Table 1.

Hypothetical framework for the human IgE response

• Allergens come in different flavors, characterized by their tendency to induce not only IgE antibodies but also IgG antibodies. For some allergens, the ratio of allergen-specific IgG to allergen-specific IgE (the sIgG/sIgE ratio) is low (often undetectable) in subjects without sIgE. The prototypic examples are the traditional atopic allergens from pollen and mites. For other allergens, the ratio is >100, and more often than not, IgG is found without demonstrable sIgE (“conventional antigens”). Prototypic examples aremilk and egg proteins, cat allergen, proteins from stinging insects, and toxoids from tetanus and diphtheria. The IgE responses in most animal models are also in this category. It is not clear which factors are responsible for these two distinct patterns of antibody formation. It may be related to dose, route of exposure, etc. Because the latter type of immune response is associated with IgG4 antibodies, indicative of a TH2 response, it has been described as a “modified TH2 response”, i.e., a TH2 response without IgE [10].

• The age of onset for sensitization to atopic allergens is predominant in infancy, whereas late onset sensitization in non-atopic subjects is linked to the modified TH2 response.

• The atopic IgE response (i.e., an immune response with a low IgG/IgE ratio) is the most relevant from the allergy point of view. Because of its very modest IgG contribution, we assume that the immune response is infrequent andminimalist, i.e., without much involvement of GCs, and thus little SHM and memory B cell formation.

• Because of this minimal GC activity, IgE-switched B cells do not expand much, do hardly ever become classical memory cells, and are not so strictly subjected to negative selection.

• The IgE repertoire tends to diversify rapidly (“broad epitope spreading”). This reflects the immunological feed-forward activity of the IgE-allergen interaction: the presence of sIgE facilitates the recruitment of additional IgE B cells with different specificities. This results not only in IgE antibodies to different epitopes on the same allergen molecule, but also to epitopes on unrelated allergens that happen to be present at the same time and place.