title: VH replacement in primary immunoglobulin repertoire diversification.
abstract: The genes encoding the variable (V) region of the B-cell antigen receptor (BCR) are assembled from V, D (diversity), and J (joining) elements through a RAG-mediated recombination process that relies on the recognition of recombination signal sequences (RSSs) flanking the individual elements. Secondary V(D)J rearrangement modifies the original Ig rearrangement if a nonproductive original joint is formed, as a response to inappropriate signaling from a self-reactive BCR, or as part of a stochastic mechanism to further diversify the Ig repertoire. VH replacement represents a RAG-mediated secondary rearrangement in which an upstream VH element recombines with a rearranged VHDHJH joint to generate a new BCR specificity. The rearrangement occurs between the cryptic RSS of the original VH element and the conventional RSS of the invading VH gene, leaving behind a footprint of up to five base pairs (bps) of the original VH gene that is often further obscured by exonuclease activity and N-nucleotide addition. We have previously demonstrated that VH replacement can efficiently rescue the development of B cells that have acquired two nonproductive heavy chain (IgH) rearrangements. Here we describe a novel knock-in mouse model in which the prerearranged IgH locus resembles an endogenously rearranged productive VHDHJH allele. Using this mouse model, we characterized the role of VH replacement in the diversification of the primary Ig repertoire through the modification of productive VHDHJH rearrangements. Our results indicate that VH replacement occurs before Ig light chain rearrangement and thus is not involved in the editing of self-reactive antibodies.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016; and.
authors.forename: Amy
authors.initials: A
authors.lastname: Sun
authors.affiliation: Immune Disease Institute, Boston, MA 02115.
authors.forename: Tatiana I
authors.initials: TI
authors.lastname: Novobrantseva
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016; and.
authors.forename: Maryaline
authors.initials: M
authors.lastname: Coffre
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016; and.
authors.forename: Susannah L
authors.initials: SL
authors.lastname: Hewitt
authors.affiliation: Immune Disease Institute, Boston, MA 02115.
authors.forename: Kari
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016; and.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Skok
authors.affiliation: Immune Disease Institute, Boston, MA 02115.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016; and sergei.koralov@nyumc.org.
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Koralov
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002451:Cell Compartmentation; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D013269:Stochastic Processes
chemical_list: D007135:Immunoglobulin Variable Region
keywords: V(D)J; VH replacement; lymphocyte development; receptor editing; secondary rearrangement