i217 Api m 10

Summary

Api m 10, a low abundance glycoprotein from Apis mellifera (honeybee) venom (HBV), of unknown biological function, is a major allergen of HBV and a marker allergen for genuine sensitization to this venom. Api m 10 is underrepresented in HBV extracts, negatively affecting the outcome of venom immunotherapy (VIT) in HBV allergic patients with dominant Api m 10 sensitization.

Epidemiology

Worldwide distribution

Api m 10 sensitization has a prevalence of 26% to 75% among HBV-allergic populations ([1-3]) and is usually considered a major allergen in HBV-allergic patients. Api m 10 monosensitization is usually not observed in HBV allergic patients [2-4], and concerns a low percentage of patients when it is identified, less than 5% [4, 5]. 

Environmental Characteristics

Source and tissue

Api m 10 is a glycoprotein secreted into the venom sac of Apis mellifera, where it contributes 0.8% of venom dry weight [6, 7]. Api m 10 is unstable in both native and recombinant forms, which may explain its underrepresentation in therapeutic HBV extracts [6, 7].

Risk factors

Sensitization to Api m 10 occurs through injection (bee sting). 

Clinical Relevance

Specific molecules

Api m 10 is a marker allergen for HBV genuine sensitization, as it does not cross-react with allergens from other Hymenoptera venoms [1].

Disease severity

Neither the prevalence, nor the level of Api m 10-specific IgE can distinguish between patients experiencing severe versus non severe systemic reactions to HBV stings, nor between HBV allergic and asymptomatic HBV sensitized subjects  [1, 3]. However, Api m 10 prevalence and specific IgE levels were reportedly lower in HBV allergic patients experiencing severe adverse effects (SAEs) during VIT compared with those without SAEs (20% and 33%, p 0.04, and median + interquartile range <0.35 + 0.29 kUA/L versus 0.35+0 kUA/L, p 0.03) [3].

Cross-reactive molecules

No cross-reactive allergen has been described so far for Api m 10 [1, 7].

Disease severity

Various patterns of sensitization to HBV allergens have been described, but no clinical correlate of severity has been identified so far [1].

Prevention and Therapy

Experimental trials

Linear IgE epitope mapping of Api m 10 has identified a peptide with broad recognition that opens the perspective of therapeutic development for immunotherapy [7].

Molecular Aspects

Biochemistry

Api m 10, also known as icarapin or CRP, is a secreted monomeric glycoprotein of 204 aminoacids in its mature form, displaying a molecular weight of 50-55 kDa, of which the non-glycosylated protein part contributes approximately 35 kDa [6]. Four N-glycosylation sites are predicted [8]. The biological function of Api m 10 is unknown, despite it being well-conserved among insects, with predicted homologues in other Hymenoptera (bumblebees, Vespids, ants), as well as in mosquitoes, flies, and beetles [7]. Api m 10 is instable, a feature that might explain its underrepresentation in therapeutic HBV extracts [1, 7].

Isoforms, epitopes, antibodies

As of July 25, 2023, a unique isoallergen, Api m 10.0101, has been included in the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature [9]. 

Cross-reactivity due to structural similarity

Despite aminoacid sequence similarity of 50% or higher between Api m 10 and other Hymenoptera venom icarapin-like proteins [7, 8], and its highly conserved status [1, 7], no cross-reactive allergen has been identified so far for rApi m 10 [1]. 

Diagnostic Relevance

Diagnosis of genuine sensitization to Apis mellifera venom

Api m 10 is a marker allergen for HBV sensitization. Therefore, the demonstration of specific IgE to Api m 10 confirms genuine sensitization to HBV [1, 10].

With a prevalence of up to 75% in HBV-allergic patients, IgE to Api m 10 is a relevant clinical tool [1]. However, using a panel of HBV marker allergens in addition to Api m 1 and Api m 10 increases the chance of demonstrating genuine sensitization to HBV [1, 2, 5, 11].

Disease severity

In Hymenoptera venom 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 10, in HBV-allergic patients varies depending on multiple factors such as geography, patient inclusion criteria, single or double positivity to HBV and Vespid venoms, use of a recombinant allergen from bacterial or insect cell expression versus a natural purified allergen, and assay format [1-3, 5, 7]. Thus, the diagnostic sensitivity of specific IgE to rApi m 10 ranges from 26 to 75% in HBV-allergic patients [1, 2, 5, 7, 11]. 

Api m 10 sensitization can be detected with commercially available singleplex methods. 

Diagnostic specificity

No IgE binding to rApi m 10 was reported in subjects without detectable IgE to HBV whole allergen extract, nor in Vespid-allergic patients without HBV sensitization, and the diagnostic specificity of IgE to rApi m 10 in HBV allergic patients was calculated at 97.6% in a performance study [2, 5, 6, 11]. 

AIT Prescription

Demonstrated sensitization to Api m 10 confirms genuine sensitization to HBV, thus supporting the accurate diagnosis in patients with double sensitivity to HBV and Vespid venom extracts, as well as in patients with inconsistent clinical history and skin prick tests, and guiding the choice of HBV AIT in eligible patients [1].

Api m 10 sensitization has been associated with poorer responses to, or even therapeutic failure of, HBV VIT, especially in patients with dominant Api m 10 sensitization, i.e. with levels of specific IgE to Api m 10 higher than 50% of the level of specific IgE to HBV extract [1, 6, 7]. This is of particular concern in areas with a high prevalence of Api m 10 sensitization, where dominant Api m 10 sensitization was reported in 10 to 12% of HBV allergic patients [7]. Conversely, a study on 332 HBV allergic patients receiving VIT reported significantly lower figures of prevalence and levels of Api m 10 specific IgE in patients experiencing SAEs as compared to those who did not experience SAEs during VIT [3].

Taken together, these data suggest that in HBV allergic patients with Api m 10 dominant sensitization, VIT should be undertaken with therapeutic HBV extracts with detectable Api m 10 amounts [7].

Compiled By

Author: Prof. Joana Vitte

Reviewer: Dr. Merima Mehic Chaveton

Last reviewed: 2023-08-01