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  • Review Article
  • Published:

The production and regulation of IgE by the immune system

Nature Reviews Immunology volume 14, pages 247–259 (2014)Cite this article

Subjects

Key Points

  • The production of IgE and its clearance from the blood are tightly regulated, which results in transient IgE antibody responses and the maintenance of low steady-state levels of IgE.

  • IgE can be generated by a direct class-switch recombination pathway from Sμ to Sε, by a sequential class-switch pathway from Sμ to Sγ1 followed by Sε, as well as by a recently described alternative sequential class-switch pathway from Sγ1 to Sε, which then joins to Sμ. Additional work is needed to better understand the contribution of each class-switch pathway to IgE production in health and disease.

  • Early IgE antibody responses arise from extrafollicular sources, whereas later IgE responses are derived from germinal centres. IgE germinal centre responses are transient, which may limit IgE production.

  • IgE plasma cells that are derived from germinal centres are predisposed to be short-lived in contrast to IgG1 plasma cells that are derived from germinal centres, and are primarily long-lived.

  • IgE memory responses can arise from both IgE memory B cells and IgG1 memory B cells, but the contribution of each memory B cell subset to total IgE memory responses remains to be clarified.

  • The high-affinity Fc receptor for IgE (FcεRI) on dendritic cells and macrophages, but not on mast cells or basophils, contributes to the clearance of serum IgE. By contrast, the low-affinity Fc receptor for IgE (FcεRII; also known as CD23) on B cells does not contribute to the clearance of serum IgE, but modulates total serum IgE levels by providing a sink that binds a substantial portion of the total IgE pool.

  • A better understanding of IgE biology may lead to new approaches to treat IgE-driven allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

Abstract

IgE not only provides protective immunity against helminth parasites but can also mediate the type I hypersensitivity reactions that contribute to the pathogenesis of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. Despite the importance of IgE in immune biology and allergic pathogenesis, the cells and the pathways that produce and regulate IgE are poorly understood. In this Review, we summarize recent advances in our understanding of the production and the regulation of IgE in vivo, as revealed by studies in mice, and we discuss how these findings compare to what is known about human IgE biology.

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Figure 1: IgE and its receptors.
Figure 2: Direct, sequential and alternative sequential IgE class-switch recombination.
Figure 3: Model for in vivo IgE production and surveillance.

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  1. Department of Immunology, Genentech Inc., 1 DNA Way, South San Francisco, 94080, California, USA

    Lawren C. Wu & Ali A. Zarrin

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  1. Lawren C. Wu
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Correspondence to Lawren C. Wu or Ali A. Zarrin.

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L.C.W. and A.A.Z. are employed by Genentech and hold equity in the Roche group.

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Human IgE class switch recombination (PDF 627 kb)

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Glossary

Type I hypersensitivity

Immunological hypersensitivity reactions have been classified into four types depending on the antigen-recognizing molecule involved. Type I hypersensitivity is defined as an IgE-mediated hypersensitivity reaction that can manifest as either systemic or localized anaphylaxis.

Anaphylaxis

A severe and rapid allergic reaction triggered by the activation of FcεRI in sensitized individuals. Systemic anaphylaxis is the most severe type, showing shock-like symptoms and usually leading to death within minutes if left untreated. Localized anaphylaxis is limited to a specific target tissue or organ, and consists of an early-phase response, such as a wheal and flare reaction in the skin, that may lead to a late-phase response characterized by a more persistent influx of immune cells.

Eicosanoid

A fatty acid derivative that is mainly derived from arachidonic acid precursors and has a wide variety of biological activities. There are four main classes of eicosanoids — prostaglandins, prostacyclins, thromboxanes and leukotrienes — which are derived from the activities of cyclooxygenases and lipoxygenases on membrane-associated fatty acid precursors.

Germinal centre

A highly specialized and dynamic microenvironment that gives rise to secondary B cell follicles during an immune response. It is the main site of B cell maturation, leading to the generation of memory B cells and plasma cells that produce high-affinity antibodies.

Class-switch recombination

DNA rearrangement of the V(D)J gene from IgM to any of the IgG, IgA and IgE constant region genes at the heavy chain locus. Recombination occurs in repetitive sequences of DNA that are located upstream of each constant gene.

Affinity maturation

A process by which the mutation of antibody variable region genes followed by the selection of higher-affinity variants in the germinal centre leads to an increase in average antibody affinity as an immune response progresses. The selection is thought to be a competitive process in which B cells compete with free antibodies to capture decreasing amounts of antigens.

Polyadenylation sites

Sequences required for the cleavage of primary RNA transcripts that are produced by RNA polymerase II. As a consequence of such cleavage, the 5′ cut-off product becomes polyadenylated, whereas the 3′ product undergoes rapid degradation that induces polymerase II release from the DNA and hence leads to transcriptional termination.

Nested PCR

A technique for improving the sensitivity and the specificity of PCR by the sequential use of two sets of oligonucleotide primers in two rounds of PCR. The second pair (known as nested primers) is located in the segment of DNA that is amplified by the first pair.

Episome

Extrachromosomal circular DNA in a cell nucleus.

Complementarity-determining regions

(CDRs). The most variable parts of immunoglobulins and T cell receptors. These regions form loops that make contact with specific ligands. There are three such regions (CDR1, CDR2 and CDR3) in each variable domain.

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Wu, L., Zarrin, A. The production and regulation of IgE by the immune system. Nat Rev Immunol 14, 247–259 (2014). https://doi.org/10.1038/nri3632

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