability to digestion by the gastrointestinal tract (30-32). The major allergens of foods - in particular, the Ara h 1 peanut allergen - have been shown to survive intact most food-processing methods and to be stable to digestion in in vitro systems designed to mimic the gastrointestinal tract. Our observations on the tertiary structure of the Ara h 1 monomer and the determination that this protein readily forms a trimeric complex may help to determine why this protein is allergenic. While there are numerous protease digestion sites throughout the length of this protein, the structure may be so compact that potential cleavage sites are inaccessible until the protein is denatured. The physical properties of the Ara h 1 molecule and the other peanut allergens may help to explain the extreme allergenicity exhibited by peanut proteins. The only therapeutic option currently available for the prevention of a peanut hypersensitivity reaction is food avoidance. Unfortunately, for a ubiquitous food such as peanut, the possibility of an inadvertent ingestion is great. Interestingly, most of the peanut allergens identified to date, including Ara h 1, 2, and 3, have sequence homology with proteins in other plants. This information may help to begin to explain the cross-reacting IgE antibodies to other legumes that are found in the sera of patients that manifest clinical symptoms to only one member of the legume family (33). Certainly, the elucidation of the position of the Ara h 1-binding epitopes clustered on the surface of the molecule may enable us to understand why these regions elicit the clinical symptoms associated with peanut hypersensitivity. Perhaps the presentation of multiple, clustered epitopes to mast cells results in a more efficient and dramatic release of mediators, resulting, in turn, in the more severe clinical symptoms observed in patients with peanut hypersensitivity. Current work is exploring this possibility by comparing the IgE-binding epitopes and tertiary structures of other legume allergens. Taken in total, these studies suggest that an altered Ara h 1, 2, or 3 gene could be developed to replace its allergenic homologue in the peanut genome, thus blunting allergic reactions in sensitive individuals who inadvertently ingest this food. Since these gene products are an abundant and integral seed storage protein, it would be necessary for the altered protein to retain as much of its native function, properties, and three-dimensional structure as possible. The information gained from these studies on the peanut allergens indicates that development of hypoallergenic seed storage proteins may be feasible. Additionally, a less allergenic peanut protein with the immunodominant IgE epitopes mutated, rather than the current peanut protein as we know it, may prove to be beneficial in feeding the at-risk group of atopic individuals. However, the effect that altering critical amino acids within each of the IgE-binding epitopes has on the properties of the seed storage proteins is currently unknown. In view of the widespread use of peanuts in consumer foods and the potential risk this poses to individuals genetically predisposed to developing peanut allergy and to the health of individuals already peanut sensitive, this approach is currently being explored in our laboratories.
Burks, W., Sampson, H. A., & Bannon, G. A. (2008). Peanut allergens. Allergy, 53(8), 725–730. https://doi.org/10.1111/j.1398-9995.1998.tb03967.x