Loss of LFA-1, but not Mac-1, protects MRL/MpJ-Fas(lpr) mice from autoimmune disease

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune complex-mediated tissue injury. Many different adhesion molecules are thought to participate in the development of SLE; however, few studies have directly examined the contributions of these proteins. Here we demonstrate that LFA-1 plays an essential role in the development of lupus in MRL/MpJ-Fas(lpr) mice. Mice deficient in LFA-1, but not Mac-1, showed significantly increased survival, decreased anti-DNA autoantibody formation, and reduced glomerulonephritis. The phenotype of the LFA-1-deficient mice was similar to that observed in beta(2) integrin-deficient (CD18-null) MRL/MpJ-Fas(lpr) mice, suggesting a lack of redundancy among the beta(2) integrin family members and other adhesion molecules. These studies identify LFA-1 as a key contributor in the pathogenesis of autoimmune disease in this model, and further suggest that therapeutic strategies targeting this adhesion molecule may be beneficial for the treatment of SLE.

Figure 1

Phenotypic characteristics of mutant MRL/MpJ-Fas^lpr mice. a: Twenty-week-old control MRL/MpJ-Fas^lpr (male), CD18^−/− (male and female), CD11b^−/− (male and female), or CD11a^−/− (male and female) are shown from left to right. b: Kaplan-Meier survival analysis between control MRL/MpJ-Fas^lpr (▪, n = 25), CD11a^−/− (▴, n = 30), and CD11b^−/− (▾, n = 24) mice. c: BUN measurements from five male and five female, 20-week-old mice. *, P < 0.05.

Figure 2

Glomerular ultrastructure. A: Control MRL/MpJ-Fas^lpr representative glomerulus from a 20-week-old mouse. Extensive electron-dense deposits (d) within the markedly expanded mesangium of the glomerulus were observed (b = basement membrane). B: CD18^−/−, 20-week-old mouse. Marked reduction in glomerular deposits with distinct, nonconfluent, small electron-dense deposits within the basement membrane. C: CD11a^−/−, 20-week-old mouse. Occasional linear electron-dense deposits were noted in the paramesangial areas abutting the basement membranes and within the glomerular basement membranes. D: CD11b^−/−, 20-week-old mouse. Abundant confluent electron-dense deposits were readily seen within the mesangial regions (arrows). Epimembranous and membranous deposits (arrowheads) were also present within glomerular basement membranes. Original magnifications, ×5000.

Figure 3

Renal lesion scores for control MRL/MpJ-Fas^lpr mice (n = 6), CD18^−/− mice (n = 3), CD11a^−/− mice (n = 6), and CD11b^−/− mice (n = 4). Means ± SD. Bars designated with different letter codes are significantly different (P < 0.05).

Figure 4

Glomerular histopathology. A: Control MRL/MpJ-Fas^lpr mouse at death (23 weeks old). Severe glomerulitis with neutrophil accumulation, necrosis, sclerosis, crescent formation with synechia, and capsular fibrosis. B: CD18^−/− mouse at death (34 weeks old). Mild neutrophil accumulation. C: CD11a^−/− mouse at death (43 weeks old). Mild neutrophil accumulation. D: CD11b^−/− mouse at death (24 weeks old). Severe glomerulitis similar to that in A. H&E. Original magnifications, ×20.

Figure 5

Serum IgG anti-double-stranded and single-stranded DNA antibodies. a: IgG anti-double-stranded DNA antibody titers between control MRL/MpJ-Fas^lpr (▪, n = 25) and CD18^−/− (•, n = 25) mice. b: IgG anti-double-stranded DNA antibody titers between control MRL/MpJ-Fas^lpr (▪, n = 25) and CD11a^−/− (▴, n = 25) mice. c: IgG anti-single-stranded DNA antibody titers between control MRL/MpJ-Fas^lpr (▪, n = 25) and CD18^−/− (•, n = 25) mice. d: IgG anti-single-stranded DNA antibody titers between control MRL/MpJ-Fas^lpr (▪, n = 25) and CD11a^−/− (▴, n = 25) mice. *, P < 0.01.

Figure 6

Total serum immunoglobulin levels. a: Total serum IgG concentrations between control MRL/MpJ-Fas^lpr (▪, n = 25) and CD18^−/− (•, n = 25) mice. b: Total serum IgM concentrations between control MRL/MpJ-Fas^lpr (▪, n = 25) and CD18^−/− (•, n = 25) mice. c: Total serum IgG concentrations between control MRL/MpJ-Fas^lpr (▪, n = 25) and CD11a^−/− (▴, n = 25) mice. d: Total serum IgM concentrations between control MRL/MpJ-Fas^lpr (▪, n = 25) and CD11a^−/− (▴, n = 25) mice. *, P < 0.01.