The Journal of allergy and clinical immunology · 2026
B-cell receptor ligation selectively inhibits IgE class switch recombination.
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Wade-Vallance Adam K, Yang Zhiyong, Libang Jeremy B, Krishnapura Ananya R, Jung James B, Matcham Emily W, Wu Chung-An M, Robinson Marcus J, Allen Christopher D C
Аннотация
BACKGROUND: Mechanisms that restrict class switch recombination (CSR) to IgE may limit the subsequent production of IgE antibodies in allergic diseases. A role for B-cell receptor (BCR) signaling in IgE regulation was revealed in mice and in cultured B cells with altered BCR signaling. While prior work has focused on BCR signaling in IgE-switched cells, BCR signaling also reportedly inhibits CSR.
OBJECTIVE: We sought to determine whether BCR signaling selectively inhibits IgE CSR.
METHODS: We assessed whether BCR signaling strength affected IgE responses in immunized mice. For mechanistic evaluation, primary mouse or human B cells were induced to switch to IgE in cell culture and were perturbed with antibodies or cognate antigen to ligate the BCR, pharmacologic inhibitors of signaling proteins, and/or additional cytokines. Primary readouts were flow cytometry and RNA analysis.
RESULTS: In immunized mice, BCR signaling strength inversely correlated with the relative frequencies of IgE-switched germinal center B cells and plasma cells. In mouse B-cell cultures, BCR signaling selectively inhibited IgE CSR in a manner dependent on ligand concentration, affinity, and avidity. This inhibition required Syk, whereas blockade of the PI3K subunit p110δ increased IgE cell frequencies independently of BCR ligation. The cytokines IL-21 or TGF-β1, in combination with BCR ligation, cooperatively inhibited IgE CSR. Similar results were observed in cultures of human tonsillar B cells.
CONCLUSION: IgE CSR is uniquely susceptible to inhibition by BCR signaling in mouse and human B cells, with important implications for the regulation and pathogenesis of allergic disease.
OBJECTIVE: We sought to determine whether BCR signaling selectively inhibits IgE CSR.
METHODS: We assessed whether BCR signaling strength affected IgE responses in immunized mice. For mechanistic evaluation, primary mouse or human B cells were induced to switch to IgE in cell culture and were perturbed with antibodies or cognate antigen to ligate the BCR, pharmacologic inhibitors of signaling proteins, and/or additional cytokines. Primary readouts were flow cytometry and RNA analysis.
RESULTS: In immunized mice, BCR signaling strength inversely correlated with the relative frequencies of IgE-switched germinal center B cells and plasma cells. In mouse B-cell cultures, BCR signaling selectively inhibited IgE CSR in a manner dependent on ligand concentration, affinity, and avidity. This inhibition required Syk, whereas blockade of the PI3K subunit p110δ increased IgE cell frequencies independently of BCR ligation. The cytokines IL-21 or TGF-β1, in combination with BCR ligation, cooperatively inhibited IgE CSR. Similar results were observed in cultures of human tonsillar B cells.
CONCLUSION: IgE CSR is uniquely susceptible to inhibition by BCR signaling in mouse and human B cells, with important implications for the regulation and pathogenesis of allergic disease.