Multiscale modelling of plasma cell differentiation in the germinal center

We developed a multiscale model (MSM) of plasma cell (PC) differentiation in the germinal center (GC). In Chapter 2 we introduce the model in which we have integrated two pre-existing models. One model is the agent based model (ABM) developed by Meyer-Hermann and collaborators (1), representing the cellular processes of the GC reaction. The second model is an ordinary differential equation (ODE) model developed by Martínez and co-workers (2), representing the core gene regulatory network (GRN) in PC differentiation. This model includes three main transcription factors (TFs; BCL6, IRF4, and BLIMP1) and two signaling pathways (BcR and CD40) to account for the interaction with the antigen (Ag) and Tfh cells respectively. We used the ODE model to replace some of the heuristic ABM rules that control PC differentiation. We then investigated the role of asymmetric Ag division, opposed to BLIMP1 expression, in PC differentiation. We considered the role of Tfh cell help and CD40 signaling. This work raised new questions with respect to the role of asymmetric division of Ag and TFs in PC differentiation. In Chapter 3 we investigated the extent to which asymmetric segregation of Ag and/or TFs recapitulates known dynamics of the GC reaction and PC differentiation. In Chapter 4 we apply the MSM to investigate the effect of common genetic alterations in DLBCL on the cellular level. Finally, in Chapter 5 we use our model to enhance the interpretation of B-cell repertoire sequencing data.