title: IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice.
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.
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Jin Huk
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Kuan-Wen
authors.initials: KW
authors.lastname: Wang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Duanwu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Quantitative Biomedical Research Center, Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Quantitative Biomedical Research Center, Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Bu
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Cassie L
authors.initials: CL
authors.lastname: Behrendt
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Ming
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Takuma
authors.initials: T
authors.lastname: Misawa
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Miao
authors.initials: M
authors.lastname: Tang
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Scott
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Sara
authors.initials: S
authors.lastname: Hildebrand
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Murray
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Eva Marie Y
authors.initials: EM
authors.lastname: Moresco
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Lora V
authors.initials: LV
authors.lastname: Hooper
authors.affiliation: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; Bruce.Beutler@UTSouthwestern.edu.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
mesh_terms: D000818:Animals; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059766:DNA End-Joining Repair; D005260:Female; D017578:Immunoglobulin Class Switching; D007072:Immunoglobulin D / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008221:Lymphoid Tissue / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota / Q000235:genetics / Q000276:immunology*; D009092:Mucous Membrane / Q000276:immunology* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011995:Recombination, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D007072:Immunoglobulin D; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D003564:Cytidine Deaminase
keywords: 53BP1; IgD; Toll-like receptor; class-switch recombination; microbiota