Differences in expression of lupus nephritis in New Zealand mixed H-2z homozygous inbred strains of mice derived from New Zealand black and New Zealand white mice. Origins and initial characterization.
BACKGROUND
F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice develop autoimmune glomerulonephritis resembling human lupus nephritis. Susceptibility to this complex autoimmune syndrome in humans and mice has been linked to genes mapping in or near the major histocompatibility complex that govern immune responses and levels of certain complement components. Previous studies showed that both parental strains contribute major histocompatibility complex-linked genes that are important for disease of the F1 hybrid.


METHODS
New inbred strains of New Zealand Mixed (NZM) mice were derived by selective inbreeding of progeny of a cross between NZB and NZW mice. Twelve of the 27 new NZM strains were selected for analysis. Mice were observed for up to 10 months of age to document the occurrence of nephritis and strain-specific differences in disease expression. H-2, Hc, and coat color loci were determined for each strain to establish homozygosity of NZB and NZW polymorphic markers. Strains were screened for the presence of anti-dsDNA autoantibodies.


RESULTS
In some NZM strains early onset of lupus nephritis in females resembled the (NZB x NZW)F1 model, whereas in other strains early disease also occurred in males. Age at death and severity of nephritis vary among the lines; a few strains remain relatively free of glomerular lesions. Histocompatibility (H-2) typing showed that all strains are homozygous for the NZW haplotype (Ku, Au, Sz, Dz). Coat color analysis for four loci on chromosomes 2, 4, and 7 was consistent with specific reassortments and recombinations to explain the grey, tan, and white mice with red/pink eyes and the presence or absence of the fifth component of serum complement (C5) (Hc, chromosome 2). Anti-dsDNA autoantibodies were found in all but one of the NZM strains reported here.


CONCLUSIONS
The NZM strains of mice are a unique set of inbred strains that have inherited various genomic segments of the two parental strains that lead to phenotypic differences in disease expression. These results indicate that the previously proposed strict requirement for H-2 heterozygosity for the development of nephritis in the (NZB x NZW)F1 hybrid mice may not be valid. It is assumed that both the Lpn-1 locus of NZB and the Lpn-2 locus of NZW and a sufficient number of other disease-associated genes of both ancestral strains have been recombined in these new strains to produce the various patterns of renal disease.
Rudofsky
U H
UH
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany.
Evans
B D
BD
Balaban
S L
SL
Mottironi
V D
VD
Gabrielsen
A E
AE
D000822:Animal Husbandry; D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D004247:DNA / Q000276:immunology; D005260:Female; D005819:Genetic Markers; D006650:Histocompatibility Testing; D006720:Homozygote; D006824:Hybridization, Genetic; D007678:Kidney Glomerulus / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics
D000974:Antibodies, Antinuclear; D005819:Genetic Markers; D004247:DNA