1 INTRODUCTION
The World Health Organization (WHO) identifies chronic respiratory diseases including allergies and chronic rhinosinusitis as one of the four major diseases affecting the world’s population1. According to the ARIA initiative (Allergic Rhinitis and its Impact on Asthma), IgE-mediated inflammation of the nasal mucosa defines allergic rhinitis and causes the respective symptoms upon allergen exposure2. Allergies are characterized by two phases: sensitization causing development of allergen-specific memory Th2 and B cells as well as the production of allergen -specific IgE at the early stage and effector functions associated with tissue inflammation and damage at later stages. Patients suffering from allergies usually treat their symptoms with antihistamines or corticosteroids or try to reduce allergen exposure by their avoidance and use of high-efficiency particulate air (HEPA) filters or temperature-controlled laminar airflows. However, for actual treatment of type I allergies, such as allergies against pollen, house dust mite, pet dander, food, or venom toxins, allergen-specific immunotherapy (AIT) represents the only disease modifying option addressing the cause of the illness2-5. Commonly, allergens are administered subcutaneously or sublingually but also novel routes such as epicutaneous and intra-lymphatic have also been established during AIT6-12. AIT usually requires numerous allergen applications over 3-5 years13,14. The main disadvantages are the duration of the therapy and the risk of severe side effect such as anaphylactic reactions. However, successful AIT induces immune tolerance to allergens and affects rhino-conjunctival symptoms and improves asthmatic conditions. AIT does not only mediate short-term but also long-term protection and is qualified as disease-modifying therapy leading overall reduced allergy disease severity, reduced less drug consumption and prevention of future allergen sensitization2-5,15-19. In addition to novel routes of allergen administration, clinical testing of AIT strives for safer and more efficient therapy conditions including use of allergens or allergoids formulated with stronger adjuvants20-25or use of peptides rather than full-length allergens26-29 In addition, we have recently proposed that allergens displayed on virus-like particles may be a safe and efficacious alternative to standard AIT protocols26,30,31.
The therapeutic mechanisms of AIT still remain a matter of debate. While some argue that induction of allergen-specific IgG antibodies is the key, as they can both neutralize the allergen and engage the inhibitory receptor FcγRIIβ32, others prefer the hypothesis that regulatory T cells are the masters to keep mast cells and basophils at bay and promote the production of IgG antibodies by altered cytokine secretion33. Recently, it has been demonstrated in mice 30and humans that monoclonal antibodies against Fel d 1, the major cat allergen, can abrogate cat allergy, clearly indicating that anti-allergen IgG antibodies can reduce allergic symptoms34. Furthermore, it is clear that successful immunotherapy correlates with induction of allergen-specific IgG435. This has led to the general consensus in the field that induction of IgG4 is the major goal of specific immunotherapy. Others, however, have argued that dominant induction of IgG4 merely reflects the way AIT is performed, namely by multiple injections of small amounts of allergen formulated in Alum and does not reflect a superior efficacy of IgG4 at neutralizing allergens or engaging FcγRIIβ12,36. In addition to IgG subclasses, affinities of the antibodies are also important, at least for neutralizing antibodies; the affinity antibodies engaging the FcγRIIβ has been shown to be less demanding37. Here we demonstrate that IgG4 binds to FcγRIIβ with similar efficiency as IgG1 and inhibits basophil activation with equivalent efficacy both via the FcγRIIβ as well as the allergen-neutralization pathway. Hence, IgG subclasses play a limited role in the efficacy of AIT.