9 Conclusions
The affinity as well as the avidity of IgE-allergen interactions play critical roles for activation of effector cells and allergic reactions. It is well accepted that specific allergen-binding of antibodies is required for cellular activation. However, the low affinity of FcεRI-bound IgE for allergens can be compensated by bivalent, high avidity binding to multiple epitopes on allergens. This appears to be the mechanism responsible for the often not expected allergen cross-reactivity which may be driven by low affinity but high avidity interactions. Similarly, IgG antibodies with low affinity for the allergen were also sufficient to inhibit mast cell activation by engaging the inhibitory FcγRIIb. Furthermore, polyclonal and monoclonal antibodies specific for a single allergen were able to block allergic symptoms mediated by whole allergen extract. This effect was also mediated by FcγRIIb and was rather independent of the affinity of the antibodies for the allergen as low affinity antibodies were also effective. Interestingly, comparison of two different IgG subclasses, IgG1 and IgG4 showed the same capacity to block mast cell activation and to bind to FcγRIIb, suggesting similar clinical efficacy for both antibody subclasses. This is currently being further validated in the clinical setting for short-course allergoid treatment options which utilizes an adjuvant system employing MPL (TLR 4 agonist).
Finally, even if FcγRIIb-mediated inhibition can be triggered by low affinity IgG antibodies, allergen neutralization still requires high affinity antibodies which are generated in the germinal centers. The generation of such antibody responses has been shown to be optimized by repetitive display and TLR signalling in B cells, which can be triggered by immunization with virus-like particles packaged with RNA and displaying antigens in a repetitive fashion.