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

Jin Huk Choi; Kuan Wen Wang; Duan-Wu Zhang Ph.D.; 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 A Beutler

doi:10.1073/pnas.1621258114

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

Jin Huk Choi, Kuan Wen Wang, Duan-Wu Zhang Ph.D., 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 A Beutler

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43 Scopus 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.

Original language	English (US)
Pages (from-to)	E1196-E1204
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	7
DOIs	https://doi.org/10.1073/pnas.1621258114
State	Published - Feb 14 2017

Keywords

53BP1
Class-switch recombination
IgD
Microbiota
Toll-like receptor

ASJC Scopus subject areas

General

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10.1073/pnas.1621258114

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Choi, J. H., Wang, K. W., Zhang Ph.D., D.-W., Zhan, X., Wang, T., Bu, C. H., Behrendt, C. L., Zeng, M., Wang, Y., Misawa, T., Li, X., Tang, M., Zhan, X., Scott, L., Hildebrand, S., Murray, A. R., Moresco, E. M. Y., Hooper, L. V., & Beutler, B. A. (2017). IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice. Proceedings of the National Academy of Sciences of the United States of America, 114(7), E1196-E1204. https://doi.org/10.1073/pnas.1621258114

Choi, JH, Wang, KW, Zhang Ph.D., D-W, Zhan, X , Wang, T, Bu, CH, Behrendt, CL, Zeng, M, Wang, Y, Misawa, T, Li, X, Tang, M, Zhan, X, Scott, L, Hildebrand, S, Murray, AR, Moresco, EMY , Hooper, LV & Beutler, BA 2017, 'IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 7, pp. E1196-E1204. https://doi.org/10.1073/pnas.1621258114

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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.",

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author = "Choi, {Jin Huk} and Wang, {Kuan Wen} and {Zhang Ph.D.}, Duan-Wu and Xiaowei Zhan and Tao Wang and Bu, {Chun Hui} and Behrendt, {Cassie L.} and Ming Zeng and Ying Wang and Takuma Misawa and Xiaohong Li and Miao Tang and Xiaoming Zhan and Lindsay Scott and Sara Hildebrand and Murray, {Anne R.} and Moresco, {Eva Marie Y} and Hooper, {Lora V} and Beutler, {Bruce A}",

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T1 - IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice

AU - Choi, Jin Huk

AU - Wang, Kuan Wen

AU - Zhang Ph.D., Duan-Wu

AU - Zhan, Xiaowei

AU - Wang, Tao

AU - Bu, Chun Hui

AU - Behrendt, Cassie L.

AU - Zeng, Ming

AU - Wang, Ying

AU - Misawa, Takuma

AU - Li, Xiaohong

AU - Tang, Miao

AU - Zhan, Xiaoming

AU - Scott, Lindsay

AU - Hildebrand, Sara

AU - Murray, Anne R.

AU - Moresco, Eva Marie Y

AU - Hooper, Lora V

AU - Beutler, Bruce A

PY - 2017/2/14

Y1 - 2017/2/14

N2 - 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.

AB - 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.

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

Abstract

Keywords

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