Exploration of factors affecting the onset and maturation course of follicular lymphoma through simulations of the germinal center.
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.
Fenwick
Michael K
MK
Department of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA. mkf7@cornell.edu
Escobedo
Fernando A
FA
D000465:Algorithms; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology; D022801:Complementarity Determining Regions / Q000235:genetics; D003198:Computer Simulation; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics; D018858:Germinal Center / Q000276:immunology / Q000473:pathology*; D006031:Glycosylation; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D008224:Lymphoma, Follicular / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D017354:Point Mutation / Q000235:genetics / Q000276:immunology; D011336:Probability; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D013269:Stochastic Processes
D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell