CD5+ B cells have attracted much attention, because of their involvement in both autoimmunity and B cell-type chronic lymphocytic leukemia (B-CLL). B-CLL is a type of leukemia most often occurring among close relatives and is partly associated with the major histocompatibility complex (MHC), a finding relevant to autoimmune disease. We established MHC (H-2)-congenic NZB x NZW (NZB/W) F1 mice (H-2d/z, H-2z/z, and H-2d/d), in that only H-2d/z heterozygotes developed severe SLE, associated with IgG anti-DNA antibodies, as the animals aged. Such age-associated changes occurred in parallel with the decrease in the splenic, but not peritoneal, CD5+ B cells. By contrast, H-2z/z homozygotes did not develop SLE but, in turn, a marked clonal proliferation of CD5+ B cells resembling B-CLL did occur. H-2d/d homozygotes also did not develop the typical SLE, and a moderate CD5+ B frequency persisted. Despite the finding that all the three H-2-congenic NZB/W F1 strains produced IgM anti-DNA antibodies, only the H-2d/z heterozygotes produced IgG antibodies. Whereas the surface phenotype of major IgM producers was CD5+ sIgM+, that of IgG producers was CD5-sIgM-. Genetic and cellular analyses supported our thesis that in the heterozygotes IgM to IgG isotype switching probably emerges in CD5+ B cells and that this event is associated with the loss of CD5 molecules. Because of the lack of genetic elements required for differentiation, only signals for proliferation would be functioning in CD5+ B cells in the H-2z/z homozygotes. These observations infer that certain different, but related, MHC haplotypes may predispose either to B-CLL or to autoimmune disease in close relatives.