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

• Published in: Journal of allergy and clinical immunology Vol. 134; no. 3; pp. 688 - 697.e6
• Main Authors: Berkowska, Magdalena A., Heeringa, Jorn J., Hajdarbegovic, Enes, van der Burg, Mirjam, Thio, H. Bing, van Hagen, P. Martin, Boon, Louis, Orfao, Alberto, van Dongen, Jacques J.M., van Zelm, Menno C.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2014; Elsevier; Elsevier Limited
• Subjects: Allergic diseases; Allergies; Allergy and Immunology; atopic dermatitis; B cell; B-Lymphocytes - immunology; Biological and medical sciences; CD40 ligand; 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; IgE; Immune system; Immunoglobulin Class Switching; Immunoglobulin E - metabolism; Immunoglobulins; Immunologic Memory; Immunopathology; Medical sciences; Mutation; plasma cell; 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; CD40L; CDR; B cell; CSR; TACI; IgE; CD40 ligand; R/S; atopic dermatitis; SHM; GC; plasma cell; Complementarity determining region; Class-switch recombination; Somatic hypermutation; Replacement/silent mutation; Germinal center; Transmembrane activator and CAML interactor; Human; Allergy; Immunopathology; Skin disease; B-Lymphocyte; Plasmocyte; Atopy; Immunology; Atopic dermatitis; T-Lymphocyte
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.03.036

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. We sought to study the immunobiology of human IgE-expressing B cells in healthy subjects and patients with allergic disease. 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. 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. 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.