Understanding the Immune Response through Modeling and Simulation

Steven H. Kleinstein, Ph.D.

Computer Science, Princeton University

Many immune responses are initiated through the binding of antibody receptors present on the surface of B cells. Once activated, these B cells proliferate and undergo a process of somatic hypermutation whereby point mutations are introduced into the DNA coding for their antibody receptor. These mutations have important consequences for the affinity and specificity of the response.

Despite the significance of somatic hypermutation, precise estimates of the mutation rate do not currently exist. We have used mathematical modeling and computer simulation to interpret data from microdissection studies and estimate this rate more accurately than previously possible. Each microdissection experiment provides a number of clonally related sequences that, through the analysis of shared mutations, can be genealogically related to each other. The 'shape' of these clonal trees is influenced by many processes including the hypermutation rate. Modeling and simulation are used to relate the ‘shapes’ of these trees to the underlying biology. This talk will describe two different methods to estimate the mutation rate based on these data. The first relies on a computer simulation of clonal expansion as a stochastic branching process. The second is analytical. By combining these models with optimization techniques we have developed precise methods for estimating the mutation rate in vivo.

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