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 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.