Api m 1
Summary
Api m 1, a glycoprotein of the phospholipase 2 (PLA2) family, is a major allergen of Apis mellifera (honeybee) venom (HBV) and a marker allergen for genuine sensitization to this venom.
Epidemiology
Worldwide distribution
Api m 1 sensitization has a prevalence of 57% to 97% among HBV-allergic populations (reviewed in [1]). Thus, Api m 1 is consistently found as a major allergen in HBV-allergic patients.
Clinical Relevance
Specific molecules
Of the 12 known allergens within HBV, Api m 1 is considered the most prominent allergen, in terms of prevalence of sensitization, levels of specific IgE to Api m 1, and quantitative correlation between Api m 1 and HBV specific IgE [5-10]. Api m 1 does not cross-react with phospholipases of the PLA1 family found in Vespid venoms, therefore, Api m 1 is a marker allergen allowing to discriminate between HBV and Vespid venom sensitization [1].
Besides Api m 1, sensitization to other HBV marker allergens may achieve a prevalence of 50% or higher among HBV-allergic patients: Api m 3, Api m 4, and Api m 10 [1].
Cross-reactive molecules
Other PLA2 venom allergens have been characterized in the Apis (bee) and Bombus (bumblebee) genera, but not in Vespids [1, 11]. Api m 1 and other PLA2 allergens do not allow discrimination between HBV and bumblebee venom sensitization [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
Diagnosis of genuine sensitization to Apis mellifera venom
Api m 1 is a marker allergen for HBV sensitization. Therefore, the demonstration of specific IgE to Api m 1 confirms genuine sensitization to HBV or bumblebee venom, and supports the initiation of HBV VIT in eligible patients [1, 18].
With a prevalence of up to 97% in HBV-allergic patients, IgE to Api m 1 is a relevant clinical tool [1]. However, in populations of HBV allergic patients with lower figures of prevalence of IgE to Api m 1, using additional HBV marker allergens such as Api m 3, Api m 4 and Api m 10 increases the chance of demonstrating genuine sensitization to HBV [1, 8, 19].
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 1, 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, 6, 7, 10, 17, 19-21]. Thus, the diagnostic sensitivity of specific IgE to rApi m 1 ranges from 56 to 97% in HBV-allergic patients [1, 8, 10, 19]. Using a panel of HBV allergens such as Api m 1, Api m 2, Api m 3, and Api m 10 improves the rate of confirmation of genuine HBV sensitization, albeit with important variations as a function of geography and patient clinical history [1, 8, 10, 22].
Api m 1 sensitization can be detected with commercially available singleplex and multiplex methods. Intermethod comparison showed good agreement between singleplex and multiplex methods for the detection of Api m 1 sensitization [21], and between different singleplex methods for quantitative assessment of IgE to rApi m 1 [22].
Diagnostic specificity
The diagnostic specificity of IgE to rApi m 1 for HBV allergy has been consistently reported at very high levels, 97 to 100% [5, 10, 19, 22]. The use of recombinant Api m 1 retains IgE reactivity comparable to the native protein but eliminates CCD binding, thus improving the identification of species-specific sensitization [1, 7, 17].
AIT Prescription
Demonstrated sensitization to Api m 1 confirms genuine sensitization to HBV, thus supporting the choice of HBV AIT in eligible patients [1].
Given the high prevalence of Api m 1 sensitization in HBV allergic patients, this allergen is the best candidate for designing AIT candidates such as mimotopes or hypoallergenic derivatives [9, 16].
Prevention And Therapy
Experimental trials
In one study, recombinant hypoallergenic variants of Api m 1 were produced with altered structural folding. This prevented recognition of Api m 1 by IgE, which relies on the allergen having the correct three-dimensional structure. Unlike correctly folded Api m 1 variants, which induced IgE secretion and TH2-type cytokine production in cultures of peripheral blood mononuclear cells, the incorrectly folded variants stimulated production of IgG4 and TH1-dominant cytokines [9].
Some studies involving short, immunodominant T cell epitope peptides derived from Api m 1 suggest that these peptides may be capable of suppressing the immune response against the entire allergen in HBV-allergic patients [9].
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.
- Spillner E, Blank S, Jakob T. Hymenoptera allergens: from venom to "venome". Front Immunol. 2014;5:77.
