Component-Resolved IgE and IgG4 Profiling Reveals Robust IgG4 Responses Primarily to Abundant Hymenoptera Allergens During Venom Immunotherapy and in Beekeepers.

Background and objectives: Venom immunotherapy (VIT) and natural exposure to Hymenoptera venom induce immune tolerance in allergic patients and beekeepers, respectively. Specific IgE (sIgE) and IgG4 (sIgG4) antibodies play crucial roles in allergic reactions and immune tolerance. To investigate the dynamics of sIgE and sIgG4 responses to Hymenoptera venom in patients undergoing VIT and in nonallergic beekeepers at a component-resolved level.

Methods: Serum samples from patients allergic to honeybee venom (HBV) or yellow jacket venom (YJV) and from beekeepers were collected during the first year of VIT and before and after the beekeeping season, respectively. sIgE and sIgG4 levels to whole venom and molecular allergens were measured using the ImmunoCAP platform.

Results: Pronounced sIgE and sIgG4 responses to Ves v 1 and 5 in YJV-allergic patients were accompanied by more frequent sensitization to Ves v 1 after up-dosing. While sIgE profiles in HBV-allergic patients were highly diverse, with a marked contribution of Api m 1 and Api m 10 sIgE, the sIgG4 response during VIT was strongly dominated by Api m 1. Different VIT preparations did not significantly affect the sIgG4 response to low-abundance HBV allergens. In beekeepers, induction of sIgG4 was dependent on sting frequency and was dominated by Api m 1.

Conclusions: Robust induction of IgG4 during VIT and natural venom exposure occurs primarily to abundant allergens and is unaffected by the choice of VIT preparation. The effectiveness of VIT and beekeepers´ tolerance to HBV indicate that strong sIgG4 responses to lowabundance allergens are not crucial for immune tolerance.