NZM2328: A new mouse model of systemic lupus erythematosus with unique genetic susceptibility loci

Among NZB/W-derived New Zealand mixed (NZM) strains, only NZM/Aeg2410 (NZM2410) has been well characterized. In contrast to NZM2410, NZM2328 mice develop autoantibodies and acute and severe chronic glomerulonephritis (GN) with female predominance similarly to NZB/WF1 and humans with systemic lupus erythematosus (SLE). Chronic GN with glomerular sclerosis and tubular atrophy but not acute GN was correlated with severe proteinuria. In a backcross analysis of (NZM2328 X C57L/J) F1 X NZM2328, four SLE susceptibility genomic intervals were identified. One of them (Cgnz1) is on the telomeric end of chromosome 1 and close to Sle1. It was significantly linked to chronic GN. A locus (Agnz1) distinct from Cgnz1 on this interval was suggestively linked to acute GN. Two genetic intervals on chromosome 17 were also suggestively linked to acute GN, one of which is the H-2-Tnf complex, while the other (Agnz2) is on the distal end of the chromosome. A single locus (Adaz1) identified in the midregion of chromosome 4 in NZM2328 mice was suggestively linked to plasma levels of IgG anti-dsDNA autoantibodies. These results differ significantly from those in the backcross analysis of (NZM2410 X C57BL/6)F1 X NZM2410 by other investigators. They support the concept that different sets of genes are involved in acute and chronic GN. The genomic differences between the NZM strains and between C57L/J and C57BL/6 account for the differences between our analysis and that on NZM 2410. These results provide evidence for the importance of background genes on the expression of SLE, with implications for genetic studies of human SLE. (C) 2001 Academic Press.