Contribution of Vh gene replacement to the primary B cell repertoire.

Academic Article

Abstract

  • V(H) replacement has been proposed as one way to modify unwanted antibody specificities, but analysis of this mechanism has been limited without a dynamic cellular model. We describe a human cell line that spontaneously undergoes serial V(H) gene replacement mediated by cryptic recombination signal sequences (cRSS) located near the 3' end of V(H) genes. Recombination-activating gene products, RAG-1 and RAG-2, bind and cleave the cRSS to generate DNA deletion circles during the V(H) replacement process. A V(H) replacement contribution to normal repertoire development is revealed by the identification of V(H) replacement "footprints" in IgH sequences and double-stranded DNA breaks at V(H) cRSS sites in immature B cells. Surprisingly, the residual 3' sequences of replaced V(H) genes contribute charged amino acids to the CDR3 region, a hallmark of autoreactive antibodies.
  • Published In

  • Immunity  Journal
  • Keywords

  • B-Lymphocytes, Base Sequence, Cells, Cultured, Complementarity Determining Regions, DNA Damage, DNA-Binding Proteins, Genes, Immunoglobulin, Homeodomain Proteins, Humans, Immunoglobulin Heavy Chains, Immunoglobulin Variable Region, Molecular Sequence Data, Nuclear Proteins, Polymerase Chain Reaction, Recombination, Genetic
  • Authorlist

  • Zhang Z; Zemlin M; Wang Y-H; Munfus D; Huye LE; Findley HW; Bridges SL; Roth DB; Burrows PD; Cooper MD
  • Start Page

  • 21
  • End Page

  • 31
  • Volume

  • 19
  • Issue

  • 1