Abstract
Germinal centers (GCs) are specialized compartments within the secondary lymphoid organs, where B cells proliferate, differentiate, and mutate their antibody genes. Upon exit from the GC, B cells terminally differentiate into plasma cells or memory B cells. While we have a good comprehension of plasma cell differentiation, memory B cell differentiation is still incompletely understood. In this paper, we extend previous models of the molecular events underlying B cell differentiation with new findings regarding memory B cell formation, and present a quantitative stochastic model of the intracellular and extracellular dynamics governing B cell maturation and exit from the GC. To simulate this model, we develop a novel extension to the Gillespie algorithm that enables the efficient stochastic simulation of the system, while keeping track of individual cell properties. Our model is able to explain the dynamical shift from memory B cell to plasma cell production over the lifetime of a GC. Moreover, our results suggest that B cell fate selection can be explained as a process that depends fundamentally on antigen affinity.
Highlights
Germinal centers (GCs) are temporary but distinct structures in the lymph nodes or the spleen, where B cell affinity maturation and differentiation into plasma cells (PCs) and memory B cells (MBCs) takes place [1,2,3,4]
Earlier work by some of us produced a quantitative kinetic model of the GC that explained B cell differentiation into the PC compartment as a result of the interplay of a small module of three antagonistic transcription factors: B cell lymphoma 6 (BCL6), a potent transcriptional repressor required for the establishment and maintenance of GC; interferon regulatory factor 4 (IRF4) and B cell-induced maturation protein 1 (BLIMP), two essential regulators of PC development
We have presented here a hybrid model of the GC that explains the terminal differentiation of GC B cells as a result of the interplay between intracellular genetic regulation and stochastic extracellular events
Summary
Marcel Jan Thomas 1,2, Ulf Klein 3, John Lygeros 2 and María Rodríguez Martínez 1*. Reviewed by: Paolo Casali, University of Texas Health Science Center San Antonio, United States. We extend previous models of the molecular events underlying B cell differentiation with new findings regarding memory B cell formation, and present a quantitative stochastic model of the intracellular and extracellular dynamics governing B cell maturation and exit from the GC. To simulate this model, we develop a novel extension to the Gillespie algorithm that enables the efficient stochastic simulation of the system, while keeping track of individual cell properties. Our model is able to explain the dynamical shift from memory B cell to plasma cell production over the lifetime of a GC.
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