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

Abstract

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 chemokines (monocyte chemoattractant protein 1, RANTES, KC), and significantly accelerated mortality. Importantly, these changes occurred within a few days after NTS administration. Finally, (B6 ؋ NZW)F 1 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.Over the last 4 decades, studies with the New Zealand strains of mice have contributed significantly to our understanding of the pathogenesis of lupus. Of particular interest are the specific genetic and immunologic contributions of the NZW and NZB strains to disease. The NZW strain is fairly healthy, but contributes to lupus nephritis, in epistasis with several other strains. When NZW mice are bred to the NZB strain, either as an F 1 hybrid or as a recombinant inbred strain, this leads to highly penetrant lupus nephritis (1-3). Likewise, when NZW mice are bred to the BXSB strain, the F 1 offspring exhibit lupus nephritis and coronary vascular disease (4). Moreover, when NZW mice are bred to B6 mice, either in the context of the lupus susceptibility locus Sle1 (5) or the Yaa locus (6), the F 1 offspring also exhibit severe proliferative glomerulonephritis (GN) and accelerated mortality. Thus, although the NZW genome by itself does not lead to the development of clinical nephritis, it clearly has the capacity to interact with several other genomes to precipitate endorgan disease.Although NZW mice are clinicall...

Excreted urinary mediators in an animal model of experimental immune nephritis with potential pathogenic significance

“…We recently noted that certain strains of mice, such as NZW, DBA/1, BUB, and 129/Sv, develop severe nephritis in response to an anti-GBM antibody insult, compared with 16 other inbred strains tested (2,3). As a quick screen for mediators that may be excreted in the urine of nephritic mice, we assayed urine from 2 strains of mice with mild experimental nephritis (i.e., B6 and BALB/c), and 2 strains of mice with severe experimental nephritis (i.e., DBA/1 and 129/Sv), 14 days following the nephrotoxic insult (the peak of disease) for the presence Figure 1.…”

“…Whereas VCAM-1 levels continued to be high past day 14 (similar to the level of protein), levels of the other 3 markers, particularly TNFRI, dropped rapidly after day 14. Because acute glomerular disease in this model reaches its peak at about day 14 (2,3), it is tempting to propose that whereas the urinary levels of P-selectin, CXCL16, and particularly TNFRI may be good markers of acute renal disease, urinary VCAM-1 may be a better marker of past or chronic nephritis.…”

“…Examples of the former include the C57BL/6 (B6) and BALB/c mouse strains, whereas the 129/Sv, BUB, NZW, and DBA/1 mouse strains develop severe proliferative renal disease following an anti-GBM antibody challenge (2,3). The genetic and molecular players that account for this strain difference currently remain unknown.…”

Sle3 and Sle5 can independently couple with Sle1 to mediate severe lupus nephritis

“…Immunofluorescence analysis of IgA deposition in kidneys was performed on 3-mm cryostat sections as described previously. 34 Fluorescein isothiocyanate-labeled rabbit antibodies against mouse IgA were purchased from MP Biomedicals (Solon, OH, USA).…”

Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 × NZW)F1 mice

“…9 NZW mice do not develop elevated levels of ANA, but have been found to show increased susceptibility to anti-glomerular autoantibodyinduced kidney disease. 11 In addition, the female F1 offspring of NZW crossed with B6.Nba2 (but not B6) develops severe proteinuria and dies from kidney failure within 1 year of age as do female (NZB Â NZW)F1 mice. [8][9][10] Thus, the combination of Nba2-dependent autoantibody production and NZW-derived kidney susceptibility may be important for full disease development in the (B6.Nba2 Â NZW)F1 model of lupus-like disease.…”