Natural evolution of a human virus-specific antibody gene repertoire by somatic hypermutation requires both hotspot-directed and randomly-directed processes

Jörn Hendrik Weitkamp, Bonnie J. LaFleur, Harry B. Greenberg, James E. Crowe

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Somatic hypermutation of antibody genes is mediated by activation-induced cytidine deaminase and targets primarily hotspot motifs. We tested the hypothesis that the antibody variable genes of virus-specific B cells from infants exhibit a decreased frequency of somatic mutations compared with adults. We also sought to determine whether virus-specific B cells exhibit predominantly hotspot or randomly directed processes. We analyzed somatic mutations in rotavirus (RV)-specific B cells from otherwise healthy but recently RV-infected infants or adults in comparison with B cells from healthy volunteers not recently infected. We compared these antibody variable gene sequences with those derived from RV-specific B cells from an adult patient with X-linked hyper-IgM syndrome (XHIM). We found that the overall mutational frequency within the antibody variable region was lowest in RV-specific B cells from RV-infected infants, followed by randomly selected B cells, followed by RV-specific B cells from the patient with XHIM. RV-specific memory B cells from healthy adults exhibited the highest frequency of mutations. Approximately half of mutations in random or RV-specific B cells from adults or infants occurred at the DGYW/WRCH or WA/TW hotspot motifs. These findings suggest that virus-specific antibodies require both hotspot and randomly-directed processes.

Original languageEnglish (US)
Pages (from-to)666-676
Number of pages11
JournalHuman Immunology
Volume66
Issue number6
DOIs
StatePublished - Jun 2005
Externally publishedYes

Keywords

  • B lymphocytes
  • CD154 antigen
  • Human
  • Rotavirus
  • Somatic hypermutation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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