Resolution of Some Paradoxes in B-Cell Binding and Activation: A Computer Study

Abstract

This is a description of work done in collaboration with Yoram Louzoun and Martin Weigert at Princeton University. In our computer study, we explain certain puzzling aspects of the binding and activation of B-Cells with a new hypothesis about the rate of endocytosis of receptors. The first such puzzle stems from experiments by Dintzis et al which suggest that the binding and activation of B-Cells is sensitive to the valence (number of binding sites or haptens) on antigen. For valence less than 10-20, B-Cells fail to activate for any concentration of antigen. For larger values of valence, they activate only in a narrow range of concentration. Another puzzle has to do with the non-immunogenicity of chimerical B-Cells, which present receptors with erroneous light chain arrangements. We performed a computer experiment to model the B-Cell surface with embedded receptors diffusing in the surface lipid layer. We presented these surface receptors with antigen with varying concentration and valence. Using experimentally reasonable values for the binding and unbinding probabilities for the binding sites on the antigens, we simulated the dynamics of the binding process. Using the single hypothesis that the rate of endocytosis of bound receptors is significantly higher than that of unbound receptors, and that this rate varies inversely as the square of the mass of the bound, connected receptor complex, we are able to reproduce all the qualitative features of the Dintzis experiment. We were also able to generate some testable predictions on how chimeric B-Cells might be non-immunogenic.