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

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86 Scopus citations

Abstract

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
JournalImmunity
Volume19
Issue number1
DOIs
StatePublished - Jul 1 2003

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Zhang, Z., Zemlin, M., Wang, Y. H., Munfus, D., Huye, L. E., Findley, H. W., Bridges, S. L., Roth, D. B., Burrows, P. D., & Cooper, M. D. (2003). Contribution of VH gene replacement to the primary B cell repertoire. Immunity, 19(1), 21-31. https://doi.org/10.1016/S1074-7613(03)00170-5