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].
Environmental Characteristics
Source and tissue
Api m 2 is an enzyme secreted into the venom sac of Apis mellifera, where it contributes 2% of venom dry weight [5].
Risk factors
Sensitization to Api m 2 occurs through injection (bee sting).
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].
Molecular Aspects
Biochemistry
Api m 2, also known as HBV hyaluronidase, is a secreted glycoprotein with a molecular weight of 39 kDa (382 aminoacids). It displays N-glycosylated side chains, disulfide bonds, and a homotetrameric structure [1, 6, 7]. Api m 2 functions as a glycosyl hydrolase, catalyzing the degradation of hyaluronan (hyaluronic acid), a high molecular weight polymer composed of disaccharides of D-glucuronic acid (GlcUA) and N-acetyl-D-glucosamine (GlcNAc), found in the extracellular matrix of the skin, into shorter oligosaccharides [1, 8]. Thus, Api m 2 facilitates the penetration of other venom constituents across the extracellular matrix surrounding the sting area, and releases shorter fragments of hyaluronan, which exert proinflammatory and adjuvant effects [8, 9].
Isoforms, epitopes, antibodies
As of July 5, 2023, a unique isoallergen, Api m 2.0101, has been included in the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature [6].
Cross-reactivity due to structural similarity
Despite amino acid sequence similarity of 50% or higher between Api m 2 and other Hymenoptera venom hyaluronidases [7], and reported cross-reactivity due to peptide cross-recognition in some studies [10], rApi m 2 seldom cross-reacts with its Vespid counterparts [1].
Diagnostic Relevance
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].
Compiled By
Author: Prof. Joana Vitte
Reviewer: Dr. Merima Mehic Chaveton
Last reviewed: 2023-07-20
