The regulation of immunoglobulin E class-switch recombination

Abstract

The increasing incidence of allergic or atopic diseases in societies with a high degree of socio-economic development is a pressing public-health problem. The regulation of IgE antibody development is central to the study of the prevention and treatment of atopic disease. The commitment of a B cell to isotype switch to an IgE-producing cell is a tightly regulated process. A two-step process of DNA excision and ligation is required for the assembly of a functional IgE gene. The classic pathway of IgE switching is T-cell dependent. The T cells are required to express CD40 ligand (CD40L) in response to antigenic stimulation and secrete the T helper 2 (T_H2)-type cytokines interleukin-4 (IL-4) and/or IL-13. CD40 ligation, which activates nuclear factor-κB (NF-κB), in synergy with IL-4/IL-13 (which, in turn, activate signal transducer and activator of transcription 6, STAT6), is required to induce transcription from the Iε exon and activation-induced cytidine deaminase (AID) promoters. Loss of either signal markedly impairs IgE class-switch recombination (CSR). T-cell-independent pathways for the induction of IgE class switching, in the presence of IL-4, include corticosteroids, BAFF/APRIL, Epstein–Barr virus infection and complement component 4 binding protein (C4BP). The regulation of IgE class switching is partly achieved through negative regulation of transcription from the Iε exon promoter. Negative signals that regulate IgE CSR include the cytokines interferon-γ (IFN-γ), transforming growth factor-β (TGF-β) and IL-21, the B-cell receptors CD45 and CD23, and the transcriptional regulators B-cell lymphoma 6 (BCL6) and inhibitor of DNA binding 2 (ID2). Genetic and environmental stimuli can effect changes in the regulation of IgE CSR. These typically regulate the balance from T_H2-cell to T_H1-cell responses and include genetic polymorphisms, genetic abnormalities or environmental influences, such as parasitic infection and hygiene-related stimuli. Therapeutic approaches to control IgE production include shifting the T-cell response to allergens towards a T_H1-type pattern through allergen-specific immunotherapy, blocking the induction of CSR and neutralization of existing IgE. The most promising new immunotherapies involve the use of bacterial CpG sequences, in combination with allergen-specific immunotherapy.