Among the phenotypically distinct types of canonical B cells that we have isolated, two are of particular interest because they express different levels of surface Ig. We are testing the hypothesis that mutation and positive selection both occur within the population expressing the higher level of sIg and that rare positively-selected cells from this population differentiate into those cells with diminished sIg, which then proliferate to expand the successful B cell clonotype. Following proliferation, these cells with diminished sIg may subsequently re-differentiate into cells of the higher sIg phenotype for repeated cycles of mutation and selection. This cyclic re-entry idea could help to explain how the immune system rapidly generates memory B cells that express mutant antibodies with improved affinity for immunogen. Germinal centers containing canonical anti-Ars B cells.
Arrows point to consistent positions and serve to orient sections.
This animal carried a canonical kappa light chain transgene in order to increase the frequency of responding B cells that also expressed an endogenous canonical heavy chain gene. E4 staining requires pairing of canonical heavy and light chain V region domains. We are also exploring the hypermutation mechanism that targets antibody V region genes during memory development. The fact that there is no biological precedent for a physiological mutator and the inherent danger associated with rapid mutagenesis make this a particularly intriguing problem. One of our approaches involves a motif analysis of mutation targets.