Alleles of MHC class II (MHC II) have been linked to susceptibility for a number of infectious diseases. The connection between the two, however, remains elusive at the molecular and cellular levels. MHC II molecules bind peptides from extracellular sources and display them on the surface of antigen-presenting cells (APC). T helper cells recognize MHC II-bound peptides on the APC surface and become activated, initiating an immune response. Possible explanations linking MHC II alleles to disease susceptibility include an inability of some MHC II to present immunodominant peptides at sufficient densities and a possible involvement of altered peptide ligands. To help test these hypotheses we developed a model that tracks the dynamics of antigen presentation within the APC and can predict the effect of MHC II polymorphism. Nonlinear ordinary differential equations were used to represent intracellular processes, and dynamics were tested against experimental data. The effect of MHC II polymorphism was represented as changes to peptide-MHC II binding affinity whose value was predicted by a matrix-based statistical method and used as a parameter within the mathematical model. Using the combined model we are able to predict how MHC II polymorphism affects the density of antigen presented on the APC surface over time.

This is a joint work with Debashis Ghosh, Jennifer J. Linderman, and Denise E. Kirschner.