B cells in the centroblast (CB) state divide in the DZ while accumulating SHMs in their BcR. (BCL6, IRF4, and BLIMP1) recapitulates the temporal switch and DZ-to-LZ percentage in the germinal center, we implemented a multiscale model that combines a core gene regulatory network for plasma cell differentiation having a SKLB1002 model describing the SKLB1002 cellular relationships and dynamics in the germinal center. Our simulations display that BLIMP1 driven plasma cell differentiation together with coupled asymmetric division of antigen and BLIMP1 with a large segregation between the daughter cells results in a germinal center DZ-to-LZ percentage and a temporal switch from memory space B cells to plasma cells that have been observed in experiments. and mouse B cells showing?that accumulated Ag is taken care of inside a polarized distribution prior to the division in approximately 72% of the B cells and that this polarization is taken care of during cell division resulting in an asymmetric division of Ag over both daughter cells (3). The child cell that receives more Ag as a result of asymmetric division was postulated to be more efficient in receiving T cell help, both in the BCT cell border and in the GC, which may affect cell fate (3). In the same issue, it was argued and demonstrated by computational modeling that asymmetric division may largely impact the production of Personal computers (4). Later, a more comprehensive computational model of the GC reaction expected that asymmetric division of Ag might codetermine B-cell fate, since inclusion of this mechanism resulted in GC transzone migration rates and DZ-to-LZ percentage in agreement with experimental data (5, 6). In addition to asymmetric Ag division, studies have shown that additional B-cell fate-altering molecules, such as transcriptional regulator B-cell lymphoma 6 (BCL6) and the receptor for interleukin-21 (IL-21R), segregate asymmetrically in approximately 44% of mitotic GC B cells (7). In contrast, IRF4 was mostly symmetrically distributed (11% asymmetry comparable to tubulin). The same study suggested that CD40 signaling facilitates TF asymmetry by providing polarity cues to B cells. However, additional polarity cues [e.g., cellCcell contacts (8)], TFs [e.g., BLIMP1 transcription (9)], and signaling pathways [e.g., nuclear element kappa B (Nf-kB)] may travel asymmetric division and/or B-cell fate. Regardless of the mechanism, asymmetric division offers been shown to result in child cells with unequal amounts of Ag and/or TF. The amount of segregation seems to vary for different TFs, and this might be dependent on polarity cues, signaling pathways and strength, and/or stochastic events. We hypothesized that (the level of) Ag and TF (BCL6, IRF4, BLIMP1) segregation affects GC dynamics and B-cell fate in different ways or to different extents. To test this SKLB1002 hypothesis, we implemented a multiscale model (MSM) that combines a core gene regulatory network for B cell of Personal computer differentiation having a model describing the cellular relationships and dynamics in the GC. Our simulations display that BLIMP1-driven PC differentiation coupled to asymmetric division of Ag and BLIMP1 with a large segregation between the daughter cells results in a GC transzone migration and a temporal switch from MBCs to Personal computers that are both observed in experiments (6, 10). As a result, these computational results prompt for more direct experiments targeted to verify or falsify this mechanism for Personal computer differentiation. Methods Multiscale Model To enable the investigation of cellular and molecular mechanisms involved in Personal computer differentiation, we recently developed a multiscale model (MSM) (11) that integrates an agent-based model (ABM) of the GC reaction (5) having a gene regulatory network (GRN) involved in Personal computer differentiation (12). We slightly altered this model to investigate NFKB1 the effect of asymmetric Ag and TF division. In brief, the ABM contains the main processes that take place in the GC reaction, which continues for 21 days (504 h). B cells in the centroblast (CB) state divide in the DZ while accumulating SHMs in their BcR. They then differentiate to CCs and migrate to the LZ where they may encounter FDCs and Tfh cells. FDCs carry Ag in their membrane, which is definitely internalized by CCs when in contact with an affinity-dependent rate. This provides CCs with survival signals that temporarily save them from apoptosis and allow them to undergo further encounter(s) with Tfh cells. CCs with higher internalized Ag, therefore higher affinity for the Ag, will outcompete additional CCs with less internalized Ag. CCs are then fully rescued from apoptosis and recycle back to the DZ as CBs. Recycled CBs further divide asymmetrically in 72% of the instances where all the internalized Ag goes to one of the child cells. The GRN of Personal computer differentiation comprises three TFs.
B cells in the centroblast (CB) state divide in the DZ while accumulating SHMs in their BcR