Why are there so few key mutant clones? The influence of stochastic selection and blocking on affinity maturation in the germinal center

Steven H. Kleinstein, Jaswinder Pal Singh

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

A small number of key somatic mutations lead to high-affinity binding in the anti-hapten immune responses to 2-phenyl-5-oxazolone (phOx) and (4-hydroxy-3-nitrophenyl)acetyl (NP). Affinity maturation models of the germinal center hold that B cells carrying these key mutations are preferentially selected for expansion within the germinal centers. However, additional factors are required to account for some quantitative aspects of affinity maturation in vivo. Radmacher et al. have shown that key mutants are observed in vivo significantly less frequently than expected by these models. To account for this finding, they propose that selection is a stochastic process where key mutants may be overlooked by positive selection or recruited out of the germinal center. While acknowledging that a minimal amount of stochastic selection is probably unavoidable in the germinal center, we instead propose a structural explanation for this key mutant discrepancy. This model is based on the existence of a large number of blocking mutations whose presence can prevent the ability of key mutations to confer high-affinity binding. Using mathematical modeling and computer simulation, we show that in addition to reconciling the key mutant discrepancy, the blocking model accounts for other aspects of experimental data that are not predicted by the stochastic selection model. In particular, the blocking model is consistent with the observation that key mutants generally exhibit a higher number of mutations per sequence in the phOx response, but a lower number in the NP response.

Original languageEnglish (US)
Pages (from-to)871-884
Number of pages14
JournalInternational Immunology
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2003

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Keywords

  • (4-hydroxy-3-nitropheny)acetyl
  • 2-phenyl-5-oxazolone
  • Mathematical modeling
  • Somatic hypermutation

Fingerprint Dive into the research topics of 'Why are there so few key mutant clones? The influence of stochastic selection and blocking on affinity maturation in the germinal center'. Together they form a unique fingerprint.

  • Cite this