Synchronous Germinal Center Onset Impacts the Efficiency of Antibody Responses

Abstract

The germinal center reaction is an important target for modulating antibody responses. Antibody production from germinal centers is regulated by a negative feedback mechanism termed antibody feedback. By imposing antibody feedback, germinal centers can interact and regulate the output of other germinal centers. Using an agent-based model of the germinal center reaction, we studied the impact of antibody feedback on kinetics and efficiency of a germinal center. Our simulations predict that high feedback of antibodies from germinal centers reduces the production of plasma cells and subsequently the efficiency of the germinal center reaction by promoting earlier termination. Affinity maturation is only weakly improved by increased antibody feedback and ultimately interrupted because of premature termination of the reaction. The model predicts that the asynchronous onset and changes in number of germinal centers could alter the efficiency of antibody response due to changes in feedback by soluble antibodies. Consequently, late initialized germinal centers have a compromised output due to higher antibody feedback from the germinal centers formed earlier. The results demonstrate potential effects of germinal center intercommunication and highlight the importance of understanding germinal center interactions for optimizing the antibody response, in particular, in the elderly and in the context of vaccination.

Intrinsic defects in lymph node stromal cells underpin poor germinal center responses during aging

“…Tfh cell help is given to interacting B cells with the highest amount of antigen, which also indicates B cell receptor affinity, and the model assumes that centrocytes interact with Tfh cells once per cycle. In the model used here, the GC is seeded with two B cell clones per hour over the first three days, each of which divides six times 70 ; this models the in vivo findings that 10-100 B cell clones seed a founder GC 71 . A full list of parameters is available in 72 .…”

Computational Model Reveals a Stochastic Mechanism behind Germinal Center Clonal Bursts

“…Of course, additional mechanisms may be at play in terminating the GC reaction, such as antibody feedback [71]. Similarly, asynchronous onset and intercommunication between GCs might alter the efficiency of antibody response and lead to compromised efficiency and earlier termination of late initialized GCs [21]. Future renditions of our work will explicitly investigate the mechanisms by which affinity influences antigen uptake and antigen presentation, including its contribution to the termination of the GC reaction.…”

“…As GCs are stochastic systems that display a high level of variability even within the same lymph node of the same individual [18], mathematical models have been widely used to deepen our understanding of the cellular and molecular processes characterising these complex dynamic systems [19]. In particular, multi-scale stochastic [20] and spatial agent-based models have been proposed [21][22][23]. The advantage of such models is their faithful replication of the probabilistic interactions between the different cellular populations in the GC.…”

Rate of immune complex cycling in follicular dendritic cell determines the extent of protecting antigen integrity and availability to germinal center B cells1

“…IL-10 produced by Tfr (T follicular regulatory) cells 57 A number of factors including antibody feedback (46)(47)(48), CD40/CD40L interactions (62,63) are able to influence GC shutdown even though the mechanism of shutdown is not well understood.…”

“…Blockade of antigen cycling slightly impaired affinity maturation ( Figure 4D Figure S2) when compared to blocking both internalization and externalization. These results suggest that antigen cycling can also be blocked to terminate GC reactions in a way similar to the effect of antibody feedback (46)(47)(48).…”