DIFFERENCES IN EXPRESSION OF LUPUS NEPHRITIS IN NEW-ZEALAND MIXED H-2(Z) 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 Whit e (NZW) mice develop autoimmune glomerulonephritis resembling human lu pus nephritis. Susceptibility to this complex autoimmune syndrome in h umans and mice has been linked to genes mapping in or near the major h istocompatibility complex that govern immune responses and levels of c ertain complement components. Previous studies showed that both parent al strains contribute major histocompatibility complex-linked genes th at are important for disease of the F1 hybrid. EXPERIMENTAL DESIGN: Ne w inbred strains of New Zealand Mixed (NZM) mice were derived by selec tive inbreeding of progeny of a cross between NZB and NZW mice. Twelve of the 27 new NZM strains were selected for analysis. Mice were obser ved for up to 10 months of age to document the occurrence of nephritis and strain-specific differences in disease expression. H-2, Hc, and c oat color loci were determined for each strain to establish homozygosi ty of NZB and NZW polymorphic markers. Strains were screened for the p resence of anti-dsDNA autoantibodies. RESULTS: In some NZM strains ear ly onset of lupus nephritis in females resembled the (NZB x NZW)F1 mod el, whereas in other strains early disease also occurred in males. Age at death and severity of nephritis vary among the lines; a few strain s remain relatively free of glomerular lesions. Histocompatibility (H- 2) typing showed that all strains are homozygous for the NZW haplotype (K(u), A(u), S(z), D(z)). Coat color analysis for four loci on chromo somes 2, 4, and 7 was consistent with specific reassortments and recom binations 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 variou s genomic segments of the two parental strains that lead to phenotypic differences in disease expression. These results indicate that the pr eviously proposed strict requirement for H-2 heterozygosity for the de velopment of nephritis in the (NZB x NZW)F1 hybrid mice may not be val id. 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 b oth ancestral strains have been recombined in these new strains to pro duce the various patterns of renal disease.