Specific antibody production by V-H-gene replacement

V-H-gene replacement is a recombination event in which a pre-existing immun oglobulin heavy chain gene can be altered by the replacement of the rearran ged V-H gene segment with another V-H gene segment. Although this event has been demonstrated in various model systems, its role in generating antibod y diversity is still unsettled. We have used a genetically modified mouse s train, QM, with a quasi monoclonal primary B cell repertoire specific for N P to determine whether V-H gene replacement can generate a new antigen spec ificity. Hybridomas generated from QM splenocytes alter immunization with d ifferent antigens, gave rise to antibodies with specificity to the immunizi ng antigen or with new specificities. We found V-H-gene replacement was use d to change the original heavy chain gene rearrangement specific for NP int o a heavy chain gene encoding the new antigen specificity. V-H-gene replace ment intermediates were detected both before and after the immunization, su ggesting that the event was selective rather than instructive. These result s demonstrate that V-H-gene replacement can generate a new antibody heavy c hain gene with a different functional and selectable antigen specificity.