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.