The human neonatal B cell response to respiratory syncytial virus uses a biased antibody variable gene repertoire that lacks somatic mutations

John V. Williams, Jörn Hendrik Weitkamp, David L. Blum, Bonnie J. LaFleur, James E. Crowe

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The human Ab repertoire exhibits restrictions during fetal life characterized by biases of variable gene segment usage and lack of junctional diversity. We tested the hypotheses that Ab repertoire restriction persists in the early postnatal period and contributes to the observed poor quality of specific Ab responses made by neonates to viruses and vaccines. We analyzed the molecular determinants of B cell responses in humans to respiratory syncytial virus (RSV). Analysis of the variable gene segment usage of adult RSV-specific B cells revealed a repertoire profile in these cells similar to that seen in randomly selected B cells, which was VH3-dominant. Four gene segments (VH3-23, VH3-30, VH3-33 and VH4-04) accounted for almost half of the VH genes used. In contrast, very young infant RSV-specific antibodies exhibited a biased repertoire characterized by comparable use of the VH1, VH3, and VH4 families, and less common use of the four immunodominant gene segments. Infants and children older than three months used an antibody repertoire similar to that of adults. Mutational analysis revealed that the antibody variable genes of infants under three months of age also possessed significantly fewer somatic mutations in both framework and complementarity-determining region (CDR) regions than those of adults, even in a child with recurrent RSV infection. These data suggest that neonates use a biased antibody gene repertoire that is less VH3-focused and that possesses a dramatically lower frequency of somatic mutations. These biased features of the RSV-specific repertoire likely contribute to the poor functional Ab response in very young infants.

Original languageEnglish (US)
Pages (from-to)407-414
Number of pages8
JournalMolecular Immunology
Volume47
Issue number2-3
DOIs
StatePublished - Dec 2009
Externally publishedYes

Keywords

  • Antibodies
  • B cells
  • Human
  • Repertoire development
  • Viral

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

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