How do we avoid developing allergy: modifications of the TH2 response from a B-cell perspective.

The synthesis of IgE by B cells occurs at a low rate compared with that of other antibodies, even in allergic subjects. One rate-limiting step is the class switch, by which B lymphocytes switch to produce immunoglobulin epsilon heavy chains rather than micro or gamma heavy chains. We propose an additional rate-limiting step: survival of the B lymphocyte after the switch to IgE. The hypothesis we present here is that the survival of the IgE-switched B cell is compromised, particularly in an active germinal center. Antigenic stimulation in the absence of a danger signal fails to induce a mature germinal center, which allows IgE-switched B cells to escape and mature into plasma cells. Antigenic stimulation in the presence of a danger signal (or under nonhygienic conditions) induces germinal centers, which eliminate IgE-switched B cells. Thus the essence of an allergen is antigenic stimulation in the absence of conditions that generate mature germinal centers. Because germinal centers are important for the generation of B-cell memory, the IgE immune response is characteristically poor in memory (but might be long lasting because of the generation of long-lived plasma cells). In addition to this direct route to IgE, typical for atopic sensitization, another type of T(H)2 response exists. On chronic allergen exposure with the concomitant induction of germinal centers, IgG4-switched B memory cells are induced that are slow to differentiate into plasma cells. These IgG4-switched B memory cells might occasionally undergo a secondary switch to IgE.