Reconciling repertoire shift with affinity maturation: The role of deleterious mutations

The shift in Ab repertoire, from Abs dominating certain primary B cell resp onses to genetically unrelated Abs dominating subsequent "memory" responses , challenges the accepted paradigm of affinity maturation. We used mathemat ical modeling and computer simulations of the dynamics of B cell responses, hypermutation, selection, and memory cell formation to test hypotheses att empting to explain repertoire shift. We show that repertoire shift can be e xplained within the framework of the affinity maturation paradigm, only whe n we recognize the destructive nature of hypermutation: B cells with a high initial affinity for the Ag are less likely to improve through random muta tions.