Exploration of factors affecting the onset and maturation course of follicular lymphoma through simulations of the germinal center

Bull Math Biol. 2009 Aug;71(6):1432-62. doi: 10.1007/s11538-009-9408-8. Epub 2009 May 2.


Genetic mutations frequently observed in human follicular lymphoma (FL) B-cells result in aberrant expression of the anti-apoptotic protein bcl-2 and surface immunoglobulins (Igs) which display one or more novel variable (V) region N-glycosylation motifs. In the present study, we develop a simulation model of the germinal center (GC) to explore how these mutations might influence the emergence and clonal expansion of key mutants which provoke FL development. The simulations employ a stochastic method for calculating the cellular dynamics, which incorporates actual IgV region sequences and a simplified hypermutation scheme. We first bring our simulations into agreement with experimental data for well-characterized normal and bcl-2(+) anti-hapten GC responses in mice to provide a model for understanding how bcl-2 expression leads to permissive selection and memory cell differentiation of weakly competitive B-cells. However, as bcl-2 expression in the GC alone is thought to be insufficient for FL development, we next monitor simulated IgV region mutations to determine the emergence times of key mutants displaying aberrant N-glycosylation motifs recurrently observed in human FL IgV regions. Simulations of 26 germline V(H) gene segments indicate that particular IgV regions have a dynamical selective advantage by virtue of the speed with which one or more of their key sites can generate N-glycosylation motifs upon hypermutation. Separate calculations attribute the high occurrence frequency of such IgV regions in FL to an ability to produce key mutants at a fast enough rate to overcome stochastic processes in the GC that hinder clonal expansion. Altogether, these simulations characterize three pathways for FL maturation through positively selected N-glycosylations, namely, via one of two key sites within germline V(H) region gene segments, or via a site in the third heavy chain complementarity-determining region (CDR-H3) that is generated from VDJ recombination.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cell Count
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Complementarity Determining Regions / genetics
  • Computer Simulation
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain / genetics
  • Germinal Center / immunology
  • Germinal Center / pathology*
  • Glycosylation
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Variable Region / genetics
  • Lymphoma, Follicular / etiology*
  • Lymphoma, Follicular / genetics
  • Lymphoma, Follicular / pathology*
  • Mice
  • Models, Biological*
  • Point Mutation / genetics
  • Point Mutation / immunology
  • Probability
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Antigen, B-Cell / genetics
  • Somatic Hypermutation, Immunoglobulin / genetics
  • Stochastic Processes


  • Complementarity Determining Regions
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Variable Region
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, B-Cell