2017•Proceedings of the National Academy of SciencesOpen access
IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice
Jin Huk Choi, Kuan-Wen Wang, Duanwu Zhang, Xiaowei Zhan, Tao Wang, Chun-Hui Bu, Cassie L. Behrendt, Ming Zeng, Ying Wang, Takuma Misawa, Xiaohong Li, Miao Tang, Xiaoming Zhan, Lindsay Scott, Sara Hildebrand, Anne R. Murray, Eva Marie Y. Moresco, Lora V. Hooper, Bruce Beutler
Open full text 56 citations
Abstract
Class-switch recombination (CSR) alters the Ig isotype to diversify antibody effector functions. IgD CSR is a rare event, and its regulation is poorly understood. We report that deficiency of 53BP1, a DNA damage-response protein, caused age-dependent overproduction of secreted IgD resulting from increased IgD CSR exclusively within B cells of mucosa-associated lymphoid tissues. IgD overproduction was dependent on activation-induced cytidine deaminase, hematopoietic MyD88 expression, and an intact microbiome, against which circulating IgD, but not IgM, was reactive. IgD CSR occurred via both alternative nonhomologous end-joining and homologous recombination pathways. Microbiota-dependent IgD CSR also was detected in nasal-associated lymphoid tissue of WT mice. These results identify a pathway, present in WT mice and hyperactivated in 53BP1-deficient mice, by which microbiota signal via Toll-like receptors to elicit IgD CSR.