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.