Api m 2
Summary
Api m 2, a member of the hyaluronidase family, is a major allergen of Apis mellifera (honeybee) venom (HBV). Its cross-reactivity with Vespid venom hyaluronidases is deemed limited outside cross-reactive carbohydrate (CCD) moieties. Thus, recombinant Api m 2 (rApi m 2) may contribute to the detection of genuine HBV sensitization.
Epidemiology
Worldwide distribution
The reported prevalence of Api m 2 sensitization among HBV-allergic populations usually ranges from 28% to 60% (reviewed in [1]), with values up to 88% reported in some studies [2]. Thus, Api m 2 is considered a major allergen in HBV-allergic patients.
Apparent monosensitization to Api m 2, i.e. without detectable sensitization to any other HBV allergen, was reported in 13-15% of HBV-allergic patients [3, 4]. In a small study, apparent Api m 2 monosensitization was not observed in patients with HBV and Vespid venom double-sensitization, nor in patients with Vespid venom sensitization alone [4]. Among 34 Japanese beekeepers having experienced systemic reactions to a bee sting, Api m 2 sensitization was present in the three patients who had undetectable IgE to Api m 1 [2].
Clinical Relevance
Specific molecules
Api m 2 belongs to the hyaluronidase family of allergens, which is widespread among Hymenoptera venoms, however, cross-reactivity between Api m 2 and its counterparts from Vespid venoms is attributed mainly to CCD. Thus, demonstration of specific IgE to rApi m 2 may contribute to the detection of genuine HBV sensitization [1]. Moreover, apparent Api m 2 monosensitization has been reported in HBV-allergic patients [3, 4]. In patients with double-positive IgE results obtained using whole venom extracts, further testing using recombinant venom allergens can differentiate between genuine double-sensitization and cross-reactivity [1].
Cross-reactive molecules
Other hyaluronidase venom allergens have been characterized in the Apis (bee) genus, as well as in Vespids, but not in bumblebee (Bombus) venom [1, 6]. Api m 2 and other hyaluronidase allergens display mainly CCD-borne cross-reactivity between HBV and Vespid venom [1].
Disease severity
Various patterns of sensitization to HBV allergens have been described, but no clinical correlate of severity has been identified so far [1].
Diagnostics
Cross-reactivity versus detection of genuine HBV sensitization
Cross-reactivity between homologous allergens, such as the hyaluronidases Api m 2 and Ves v 2, can result in apparent double-positivity to HBV and Vespid venom whole extracts [1, 4, 11]. However, it is currently considered that the cross-reactivity of Api m 2 and the hyaluronidase Ves v 2, a minor allergen of the common wasp (Vespula vulgaris) venom, is not clinically relevant, with the recombinant form rApi m 2, devoid of CCD, reported as able to detect genuine HBV sensitization [1-4].
Disease severity
In Hymenoptera IgE testing, the quantitative result of specific IgE to a molecular allergen or whole venom extract is neither predictive of, nor correlated to the severity of the reaction [1].
Sensitivity of in vitro assays
The prevalence of sensitization to individual HBV allergens, including Api m 2, in HBV-allergic patients varies depending on multiple factors such as geography, patient inclusion criteria, single or double positivity to HBV and Vespid venoms, underlying sensitization profile, use of a recombinant allergen versus a natural purified allergen, and the assay format [1, 2, 12, 13]. Thus, the diagnostic sensitivity of specific IgE to rApi m 2 ranges from 28 to 88% in HBV-allergic patients [1, 2, 12, 14]. Using a panel of HBV allergens including rApi m 2 besides available HBV marker allergens Api m 1, Api m 3, and Api m 10 improves the rate of confirmation of genuine HBV sensitization [1, 2, 13, 14]. Api m 2 sensitization can be detected with commercially available singleplex methods. Intermethod comparison showed acceptable agreement between singleplex methods [13].
Diagnostic specificity
The diagnostic specificity of IgE to rApi m 2 for HBV allergy has been consistently reported at high levels, 90 to 100% [2, 12, 13].
AIT Prescription
The demonstration of Api m 2-specific IgE contributes to the identification of genuine HBV sensitization, thus supporting the choice of HBV AIT in eligible patients [1].
References
- Dramburg S, Hilger C, Santos AF, de Las Vecillas L, Aalberse RC, Acevedo N, et al. EAACI Molecular Allergology User's Guide 2.0. Pediatr Allergy Immunol. 2023;34 Suppl 28:e13854.
- Hirata H, Sato K, Ogasawara T, Funakoshi T, Shima D, Tatewaki M, et al. Sensitization to Api m 1, Api m 2, and Api m 4 in Japanese beekeepers who had experienced systemic reactions to honeybee stings. Allergol Int. 2019;68(2):261-3.
- Sturm GJ, Hemmer W, Hawranek T, Lang R, Ollert M, Spillner E, et al. Detection of IgE to recombinant Api m 1 and rVes v 5 is valuable but not sufficient to distinguish bee from wasp venom allergy. J Allergy Clin Immunol. 2011;128(1):247-8; author reply 8.
- Jovanovic D, Peric-Popadic A, Djuric V, Stojanovic M, Lekic B, Milicevic O, et al. Molecular diagnostics and inhibition of cross-reactive carbohydrate determinants in Hymenoptera venom allergy. Clin Transl Allergy. 2023;13(3):e12230.
- Spillner E, Blank S, Jakob T. Hymenoptera allergens: from venom to "venome". Front Immunol. 2014;5:77.
- IUIS/WHO. IUIS/WHO Apis mellifera 2023 [Available from: http://allergen.org/search.php?allergenname=&allergensource=apis+mellifera&TaxSource=&TaxOrder=&foodallerg=all&bioname=.
- UniProt. UniProt Q08169 for Api m 2 2023 [Available from: https://www.uniprot.org/uniprotkb/Q08169/entry.
- King TP, Wittkowski KM. Hyaluronidase and hyaluronan in insect venom allergy. Int Arch Allergy Immunol. 2011;156(2):205-11.
- Elieh Ali Komi D, Shafaghat F, Zwiener RD. Immunology of Bee Venom. Clin Rev Allergy Immunol. 2018;54(3):386-96.
- Jin C, Focke M, Leonard R, Jarisch R, Altmann F, Hemmer W. Reassessing the role of hyaluronidase in yellow jacket venom allergy. J Allergy Clin Immunol. 2010;125(1):184-90 e1.
- Jakob T, Rafei-Shamsabadi D, Spillner E, Muller S. Diagnostics in Hymenoptera venom allergy: current concepts and developments with special focus on molecular allergy diagnostics. Allergo J Int. 2017;26(3):93-105.
- Schrautzer C, Bokanovic D, Hemmer W, Lang R, Hawranek T, Schwarz I, et al. Sensitivity and specificity of Hymenoptera allergen components depend on the diagnostic assay employed. J Allergy Clin Immunol. 2016;137(5):1603-5.
- Vachova M, Panzner P, Kopac P, Bidovec Stojkovic U, Korosec P. Routine clinical utility of honeybee venom allergen components. J Allergy Clin Immunol Pract. 2018;6(6):2121-3 e1.
- Kohler J, Blank S, Muller S, Bantleon F, Frick M, Huss-Marp J, et al. Component resolution reveals additional major allergens in patients with honeybee venom allergy. J Allergy Clin Immunol. 2014;133(5):1383-9, 9 e1-6.