title: Characterization of a new V gene replacement in the absence of activation-induced cytidine deaminase and its contribution to human B-cell receptor diversity.
abstract: In B cells, B-cell receptor (BCR) immunoglobulin revision is a common route for modifying unwanted antibody specificities via a mechanism called VH replacement. This in vivo process, mostly affecting heavy-chain rearrangement, involves the replacement of all or part of a previously rearranged IGHV gene with another germline IGHV gene located upstream. Two different mechanisms of IGHV replacement have been reported: type 1, involving the recombination activating genes complex and requiring a framework region 3 internal recombination signal; and type 2, involving an unidentified mechanism different from that of type 1. In the case of light-chain loci, BCR immunoglobulin editing ensures that a second V-J rearrangement occurs. This helps to maintain tolerance, by generating a novel BCR with a new antigenic specificity. We report that human B cells can, surprisingly, undergo type 2 replacement associated with κ light-chain rearrangements. The de novo IGKV-IGKJ products result from the partial replacement of a previously rearranged IGKV gene by a new germline IGKV gene, in-frame and without deletion or addition of nucleotides. There are wrcy/rgyw motifs at the 'IGKV donor-IGKV recipient chimera junction' as described for type 2 IGHV replacement, but activation-induced cytidine deaminase (AID) expression was not detected. This unusual mechanism of homologous recombination seems to be a variant of gene conversion-like recombination, which does not require AID. The recombination phenomenon described here provides new insight into immunoglobulin locus recombination and BCR immunoglobulin repertoire diversity.
authors.affiliation: Unité EA4666, SFR CAP Santé, Université Picardie Jules Verne, Amiens, France; Unité Inserm U925, Université Picardie Jules Verne, Amiens, France.
authors.forename: Hakim
authors.initials: H
authors.lastname: Ouled-Haddou
authors.forename: Hussein
authors.initials: H
authors.lastname: Ghamlouch
authors.forename: Aline
authors.initials: A
authors.lastname: Regnier
authors.forename: Stephanie
authors.initials: S
authors.lastname: Trudel
authors.forename: Didier
authors.initials: D
authors.lastname: Herent
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Lefranc
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Marolleau
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gubler
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D003564:Cytidine Deaminase / Q000502:physiology*; D015321:Gene Rearrangement; D059765:Homologous Recombination; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011947:Receptors, Antigen, B-Cell; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: AICDA; B-cell receptor immunoglobulin repertoire diversity; IGKV replacement; gene conversion-like recombination; immunoglobulin genes; immunoglobulin κ