The regulation of immunoglobulin E class-switch recombination

Key Points

  • 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 (TH2)-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 TH2-cell to TH1-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 TH1-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.

Abstract

Immunoglobulin E (IgE) isotype antibodies are associated with atopic disease, namely allergic rhinitis, asthma and atopic dermatitis, but are also involved in host immune defence mechanisms against parasitic infection. The commitment of a B cell to isotype class switch to an IgE-producing cell is a tightly regulated process, and our understanding of the regulation of IgE-antibody production is central to the prevention and treatment of atopic disease. Both those that are presently in use and potential future therapies to prevent IgE-mediated disease take advantage of our existing knowledge of the specific mechanisms that are required for IgE class switching.

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Figure 1: Biological effects of IgE binding.
Figure 2: Deletional class-switch recombination of the human immunoglobulin locus.
Figure 3: Cellular interactions important for IgE class-switch recombination.
Figure 4: IL-4 and CD40 activation signals lead to Cε germline and AID transcription.
Figure 5: Negative regulation of IgE class switching.

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Acknowledgements

This work was supported by the National Institutes of Health and the March of Dimes Birth Defects Foundation.

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Correspondence to Raif S. Geha.

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DATABASES

LocusLink

AID

APRIL

BAFF

BAFFR

BCL6

BCMA

CD23

CD40

CD45

CD40L

CTLA4

FOXP3

GATA3

HAVCR1

ID2

IKKγ

IL-4

IL-12B

IL-13

LAT

MAPK14

SPINK5

STAT6

TACI

T-bet

TRAF2

TRAF3

TRAF5

TRAF6

WASP

OMIM

hyper-IgE syndrome

WAS

FURTHER INFORMATION

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Glossary

LIPID RAFTS

Cholesterol and sphingolipid-enriched membrane detergent-resistant microdomains (DRMs), which function as aggregation points for membrane and cytosolic signalling complexes.

CORTICOSTEROIDS

Small lipophilic molecules that regulate physiological processes, including immune responses, by binding cytoplasmic receptors. They have broad therapeutic use as potent anti-inflammatory and immunosuppressive agents.

HUMANIZED SEVERE COMBINED IMMUNODEFICIENCY (SCID) MICE

Mice that have the Scid mutation, which leads to an absence of T and B cells, that have been reconstituted with T and B cells from human peripheral blood.

CPG MOTIFS

Hypomethylated DNA sequences that typically contain a purine-purine-C-G-pyrimidine-pyrimidine core hexamer. These motifs are suppressed in mammalian DNA, but are enriched in bacterial active DNA. The mammalian innate immune system is stimulated by CpG motifs though Toll-like receptor 9.

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Geha, R., Jabara, H. & Brodeur, S. The regulation of immunoglobulin E class-switch recombination. Nat Rev Immunol 3, 721–732 (2003). https://doi.org/10.1038/nri1181

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