Reviews and feature article
Primary immune deficiencies with aberrant IgE production

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IgE antibodies play a central role in the pathogenesis of atopic diseases and in host immunity against parasitic infections. IgE has potent activities on mast cells and basophils. IgE class switching is a very tightly controlled process, and serum IgE levels are very low compared with other immunoglobulin isotypes. Transcription factors that activate or inhibit the IgE gene promoter, as well as TH1 and TH2 cytokines are important in the regulation of IgE levels. Hyper-IgE syndrome; Wiskott-Aldrich syndrome; immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX); Omenn syndrome; and atypical complete DiGeorge syndrome are primary immune deficiencies that are associated with elevated serum IgE levels. Increased IgE levels in IPEX, Wiskott-Aldrich syndrome and Omenn syndrome are likely related to increased TH2 cytokine production caused by decreased a number or function of CD4+CD25+forkhead box protein P3+ regulatory T cells. The link between signal transducer and activator of transcription 3 mutations and elevated serum IgE levels in hyper-IgE syndrome is unclear. Insight into IgE regulation provided by the study of primary immune deficiencies with elevated IgE has important implications for allergic diseases.

Section snippets

Molecular basis of isotype switching to IgE

Pre-B cells go through VH-D-JH recombination in which individual heavy-chain variable (VH), diversity (D), and joining (JH) exons randomly combine and encode the antigen-specific VH domain. In naive B cells, the recombined VH-D-JH cassette lies upstream of the constant (C) μ exons, leading to IgM production. On stimulation, mature B cells undergo class switch recombination (CSR). Each constant heavy chain (CH) gene, except Cδ, is preceded by specialized DNA sequences with tandem repeats, called

PIDs with elevated IgE

Gene defects, mechanism of immune deficiency, and mechanism of IgE elevation of PIDs mentioned in this section are listed in Table II.

Conclusion

Three of the PIDs associated with high levels of IgE (IPEX, WAS, and Omenn syndrome) display a defective Treg cell number or function, which results in autoimmunity and a TH2 phenotype with increased IgE levels. HSCT is the standard curative therapy for IPEX, WAS, and Omenn syndrome and results in normalization of immune function and of serum IgE levels. HSCT recipients might have a lower risk of GVHD if the donor cells are enriched with Treg cells. The underlying cause of elevated IgE in HIES

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    (Supported by an educational grant from Merck & Co., Inc.)

    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

    Supported by National Institutes of Health grants P01-AI-031541 and P01-AI-076210.

    Terms in boldface and italics are defined in the glossary on page 1055.

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