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Comparative Study
. 2007 Jan;122(1):101-7.
doi: 10.1016/j.clim.2006.09.009. Epub 2006 Nov 1.

A Female Preponderance for Chemically Induced Lupus in SJL/J Mice

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Free PMC article
Comparative Study

A Female Preponderance for Chemically Induced Lupus in SJL/J Mice

Deborah L Smith et al. Clin Immunol. .
Free PMC article

Abstract

Both spontaneous and chemically induced rodent models of autoimmune nephritis and autoantibody production have been explored to understand mechanisms involved in human systemic lupus erythematosus (SLE). While it has been known for decades that women are more susceptible than men to SLE, mechanisms underlying this female preponderance remain unclear. One chemically induced model involves injection of hydrocarbon oils such as pristane into otherwise normal mouse strains, which results in the development of autoantibodies and inflammation in organs such as kidney and liver. It is unknown whether lupus-like disease induced by chemicals would exhibit a sex bias in disease susceptibility. Here, we show that SJL/J female mice injected with pristane display greater mortality, kidney disease, serum anti-nuclear and anti-dsDNA antibodies than their male siblings. This is the first evidence that a female sex bias exists in a chemically induced lupus model.

Figures

Figure 1
Figure 1
Reduced survival in female pristane-induced lupus mice. Female (n=44) and male (n=49) mice were injected with pristane and animals monitored for survival (p<0.0017; Kaplan–Meier log rank test). 19 females and 8 males, which were sacrificed during study for tissue harvesting, were censored from analysis (open circles). There was no difference in survival outcome among the three experiments (Cox proportional hazards model).
Figure 2
Figure 2
Representative renal histology from pristane-induced lupus SJL/J mice. Mice were injected with pristane at 6 weeks of age and sacrificed at 32 weeks. Kidneys were harvested, fixed in 4% formalin and paraffin sections were stained with H&E and PAS. (A, D) Representative sections from male and (B, C, E) female mice are shown. These figures show typical epithelial and endothelial deposits (denoted by *), focal proliferative nephritis (FPN), diffuse glomerular hypercellularity (in D and E), cellular and fibrous crescents (Cres), tubular dilatation and atrophy (TA) and casts (TC) and tubular epithelial cell and macrophages (#) in tubular lumen. Summary of disease grades with differences in female versus male is shown in Fig. 3.
Figure 3
Figure 3
Female pristane-induced lupus mice have significantly greater kidney disease pathology as compared to males. (A) In one experiment, 8 female and 12 male pristane-injected mice were sacrificed at 32 weeks post-injection. (B) In a second experiment, twelve female and fifteen male pristane-injected mice were sacrificed at 21 weeks post-injection. H&E- and PAS-stained kidney sections from both experiments were scored for lesions. Kidney pathology scores were quantified and statistically analyzed by the Wilcoxon test. (A) Note that at a late stage in the disease (32 weeks post-pristane injection), female mice experienced significantly more severe pristane-induced lupus disease pathology overall than their male siblings, p<0.03. (B) At an earlier stage (21 weeks post-pristane injection), females experienced significantly more glomerular hypercellularity and necrosis (Glm cell), p<0.0128, and also displayed a trend for greater disease pathology overall, greater glomerulosclerosis (GSc), greater cellular crescent formation (Cres/PGF) and greater interstitial infiltration (PVI), while there was no sex difference in tubular disease (Tub dz). Histograms show means and SEM for mice in each group. *p<0.05.
Figure 4
Figure 4
Autoantibody levels were significantly higher in sera from female, as compared to male SJL/J mice with pristane-induced lupus. (A) Sixteen weeks post-pristane injection, female mice (n=9) produced more serum IgG ANA than male mice (n=13), p=0.0002. (B) Female mice (n=29) produced more serum anti-dsDNA IgG Ab than male mice (n=31), p=0.03. (C and D) Female mice (n=10) produced more serum anti-dsDNA IgG1 and IgG2a Ab than male mice (n=13), p=0.024 and p=0.039, respectively. Autoantibody levels were determined using a reference-positive standard of pooled serum and expressed as attributed units per milliliter. Histograms show means and SEM for mice in each group. *p<0.05; ***p<0.0005. ANA and anti-dsDNA data are representative of two independent experiments on different sets of mice.

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