Honeybee Venom Immunotherapy

Certainties and Pitfalls

M Beatrice Bilò; Leonardo Antonicelli; Floriano Bonifazi


Immunotherapy. 2012;4(11):1153-1166. 

In This Article

HB Venom Allergens

Although their sacs may hold up to more than 300 µg of venom the amount of HB venom protein released by honeybees per sting ranges from 50 to 140 µg.[1]

HB venom is a mixture of proteins and other pharmacologically active molecules that diffuse into the tissue after a sting. While it is the biogenic amines and peptides that primarily cause local pain and inflammation at the sting site, allergic sensitization is most often due to proteins.[11]

It is of interest that a recent study was able to map the diffusion and distribution of HB venom allergens and toxins in different layers of the skin of a rat from a live HB sting.[12]

Knowledge of venom composition and the structure of allergens is a prerequisite for the accurate diagnosis and treatment of insect venom allergy (Table 1). The sequences and structures of the majority of major venom allergens have been cloned and sequenced; several major allergens have been expressed in recombinant form.

Currently, a total of 12 HBV allergens are known.[101] The most important allergen in HB venom is phospholipase A2 (PLA2), also referred to as Api m 1, which is a glycoprotein with 134 amino acid residues. In addition to the IgE response it elicits, its actions on the human immune system may enhance an immediate immune response, by increasing leukotriene production.[13] Another well-known HB venom allergen, hyaluronidase (HYA; also called Api m 2),[14] a 43-kd glycosylated enzyme, is able to enhance the penetration of venom components through the tissue fluid. Api m 2 shares a 50% sequence identity with vespid venom HYA, although a recent paper demonstrated that much of the cross-reactivity between yellow jacket and HB HYAs is not due to protein cross-reactivity but rather to cross-reactive carbohydrate determinants (CCDs).[15] It seems reasonable to assume that antibody binding to HYA from other types of Hymenoptera like the HB may be due to CCDs in many cases, making it important to reinvestigate the role of hyaluronidase in HB venom allergy, in which Api m 2 is considered the second most important allergen after PLA2 (Table 1).

Acid phosphatase (Api m 3), a 45-kd, glycosylated enzyme is probably a minor allergen.[16] Melittin (Api m 4), a peptide, with a molecular weight of 2.84 kd, is the most important and abundant peptide in HB venom, even though only 28% of patients have specific IgE antibodies against this peptide.[11] Melittin can trigger lysis of a wide range of cells, such as mast cells, which can lead to the release of histamine and other intracellular components into surrounding tissue. Interestingly, cell lysis is further enhanced when it is presented together with PLA2 (Api m 1).[17]

Other HB venom allergens have also been identified, and include dipeptidylpeptidase (Api m 5), cysteine-rich trypsin inhibitor (Api m 6), CUB serine protease (Api m 7), carboxylesterase (Api m 8), serine carboxylesterase (Api m 9) and icarapin (Api m 10) (Table 1).[18–20] A recent study showed that Api m 10 seems to be a genuine HB venom allergen with IgE-sensitizing potential in a significant percentage of allergic patients, and that three therapeutic HB venom extracts lacked detectable amounts of this component.[20]

Other low-molecular weight components of HB venom are histamine, dopamine, noradrenalin, free amino acids, lipids, pheromones and the peptides apamine, mast cell degranulating (MCD) peptide, tertiapin and secapin.[11]