Rule-Based Modeling of B-Cell Receptor Clustering

Transmembrane B-Cell Receptors (BCRs) can bind to extracellular antigens with high affinity and specificity, and initiate a signaling cascade leading to an immune response.  While the cytoplasmic signaling components of B-Cells have been elucidated, the mechanism by which antigen binding transmits a signal across the plasma membrane is poorly understood.  Several studies have shown that antigen induced clustering of BCRs on the plasma membrane is critical for B-Cell activation, suggesting that spatial reorganization is the mode of signal transmission.  Experimental evidence has implicated the Cµ4 ectodomain of BCRs in their clustering, but no model has been reported which explains this phenomenon in detail.  We have developed a rule-based model to describe how cooperativity between antigen binding BCRs and BCR dimerization at this domain leads to the formation of higher order oligomers.  Using Monte Carlo simulations in the MCell software suite, we tested our model and statistically characterized the degree to which cooperativity leads to BCR clustering.