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.

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Keywords atopic dermatitis, B cell, CD40 ligand, IgE, plasma cell
Persistent URL dx.doi.org/10.1016/j.jaci.2014.03.036, hdl.handle.net/1765/67203
Journal Journal of Allergy and Clinical Immunology
Citation
Berkowska, M.A, Heeringa, J.J, Hajdarbegovic, E, van der Burg, M, Thio, H.B, van Hagen, P.M, … van Zelm, M.C. (2014). Human IgE+ B cells are derived from T cell-dependent and T cell-independent pathways. Journal of Allergy and Clinical Immunology. doi:10.1016/j.jaci.2014.03.036