In silico analysis of the mechanism and regulation of germinal center shutdown

Abstract

Humoral immunity following an infection relies on Germinal centres (GCs), transient structures in the secondary lymphoid organs. B cells undergo affinity maturation in GCs, thus producing high affinity plasma and memory cells. Dysregulations in GC shutdown leads to various pathological conditions. As the mechanism and factors regulating GC shutdown are not well understood, the main aim of this study is to contribute to an improved understanding of GC shutdown with mathematical models. Antigen accessibility is a potential factor that regulates GC shutdown, and can be modulated by antibody feedback, a process where soluble antibodies mask the antigen on Follicular dendritic cells (FDCs). Simulations suggested a strong influence of soluble antibodies on GC shutdown and predicted that antibody feedback could also impair the affinity maturation of GC B cells by terminating GCs earlier. Similarly, changes in immune complex (IC) cycling kinetics impacted GC dynamics by regulating antigen protection from degradation. Blocking IC cycling terminated GCs suggesting a therapeutic opportunity to disrupt ectopic GCs. Analysis of published experimental data on GC kinetics suggested that lifetime of GCs in the same lymphoid organ might be highly variable potentially due to differences in antigen availability or founder cell composition among individual GCs. Simulations of GC-GC interactions by soluble antibodies predicted changes in GC kinetics and affinity maturation. Finally, simulations predicted that GCs could be terminated independently by antigen limitation, changes in Tfh signals, decreased B cell division capacity and faster terminal differentiation. These findings predict strategies for improving GC responses to vaccination, namely altering IC cycling dynamics by engineering IC particles and overcoming antibody mediated inhibition by persistent antigen delivery. These results also suggest ways to design future experiments to gain a more complete understanding of GC shutdown.