Peanut allergy—Individual molecules as a key to precision medicine
Authors: Uta Jappe, Heimo Breiteneder
Journal: Allergy (2018)

Peanut allergy is one of the most severe food allergies affecting millions of individuals worldwide. In German-speaking countries, peanut allergy is the most important cause of anaphylaxis in children and adolescents.1 This Editorial highlights the impact of individual peanut allergens on the severity of symptoms and summarizes the allergens’ biological characteristics and usefulness as tools for precision diagnostic tests. While peanuts are consumed cooked, roasted, or as peanut butter, roasting is the one processing method that considerably increases the allergenicity of peanuts (Figure 1). Atopic children with impaired skin barrier functions may experience severe allergic reactions to peanuts without prior consumption illustrating the importance of the cutaneous route for sensitization.2 Sensitization via the gastrointestinal tract, breastfeeding, or inhalation is also highly probable (Figure 1).3 Symptoms range from oral allergy syndrome, mostly related to pollen-associated peanut allergy, to severe dyspnoea, anaphylaxis, and sometimes death.4 If peanut allergy starts in early childhood, it will persist for life in the majority of cases. To date, no safe and efficacious causative treatment for peanut allergy has been authorized. However, epicutaneous immunotherapy with peanut extract is in a phase III trial.5 Currently, early exposure is intensely discussed as a preventive measure.6 During recent years, diagnostic tests have been improved considerably driven by molecular allergology research (Figure 1). Besides aqueous peanut extracts, six individual peanut allergens are already available for routine in vitro diagnostic tests in single- and multiplex formats (Figure 1). The systematic allergen nomenclature provided by the WHO/IUIS Allergen Nomenclature Sub-Committee (http://www.allergen.org) is the only allergen nomenclature accepted by the World Health Organization (WHO) and the International Union of Immunological Societies (IUIS). At present (09/2018), 16 peanut allergens are officially recognized (Table 1). The designation Ara h 4 is no longer in use; it was renamed Ara h 3.02. The biology and immunology of individual peanut allergens was reviewed in detail recently.7 AAB00861 P43238 AAA60336 P43237 AAC63045 O82580 AAD47382 Q9SQH7 Prolamin (CL0482) Protease inhibitor/seed storage/LTP (PF00234) AAN77576 Q6PSU2 AAD56337 Q647G9 AAD56719 Q9SQH1 ABW17159 B4XID4 AAU21496 Q647G8 ABX56711 B6CEX8 ABX75045 B6CG41 Profilin-like (CL0432) Profilin (PF00235) AAD55587 Q9SQI9 Bet v 1-like (CL0209) Bet v 1 (PF00407) AAQ91847 Q6VT83 ABP97433 B0YIU5 No superfamily defined Oleosins (PF01277) AAU21499 Q647G5 AAU21500 Q647G4 AAZ20276 Q45W87 AAZ20277 Q45W86 AAK13449 Q9AXI1 Pons, Plant Physiol Biochem. 2005;43:659 Schwager, PLoS One 2015;10(4):e0123419 AAK13450 Q9AXI0 AAT11925 Q6J1J8 AAU21501 Q647G3 Scorpion toxin-like knottin (CL0054) Plant defensin (PF00304) Ara h 1 and Ara h 3 are seed storage proteins. Both allergens possess two beta-barrel cupin domains and are members of the cupin superfamily and the cupin 1 protein family. The protein family database Pfam (https://pfam.xfam.org/) refers to protein superfamilies as clans, abbreviated CL. While Ara h 1 monomers aggregate to form trimers, known as vicilins, Ara h 3 monomers form hexamers, known as legumins. Cupin seed storage proteins serve as source of amino acids and energy during seed germination. In many plant species, cupins are involved in the defense against fungi and insects. Cupin storage proteins play an important role as allergens for primary peanut allergy, particularly in children, who develop allergy at a young age.8 Individual allergens are already used as tools to elucidate the sensitization process.9 The prolamin superfamily comprises several protein families with limited sequence similarities, among them two families of low molecular weight proteins, the 2S albumins and the nonspecific lipid transfer proteins (nsLTPs). These are heavily disulfide-bonded resulting in the high stability of the allergenic peanut 2S albumins Ara h 2, 6, and 7. 2S albumins in seeds store amino acids, but they also possess antifungal and antibacterial properties. nsLTPs are divided into the 9 kDa nsLTP1 and the 7 kDa nsLTP2 subfamilies. Both nsLTP1s and nsLTP2s are found in seeds where they play important roles in resistance to biotic and abiotic stress, plant growth, and development. Ara h 9 and 17 are nsLTP1s, and Ara h 16 is an nsLTP2. Due to their high stability, allergens of the prolamin superfamily are associated with severe symptoms (Figure 1). Among the 2S albumins, Ara h 2 has a prominent role as marker allergen for the severity of the reaction, followed in significance by Ara h 6 (Figure 1). Peanut is an oilseed crop, and its oil content is around 50%. Oleosins are the major oil body stabilizing proteins. Eight allergenic peanut oleosins have been identified and classified into four allergen groups, namely Ara h 10, 11, 14, and 15. All patients with severe peanut allergy have IgE to oleosins (Figure 1). This is in contrast to defensins, to which not all patients with severe allergic reactions have IgE antibodies. Roasting increases the allergenicity of oleosins which was also observed for Ara h 1, 2, and 6 (Figure 1). Plant defensins are a family of peptides involved in the protection of seeds and reproductive tissues. Defensins are disulfide-rich antimicrobial peptides. Their activity is primarily directed against fungi but also against bacteria and insects. Membrane targeting via specific membrane phospholipids and membrane disruption are functions of many defensins. Ara h 12 and 13 are peanut defensins. They are not yet available for component-resolved diagnosis, but preliminary data indicate their high significance for patients with severe reactions to peanuts. The profilin family comprises proteins that are present in all eukaryotic cells and that are highly conserved in higher plants. Profilins are involved in the turnover and restructuring of the actin cytoskeleton. Ara h 5, the peanut profilin, cross-reacts with many other plant profilins and, hence, can decrease the test specificity. Proteins with the typical Bet v 1 architecture are found in all kingdoms of life. The Bet v 1-like superfamily comprises 17 families including the Bet v 1 family with its several subfamilies. Most of the Bet v 1-homologous allergens known belong to the PR-10 subfamily. Ara h 8, the Bet v 1 homolog from peanut, is linked to pollen-associated peanut allergy with mostly mild or moderate symptoms (Figure 1). As Ara h 8 associates with lipids via its hydrophobic cavity, thereby protecting the protein from degradation, it may also be responsible for severe allergic reactions. Peanut-allergic patients react to different peanut allergens and, therefore, require individualized allergy diagnostic testing. Marker allergens will allow molecular phenotyping in the future. While improved component-resolved diagnosis will help to identify patients who will profit from specific immunotherapy, only a thorough understanding of the mechanistic processes of sensitization and symptom elicitation based on studies using the same individual allergens will enable us to cure the disease. Author UJ gratefully acknowledges the funding by the German Research Foundation (DFG) grant JA-1007/2-1 and the German Center for Lung Research (DZL). Author HB acknowledges the support of the Austrian Science Fund (FWF) Doctoral Program MCCA W1248-B30. Author UJ reports grants from the German Research Foundation, the German Center for Lung Research, and from Phadia ThermoFisher Scientific, and personal fees from the Fraunhofer Zukunftsstiftung. Author HB declares that he has no conflict of interest in relation to this manuscript.