i215 Api m 3

Summary

Api m 3, a glycoprotein of the acid phosphatase family, is a major allergen of Apis mellifera (honeybee) venom (HBV) and a marker allergen for genuine sensitization to this venom.

Api m 3 may be underrepresented in HBV extracts, which may affect the outcome of VIT if Api m 3 is the predominant sensitizer.

Epidemiology

Worldwide distribution

Api m 3 sensitization has a prevalence of 28% to 63% among HBV-allergic populations (reviewed in [1]). Thus, Api m 3 is considered a major allergen in HBV-allergic patients.

Apparent monosensitization to recombinant (r)Api m 3, i.e. without detectable sensitization to any other HBV allergen, was reported in 5% of a German cohort of 144 HBV-allergic patients displaying 50% overall prevalence of Api m 3-specific IgE [2].

Environmental Characteristics

Source and tissue

Api m 3 is an enzyme secreted into the venom sac of Apis mellifera, where it contributes 1.7% ± 0.4% of venom dry weight [3].

Risk factors

Sensitization to Api m 3 occurs through injection (bee sting).

Clinical Relevance

Specific molecules

Api m 3 does not cross-react with Vespid venom allergens, therefore, Api m 3 is a marker allergen allowing to discriminate between HBV and Vespid venom sensitization and identifyf genuine HBV sensitization [1].

Cross-reactive molecules

An acid phosphatase from bumblebee venom, not yet included in the IUIS/WHO database of allergens, was shown to display moderate cross-reactivity with Api m3 [1]. Acid phosphatases from other Hymenoptera venoms (bumblebees, ants, but not Vespids) exhibit sequence identity of 50% or higher with Api m 3 [1, 4].

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

Also known as acid phosphatase, Api m 3 is a secreted glycoprotein with a molecular weight of 43 kDa (388 aminoacids in the pro-form), displaying N-glycosylated side chains and disulfide bonds, found in HBV as monomers or homodimers [1, 4, 5]. The exact biological function of Api m 3 as an acid phosphatase is still elusive [1].

Isoforms, epitopes, antibodies

As of July 8, 2023, a unique isoallergen, Api m 3.0101, 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

Api m 3 displays aminoacid sequence similarity of 50% or higher restricted to venoms from bees, bumblebees, and ants [4].

Diagnostic Relevance

Diagnosis of genuine sensitization to Apis mellifera venom

The demonstration of specific IgE to Api m 3 confirms genuine sensitization to HBV or bumblebee venom [1]. With a prevalence of up to 63% in HBV-allergic patients, IgE to Api m 3 is a relevant clinical tool [1]. Indeed, in populations of HBV allergic patients with low figures of prevalence of Api m 1-specific IgE, using additional HBV marker allergens, mainly Api m 3, Api m 4 and Api m 10, increases the chance of demonstrating genuine sensitization to HBV [1, 2, 7].

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. 

Sensitivity of in vitro assays

The prevalence of sensitization to individual HBV allergens, including Api m 3, 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, the assay format [1, 7]. Thus, the diagnostic sensitivity of rApi m 3-specific IgE ranges from 28 to 63% in HBV-allergic patients [1, 2, 7]. Using a panel of HBV marker allergens such as Api m 1, Api m 3, and Api m 10 improves the rate of confirmation of genuine HBV sensitization [1, 2, 7].

As an example, in a study addressing European HBV-allergic patients from the Czech Republic and Slovenia, the diagnostic sensitivity of rApi m 3-specific IgE was 28% in HBV-allergic patients devoid of Vespid sensitization and 49% in patients exhibiting HBV and Vespid venom sensitization, with an overall diagnostic sensitivity of 38% [7]. In this cohort, a panel comprising Api m 1, Api m 2, Api m 3, and Api m 10 increased the diagnostic sensitivity to 91% , in line with previous reports from other cohorts [2, 7].

Diagnostic specificity

The reported diagnostic specificity of IgE to rApi m 3 for HBV allergy is 100% [2, 7]. Api m 3 sensitization was not detected in subjects without HBV allergy, even in those with a history of bee stings or detectable IgE to HBV whole extract [2, 7]

AIT Prescription

The demonstration of Api m 3-specific IgE contributes to the identification of genuine HBV sensitization, thus supporting the choice of HBV AIT in eligible patients [1].

It has been suggested that Api m 3 might be underrepresented in therapeutic HBV extracts for VIT [2]. A lack of inhibition of IgE binding to Api m 3 following serum preincubation with HBV therapeutic extract, and failure to mount a specific IgG4 response to Api m 3 were observed, and might influence the outcome of immunotherapy [2]. 

Compiled By

Author: Prof. Joana Vitte

Reviewer: Dr. Merima Mehic Chaveton

Last reviewed: 2023-07-20