New Zealand mixed mice: a genetic systemic lupus erythematosus model for assessing environmental effects.

Abstract

Systemic lupus erythematosus (SLE) is a multiphenotypic autoimmune disease. The hallmark of SLE is the production of anti-double-stranded DNA autoantibodies and the deposition of immune complexes in target tissues such as the kidney, skin, and brain. Additional phenotypic traits are the presence of arthritis, anemia, central nervous system involvement, and a variety of autoantibodies. Females of childbearing age are particularly at risk. Recent genetic analysis of murine SLE shows that susceptibility is under complex polygenic control. It is also apparent that environmental factors contribute to the induction and exacerbation of SLE. We describe here the genotypic and phenotypic characterization of a group of recombinant inbred strains of SLE-prone mice that were derived from NZB and NZW progenitors, the parental strains of the classic female F1 hybrid lupus model. Recombination and reassortment of these ancestral genomes resulted in the NZM (New Zealand mixed) strains with strain-specific patterns of renal disease penetrance and other autoimmune traits such as Coombs positive anemia and neurologic deficits. Multiple susceptibility loci of the ancestral strains demonstrate that SLE is inherited as a threshold trait. Because some of these loci co-localize with the susceptibility loci of the insulin-dependent diabetes of nonobese diabetic strain, it is apparent that there are disease-specific as well as autoimmunity-promoting genes. It is proposed that the NZM strains, particularly those with reduced disease penetrance or partial genotypes, provide an improved genetic model for assessment of the effects of environmental agents on SLE and autoimmunity. Images Figure 2 Figure 3 Figure 4

Particulate Matter Immunomodulatory Effects on Autoantibody Development in New Zealand Mixed Mice

“…A rapid onset of glomerulonephritis with high proteinuria levels (greater than 500 mg/dl) in both male and female NZM mice have been previously reported (Rudofsky and Lawrence, 1999;Brown et al, 2003). In this study, none of the particulate or saline instilled NZM mice developed high proteinuria levels within 17 weeks following exposure (data not shown).…”

“…The arrows indicate PM within the lungs 17 weeks following instillation. Lawrence, 1999;Brown et al, 2003). Therefore, these biomarkers were examined in NZM mice following instillation of saline or saline suspensions of acid-washed PM 1648, PM 1648, and PM 2.5 at 16 weeks when they should be prevalent.…”

“…Lupus-prone New Zealand mixed mice provide an appropriate model to assess the effects of environmental agents on the progression of autoimmune diseases such as systemic lupus erythematosus (SLE) in a sensitive population (Rudofsky and Lawrence, 1999;Brown et al, 2003). NZM mice are a moderately lupus-prone strain with reduced disease penetrance, therefore an environmental influence on SLE in these mice would be more readily observed (Rudofsky and Lawrence, 1999;Brown et al, 2003).…”

“…NZM mice are a moderately lupus-prone strain with reduced disease penetrance, therefore an environmental influence on SLE in these mice would be more readily observed (Rudofsky and Lawrence, 1999;Brown et al, 2003). These mice spontaneously develop pathologic hallmarks of SLE between 6 months and 1 year of age (Rudofsky and Lawrence, 1999;Brown et al, 2003). The most characteristic of these traits are the development of anti-ssDNA, anti-dsDNA, anti-histone, anti-nuclear antigen (ANA), and anti-IgG autoantibodies as well as increased levels of circulating immune complexes (Rudofsky and Lawrence, 1999;Brown et al, 2003).…”

“…These mice spontaneously develop pathologic hallmarks of SLE between 6 months and 1 year of age (Rudofsky and Lawrence, 1999;Brown et al, 2003). The most characteristic of these traits are the development of anti-ssDNA, anti-dsDNA, anti-histone, anti-nuclear antigen (ANA), and anti-IgG autoantibodies as well as increased levels of circulating immune complexes (Rudofsky and Lawrence, 1999;Brown et al, 2003).…”