MAPPING OF A GENE FOR HYPERGAMMAGLOBULINEMIA TO THE DISTAL REGION ON CHROMOSOME-4 IN NZB MICE AND ITS CONTRIBUTION TO SYSTEMIC LUPUS-ERYTHEMATOSUS IN (NZB X NZW)F-1 MICE

IgM class hypergammaglobulinemia develops spontaneously in the early life of NZB mice. To determine the chromosomal location of the NZB gene(s) linked to this hypergammaglobulinemia and possible contribution to systemic lupus erythematosus (SLE)-like autoimmune disease observed in (NZB x NZW)F-1 hybrid mice, we examined (NZB x NZW)F-1 x NZW backcross mice, using a mapping technique based on polymorphism in simple nucleotide sequence repeats. In light of our previous data, we directed attention to chromosome 4. A single NZB locus or tightly linked group of loci on the distal region (70-90 cM distal from the centromere), theoretically mapped to 14.3 cM distal from marker locus D4Mit48, had the strongest association with IgM hypergammaglobulinemia. The backcross progeny heterozygous for this locus on chromosome 4, in association with heterozygosity of the MHC haplotype (H-2(d) from NZB/H-2(z) from NZW) on chromosome 17, showed significantly higher serum levels of IgG anti-DNA antibodies and more severe lupus nephritis than did the progeny heterozygous for either one of the two loci or homozygous for both loci on chromosomes 4 and 17. The NZB gene in the distal region of chromosome 4 is likely to be responsible for terminal maturation of B cells and, in concert with the effect of H-2 heterozygosity, may predispose to the full expression of SLE in (NZB x NZW)F-1 mice.