LIGHT-CHAIN REPLACEMENT - A NEW MODEL FOR ANTIBODY GENE REARRANGEMENT

A functional B cell antigen receptor is thought to regulate antibody g ene rearrangement either by stopping further rearrangement (seclusion) or by promoting additional rearrangement (editing). We have developed a new model to study the regulation of antibody gene rearrangement. I n this model, we used gene targeting to replace the J kappa region wit h a functional V kappa-J kappa light chain gene. Two different strains of mice were created; one, V kappa 4R, has a V kappa 4-J kappa 4 rear rangement followed by a downstream J kappa 5 segment, while the other, V kappa 8R, has a V kappa 8-J kappa 5 light chain. Here, we analyze t he influence of these functional light chains on light chain rearrange ment. We show that some V kappa 4R and V kappa 8R B cells only have th e V kappa R light chain rearrangement, whereas others undergo addition al rearrangements. Additional rearrangement can occur not only at the other kappa allele or isotype (lambda), but also at the targeted locus in both V kappa 4R and V kappa 8R. Rearrangement to the downstream J kappa 5 segment is observed in V kappa 4R, as is deletion of the targe ted locus in both V kappa 4R and V kappa 8R. The V kappa R models illu strate that a productively rearranged light chain can either terminate further rearrangement or allow further rearrangement. We attribute th e latter to editing of autoantibodies and to corrections of dysfunctio nal receptors.