title: Antibody repertoire diversification through VH gene replacement in mice cloned from an IgA plasma cell.
abstract: In mammals, VDJ recombination is responsible for the establishment of a highly diversified preimmune antibody repertoire. Acquisition of a functional Ig heavy (H) chain variable (V) gene rearrangement is thought to prevent further recombination at the IgH locus. Here, we describe VHQ52(NT); Vκgr32(NT) Ig monoclonal mice reprogrammed from the nucleus of an intestinal IgA(+) plasma cell. In VHQ52(NT) mice, IgA replaced IgM to drive early B-cell development and peripheral B-cell maturation. In VHQ52(NT) animals, over 20% of mature B cells disrupted the single productive, nonautoimmune IgH rearrangement through VH replacement and exchanged it with a highly diversified pool of IgH specificities. VH replacement occurred in early pro-B cells, was independent of pre-B-cell receptor signaling, and involved predominantly one adjacent VH germ-line gene. VH replacement was also identified in 5% of peripheral B cells of mice inheriting a different productive VH rearrangement expressed in the form of an IgM H chain. In summary, editing of a productive IgH rearrangement through VH replacement can account for up to 20% of the IgH repertoire expressed by mature B cells.
authors.affiliation: The Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), Milan 20139, Italy;
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Institute of Immunology, University Clinic Ulm, 89081 Ulm, Germany; Department of Molecular Immunology, Albert-Ludwigs University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany;
authors.forename: Martina P
authors.initials: MP
authors.lastname: Bach
authors.affiliation: The Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), Milan 20139, Italy;
authors.forename: Federica
authors.initials: F
authors.lastname: Mainoldi
authors.affiliation: Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Kanagawa 230-0045, Japan;
authors.forename: Mikako
authors.initials: M
authors.lastname: Maruya
authors.affiliation: RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan; and.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishigami
authors.affiliation: Institute of Immunology, University Clinic Ulm, 89081 Ulm, Germany; Department of Molecular Immunology, Albert-Ludwigs University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany;
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
authors.affiliation: RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan; and.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Wakayama
authors.affiliation: Akashi City Hospital, Akashi 673-8501, Japan.
authors.forename: Osami
authors.initials: O
authors.lastname: Kanagawa
authors.affiliation: Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama, Kanagawa 230-0045, Japan;
authors.forename: Sidonia
authors.initials: S
authors.lastname: Fagarasan
authors.affiliation: The Institute of Molecular Oncology (IFOM) of the Italian Foundation for Cancer Research (FIRC), Milan 20139, Italy; stefano.casola@ifom.eu.
authors.forename: Stefano
authors.initials: S
authors.lastname: Casola
mesh_terms: D000818:Animals; D001483:Base Sequence; D019976:Cloning, Organism; D007070:Immunoglobulin A / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction
chemical_list: D007070:Immunoglobulin A; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region
keywords: B cells; IgA; VH replacement; antibody repertoire; nuclear cloning