Contribution of VH gene replacement to the primary B cell repertoire

Zhixin Zhang, Michael Zemlin, Yui Hsi Wang, Delicia Munfus, Leslie E. Huye, Harry W. Findley, S. Louis Bridges, David B. Roth, Peter D. Burrows, Max D. Cooper

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


VH 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 VH gene replacement mediated by cryptic recombination signal sequences (cRSS) located near the 3′ end of VH genes. Recombination-activating gene products, RAG-1 and RAG-2, bind and cleave the cRSS to generate DNA deletion circles during the VH replacement process. A VH replacement contribution to normal repertoire development is revealed by the identification of VH replacement "footprints" in IgH sequences and double-stranded DNA breaks at VH cRSS sites in immature B cells. Surprisingly, the residual 3′ sequences of replaced VH genes contribute charged amino acids to the CDR3 region, a hallmark of autoreactive antibodies.

Original languageEnglish (US)
Pages (from-to)21-31
Number of pages11
Issue number1
StatePublished - Jul 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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