IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice

Posted by: | March 15, 2017 | Comments

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Significance

Immunoglobulins exist in several forms, or isotypes, that carry out distinct effector functions. During an antibody response, B cells can switch their immunoglobulin isotype through the process of class-switch recombination (CSR). CSR to IgD is a rare event compared with CSR to other isotypes, and its regulation is poorly understood. Here we report that mice lacking the DNA damage-response protein 53BP1 display a hyper-IgD syndrome despite deficiencies of other immunoglobulin classes. By studying these mice, we discovered that CSR to IgD in 53BP1 mutant mice and in wild-type mice depends on an intact microbiome and Toll-like receptor signaling, and is anatomically confined to B cells of mucosa-associated lymphoid tissues.

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.

Find out more at: PNAS

Jin Huk Choi, Kuan-wen Wang, Duanwu Zhang, Xiaowei Zhan, Tao Wang, Chun-Hui Bu, Cassie L. Behrendt, Ming Zenga, Ying Wang, Takuma Misawa, Xiaohong Li, Miao Tang, Xiaoming Zhan, Lindsay Scott, Sara Hildebrand, Anne R. Murray, Eva Marie Y. Moresco, Lora V. Hooper, and Bruce Beutler. 1 vol. 114 no. 7. E1196–E1204, doi: 10.1073/pnas.1621258114.





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