Enhanced susceptibility to end-organ disease in the lupus-facilitating NZW mouse strain

Objective. Although the NZW mouse strain is phenotypically normal, fulminant lupus glomerulonephritis (GN) develops when NZW mice are bred to several other strains, such as NZB, BXSB, B6.Sle1, and B6.Yaa. Based on the observation that aging NZW mice exhibit histologic evidence of GN, we sought to test our hypothesis that NZW mice may be more susceptible to immune-mediated renal damage. Methods. NZW mice, as well as C57BL/6 (B6) and BALB/c control mice, were challenged with rabbit antiglomerular basement membrane nephrotoxic sera (NTS), to induce renal disease. The different mouse strains were monitored for the degree of clinical disease, renal pathology, chemokine profiles, and cellular infiltrates. Results. Although the NZW and control strains showed similar glomerular deposits of rabbit Ig and exhibited similar levels of anti-rabbit xenogeneic immune response, the NZW mice had significantly worse pathologic changes and disease. Compared with the control strains, the NTS-injected NZW mice demonstrated significantly increased proteinuria, elevated blood urea nitrogen levels, more severe histologic GN and tubulointerstitial nephritis, increased glomerular crescent formation with macrophage and neutrophil infiltrates, elevated expression of CC and CXC chemo kines (monocyte chemoattractant protein 1, RANTES, KC), and significantly accelerated mortality. Importantly, these changes occurred within a few days after NTS administration. Finally, (B6 × NZW)P₁ mice were as susceptible as the NZW parents, which indicates dominant NZW contributions. Conclusion. Collectively, these findings support the notion that a lupus-facilitating genome may contribute to disease susceptibility by modulating the degree of immune-mediated end-organ damage. The availability of B6-based congenic strains bearing individual NZWderived lupus susceptibility loci will permit future genetic dissection of end-organ susceptibility in murine lupus.