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Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1196-E1204. doi: 10.1073/pnas.1621258114. Epub 2017 Jan 30.

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

Author information

1
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
Quantitative Biomedical Research Center, Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX 75390.
3
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
4
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; Bruce.Beutler@UTSouthwestern.edu.

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.

KEYWORDS:

53BP1; IgD; Toll-like receptor; class-switch recombination; microbiota

PMID:
28137874
PMCID:
PMC5321007
DOI:
10.1073/pnas.1621258114
[Indexed for MEDLINE]
Free PMC Article

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