|Budget Amount *help
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1991: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1990: ¥3,600,000 (Direct Cost: ¥3,600,000)
CD^<5+> 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 occuring 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)Fl mice(H-2^<d/z>, H-2^<z/z>, and H-2^<d/d>), in that only H-2^<d/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 CD^<5+> B cells. By contrast, H-2^<z/z> homozygotes did not develop SLE but, in turn, a marked clonal proliferation of CD^<5+> B cells resembling B-CLL did occur. H-2^<d/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 Fl strains produced IgM anti-DNA antibodies, only the H-2^<d/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 (H-2^<d/Z>) required for differentiation, only signals for proliferation would be functioning in CD5^+ B cells in the H-2^<z/z> homozygotes. These observations infer that certain different, but related, MHC haplotypes may predispose either to B-CLL orto autoimmune disease in close relatives.