Genetic susceptibility to PolyI:C-induced IFNα/β-dependent accelerated disease in lupus-prone mice

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. Associations between viral infections and the onset of SLE have been suggested, and recent studies have provided evidence that type I interferons (IFNa/b) might play a role in the SLE disease process. Viruses and interferons have also been implicated in mouse models of SLE. We generated a model of accelerated proteinuria, in which lupus-prone mice were injected repeatedly with polyinosinic:polycytidylic acid (polyI:C), mimicking exposure to virus-derived double stranded RNA (dsRNA), leading to the production of IFNa/b. PolyI:Ctreated (B6.Nba2 Â NZW)F1 and (B6 Â NZW)F1 hybrid mice developed significantly increased levels of anti-dsDNA autoantibodies, characteristic of lupus. Most significantly, polyI:C-treated (B6.Nba2 Â NZW)F1 mice, but not (B6 Â NZW)F1 or parental strains, developed lupus-like nephritis in an accelerated fashion, which was dependent on IFNa/b and associated with elevated deposition of total IgG, IgG2a and complement factor C3 in the glomerular capillary walls. These data suggest that reagents, which increase the levels of endogenous IFNa/b (directly or indirectly), can accelerate the course of lupus-like nephritis, the development of which is dependent on the presence of both NZW-and Nba2-encoded genes.

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

“…Shown are representative pictures from one IFNAR þ / þ B6.Nba2 and one IFNAR À/À B6.Nba2 mouse. (b) Morphometric analysis of IgG deposition was performed as described previously, 4 and revealed no significant difference among IFNAR-sufficient and IFNAR-deficient mice in the percentage of area per glomerulus that stained positive for IgG (P ¼ 0.79). IFNAR, IFNab-receptor 1; Ig, immunoglobulin; Nba2, New Zealand black autoimmunity 2.…”

“…4,[17][18][19] In NZB mice, IFNAR deficiency led to a reduction in disease IFNab receptor deficient B6.Nba2 mice TN Jørgensen et al characteristics including those involving autoantibody production and IgG deposition, 17 whereas treatment with recombinant IFNa accelerated disease. 18 Likewise, elevated IFNab levels accelerated disease in (B6.Nba2 Â NZW)F1 mice, although this effect was not seen in parental B6.Nba2 mice.…”

“…18 Likewise, elevated IFNab levels accelerated disease in (B6.Nba2 Â NZW)F1 mice, although this effect was not seen in parental B6.Nba2 mice. 4 On the other hand, in MRL-Fas lpr mice, IFNAR deficiency exacerbated disease, resulting in higher levels of autoantibodies and more severe glomerulonephritis. 19 In the current study we have investigated IFNARdeficient B6.Nba2 congenic mice and the consequences of IFNAR deficiency for spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 Â NZW)F1 mice.…”

“…1 Recently, SLE has been tightly associated with increased type I interferon (IFNab) activity in humans and in mouse models of spontaneous lupus-like disease. [2][3][4] Most strikingly, gene expression profile analyses have shown that peripheral blood mononuclear cells from SLE patients harbor a signature resembling that of cells exposed to IFNab, and that this signature can distinguish SLE patients from patients with rheumatoid arthritis. 3,5 New Zealand hybrid mice are a well-studied mouse model of lupus-like disease.…”

“…4 To dissect this phenomenon in more detail, we examined the consequences of deleting the receptor for IFNab on B6.Nba2 and (B6.Nba2 Â NZW)F1 animals. In the current study, we found that IFNab-receptor 1 (IFNAR) deficiency led to reduced ANA production in B6.Nba2 mice.…”