Human IgE+ B cells are derived from T cell–dependent and T cell–independent pathways

Background The prevalence of IgE-mediated diseases has been increasing worldwide, yet IgE-expressing B cells are poorly characterized, mainly because of their scarcity and low membrane IgE levels. Objective We sought to study the immunobiology of human IgE-expressing B cells in healthy subjects and...

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Published in:Journal of allergy and clinical immunology 2014-09, Vol.134 (3), p.688-697.e6
Main Authors: Berkowska, Magdalena A., PhD, Heeringa, Jorn J., MD, Hajdarbegovic, Enes, MD, van der Burg, Mirjam, PhD, Thio, H. Bing, MD, PhD, van Hagen, P. Martin, MD, PhD, Boon, Louis, PhD, Orfao, Alberto, MD, PhD, van Dongen, Jacques J.M., MD, PhD, van Zelm, Menno C., PhD
Format: Article
Language:English
Subjects:
Allergic diseases
Allergies
Allergy and Immunology
B-Lymphocytes - immunology
Biological and medical sciences
CD40 Ligand - genetics
CD40 Ligand - metabolism
Cell Communication
Cell Separation
Cells, Cultured
Flow Cytometry
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Germinal Center - immunology
Humans
Hypersensitivity - immunology
Immune system
Immunoglobulin Class Switching
Immunoglobulin E - metabolism
Immunoglobulins
Immunologic Memory
Immunopathology
Medical sciences
Mutation
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Skin allergic diseases. Stinging insect allergies
Somatic Hypermutation, Immunoglobulin
T-Lymphocytes, Helper-Inducer - immunology
Tumor Necrosis Factor Receptor Superfamily, Member 7 - metabolism
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Summary:Background The prevalence of IgE-mediated diseases has been increasing worldwide, yet IgE-expressing B cells are poorly characterized, mainly because of their scarcity and low membrane IgE levels. Objective We sought to study the immunobiology of human IgE-expressing B cells in healthy subjects and patients with allergic disease. Methods We used a stepwise approach for flow cytometric detection and purification of human IgE-expressing B cells in control subjects, CD40 ligand–deficient patients, and patients with atopic dermatitis. Molecular analysis of replication histories, somatic hypermutation (SHM), and immunoglobulin class-switching was performed. Results Using multicolor flow cytometry, we reliably detected IgE-expressing plasma cells and 2 IgE-expressing memory B-cell subsets. These IgE-expressing cells showed molecular and phenotypic signs of antigen responses. The replication history and SHM levels of IgE+ plasma cells and CD27+ IgE+ memory B cells fitted with a germinal center (GC)–dependent pathway, often through an IgG intermediate, as evidenced from Sγ remnants in Sμ-Sε switch regions. CD27− IgE+ cells showed limited proliferation and SHM and were present in CD40 ligand–deficient patients, indicating a GC-independent origin. Patients with atopic dermatitis had normal numbers of blood IgE+ plasma cells and CD27+ IgE+ memory B cells but increased numbers of CD27− IgE+ memory B cells with high SHM loads compared with those seen in healthy control subjects and patients with psoriasis. Conclusions We delineated GC-dependent and GC-independent IgE+ B-cell responses in healthy subjects and indicated involvement of the GC-independent pathway in a human IgE-mediated disease. These findings provide new insights into the pathogenesis of IgE-mediated diseases and might contribute to accurate monitoring of IgE+ B cells in patients with severe disease undergoing anti-IgE treatment.
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2014.03.036