Genetic contributions to lupus-like disease in NZB/NZW mice.
In contrast to parental New Zealand Black (NZB) or New Zealand White (NZW) mice, (NZB x NZW)F1 mice exhibit a lupus-like disease characterized by high levels of immunoglobulin G (IgG) antinuclear antibodies in their serum and a fatal immune-complex glomerulonephritis. At least three gene loci have been identified in NZW mice that could potentially contribute to a T cell-dependent autoimmune disease, including the T cell receptor alpha- and beta-chain gene complexes and the major histocompatibility complex (MHC). The NZW T cell receptor beta-chain complex appeared to be particularly unusual in that the C-beta-1, D-beta-2, and J-beta-2 gene segments have been deleted. Approximately one half of (NZB x NZW)F1 x NZB backcross mice developed severe renal disease and elevated levels of IgG antibodies to double-stranded deoxyribonucleic acid and histone, suggesting that only one dominant gene or closely linked group of genes accounts for the NZW genetic contribution to F1 disease. Despite the extremely unusual nature of the NZW T cell receptor beta-chain gene complex, we found no association of disease expression with the presence of this allele in the backcross mice. There was also no correlation of disease incidence with the presence of the NZW T cell receptor alpha-chain allele. In contrast, nearly 90 percent of the backcross mice with the NZW MHC expressed severe autoimmune disease compared with 12 percent of the mice that did not carry this haplotype. Thus, the NZW MHC or gene(s) linked to this locus appears to be the only dominant NZW genetic contribution to F1 disease. Recent preliminary studies mapping genes that are located centromeric and telomeric to the NZW MHC suggest that the disease-associated gene(s) lies within the MHC.
Kotzin
B L
BL
Department of Microbiology/Immunology, University of Colorado Health Sciences Center, Denver 80262.
Palmer
E
E
D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D015342:DNA Probes; D005260:Female; D005838:Genotype; D006824:Hybridization, Genetic; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008285:Major Histocompatibility Complex; D051379:Mice; D008815:Mice, Inbred Strains; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*
D000974:Antibodies, Antinuclear; D015342:DNA Probes; D011948:Receptors, Antigen, T-Cell