- UniProt. UniProt P00630 for Api m 1 2023 [Available from: https://www.uniprot.org/uniprotkb/P00630/entry.
- Elieh Ali Komi D, Shafaghat F, Zwiener RD. Immunology of Bee Venom. Clin Rev Allergy Immunol. 2018;54(3):386-96.
- Hofmann SC, Pfender N, Weckesser S, Huss-Marp J, Jakob T. Added value of IgE detection to rApi m 1 and rVes v 5 in patients with Hymenoptera venom allergy. J Allergy Clin Immunol. 2011;127(1):265-7.
- Korosec P, Valenta R, Mittermann I, Celesnik N, Erzen R, Zidarn M, et al. Low sensitivity of commercially available rApi m 1 for diagnosis of honeybee venom allergy. J Allergy Clin Immunol. 2011;128(3):671-3.
- Jakob T, Kohler J, Blank S, Magnusson U, Huss-Marp J, Spillner E, et al. Comparable IgE reactivity to natural and recombinant Api m 1 in cross-reactive carbohydrate determinant-negative patients with bee venom allergy. J Allergy Clin Immunol. 2012;130(1):276-8; author reply 8-9.
- 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.
- Zahirovic A, Luzar J, Molek P, Kruljec N, Lunder M. Bee Venom Immunotherapy: Current Status and Future Directions. Clin Rev Allergy Immunol. 2020;58(3):326-41.
- 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.
- IUIS/WHO. IUIS/WHO Apis mellifera 2023 [Available from: http://allergen.org/search.php?allergenname=&allergensource=apis+mellifera&TaxSource=&TaxOrder=&foodallerg=all&bioname=.
- Ogden HL, Lai Y, Nolin JD, An D, Frevert CW, Gelb MH, et al. Secreted Phospholipase A(2) Group X Acts as an Adjuvant for Type 2 Inflammation, Leading to an Allergen-Specific Immune Response in the Lung. J Immunol. 2020;204(12):3097-107.
- Chung ES, Lee G, Lee C, Ye M, Chung HS, Kim H, et al. Bee Venom Phospholipase A2, a Novel Foxp3+ Regulatory T Cell Inducer, Protects Dopaminergic Neurons by Modulating Neuroinflammatory Responses in a Mouse Model of Parkinson's Disease. J Immunol. 2015;195(10):4853-60.
- Choi GM, Lee B, Hong R, Park SY, Cho DE, Yeom M, et al. Bee venom phospholipase A2 alleviates collagen-induced polyarthritis by inducing Foxp3(+) regulatory T cell polarization in mice. Sci Rep. 2021;11(1):3511.
- Santos MCP, Serra-Caetano A, Pedro E, Melo A, Caramalho I, Barbosa MP, et al. Expansion of FOXP3(+) regulatory CD4 T cells upon exposure to hymenoptera venom during the beekeeping season. Allergy. 2019;74(6):1182-4.
- Zahirovic A, Koren A, Kopac P, Strukelj B, Korosec P, Lunder M. Identification of bee venom Api m 1 IgE epitopes and characterization of corresponding mimotopes. J Allergy Clin Immunol. 2019;143(2):791-4 e5.
- Gattinger P, Bidovec-Stojkovic U, Zidarn M, Korosec P, Valenta R, Mittermann I. Glycosylation enhances allergenic activity of major bee venom allergen Api m 1 by adding IgE epitopes. J Allergy Clin Immunol. 2021;147(4):1502-4 e5.
- Blank S. Marker allergens in Hymenoptera Venom Allergy - Characteristics and potential use in precision medicine. Allergo J Int. 2020.
- 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.
- Jakob T, Spillner E. Comparing sensitivity of Hymenoptera allergen components on different diagnostic assay systems: Comparing apples and oranges? J Allergy Clin Immunol. 2017;139(3):1066-7.
- Bidovec-Stojkovic U, Vachova M, Kosnik Z, Kosnik M, Panzner P, Volfand J, et al. Methodological and diagnostic relevance of IgEs to recombinant allergens Api m 1 and Ves v 5 determined by the multiplex test ImmunoCAP ISAC. Clin Exp Allergy. 2020;50(8):981-3.
- 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.