Publications

Abstract

The production of IgE is tightly regulated. This is evidenced by the fact that it comprises <0.0001% of serum Ig, and aberrant production causes atopic conditions including allergy, rhinitis and anaphylaxis. IL-4 is a well-characterised inducer of IgE by human and murine B cells, while IFN-gamma can antagonise this effect. IL-21 has also been recognised for its ability to suppress IL-4-induced IgE production by murine B cells. Here, we identified IL-21 as an inducer of IgE production by CD40L-stimulated human naive B cells. Furthermore, there was a striking synergistic effect between IL-4 and IL-21 on inducing IgE secretion by all subsets of CD40L-stimulated human B cells, such that the levels detected under these conditions exceeded those induced by IL-4 or IL-21 alone by >10 fold. IL-21 induced activation of STAT3 and analysis of B cells from patients with loss-of-function STAT3 mutations revealed that the ability of IL-21 to induce IgE secretion, and augment that driven by IL-4, was STAT3-dependent. These findings highlight a fundamental difference between the regulation of IgE production by human and murine B cells and have implications for the dysregulated production of IgE in conditions characterised by extremely high levels of serum IgE.