Activation of rheumatoid factor (RF) B cells and somatic hypermutation outside of germinal centers in autoimmune-prone MRL/lpr mice.

Two critical questions need to be answered concerning the origins of autoreactive B cells in autoimmunity. First, how are autoreactive B cells regulated in normal situations? Second, how do such B cells escape tolerance mechanisms during autoimmunity? To address these questions, an Ig transgenic (Tg) mouse system based on the rheumatoid factor (RF) specificity has been developed. Tg mice express either the H or both H and L chains from AM14, an MRL/lpr-derived RF. Using this system, it was first shown that RF B cells are neither tolerized nor activated in a normal mouse. New insights into the timing and sites of initial RF B cell activation in MRL/lpr mice have been gained recently. RF B cells are activated. It was found, unexpectedly, that RF B cell activation, somatic hypermutation, and selection take place outside of the germinal center. We discuss the implications of this for the regulation of autoreactive B cells as well as for the regulation of hypermutation.