What causes the all-too-familiar symptoms of sneezing or itchy eyes? Serum immunoglobulin (Ig) E, produced by antibody-secreting B cells, is the culprit. For most of us, IgE levels are kept low, but for an unfortunate few, IgE concentration becomes inappropriately elevated, giving rise to the activation of inflammatory cells and to the classic symptoms of allergy. In the January issue of Nature Immunology, Shimizu and colleagues elucidate the molecular mechanism that suppresses IgE production at the level of transcription, which makes this pathway a potential target for therapy.

Antibodies come in a five flavours, or isotypes, each of which has a distinct constant region in its heavy chains encoded by a specific gene. During an immune response, B cells begin by producing antibodies of the isotype IgM, and then a process called class switching — a molecular heavy-chain mix-and-match — permits the secretion of different antibody isotypes. This process, which occurs by transcriptionally regulated region-specific recombination involving deletion of the intervening DNA, does not markedly affect antibody specificity, but alters and diversifies the effector functions of the antibody.

The starting point for understanding the pathway to IgE class switching came from the demonstration that mice deficient in Id2 — a negative regulator of transcription — are impaired in specific aspects of immune function, and secrete large amounts of serum IgE. Shimizu and colleagues showed that there is a dramatic increase in the number of IgE+ B cells produced in response to immunization and that this reflects class switching to the E isotype. Id2 acts as a negative regulator of class switching by binding the E2A transcription factor, which promotes transcription at the E switch region. Not surprisingly, Id2-deficient B cells have increased E2A activity. Further studies showed that Id2 is regulated by the cytokine transforming growth factor (TGF) β1; the addition of the cytokine to wild-type B cells increased the levels of Id2 and suppressed class switching to IgE.

These results are exciting because the class-switching functions described for Id2 are very specific. Although IgE antibodies provide protection against a limited spectrum of parasites, other than that, would we really miss them?