Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice

Physiol Genomics. 2004 Aug 11;18(3):261-72. doi: 10.1152/physiolgenomics.00209.2003.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder with immune-complex deposition that affects multiple organs. Previous studies have suggested the involvement of oxidative stress and apoptosis in SLE, but no clear link to etiology has been established. Here we show that mice deficient in a transcription factor responsible for controlling the expression of numerous detoxification and antioxidant genes develop an autoimmune disease with multiple organ pathologies that closely resembles human SLE. Aged female mice with a knockout of nuclear factor, erythroid-derived 2, like 2 (nrf2) are prone to develop antibodies against double-stranded DNA and the Smith antigen as well as IgG, IgM, and C3 deposition in kidney, liver, heart, and brain. Prior to the development of autoimmune antibodies and organ pathology, oxidative damage occurs in the liver and kidney as indicated by the increased levels of the DNA oxidation marker 8-hydroxydeoxyguanosine and the later increase in the lipid peroxidation product malondialdehyde. Gene expression profiles demonstrate an early decrease in numerous antioxidant and detoxification genes in the livers and altered levels of cytokines and T and B cell-specific genes in the spleens of nrf2 knockout mice. These data strongly suggest that a deficiency in detoxification and increased oxidative stress can result in the development of a systemic autoimmune disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Animals
  • Apoptosis / physiology
  • Autoantibodies / biosynthesis
  • Autoantibodies / blood
  • Crosses, Genetic
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • Deoxyguanosine / analogs & derivatives*
  • Deoxyguanosine / immunology
  • Female
  • Gene Expression Profiling / methods
  • Kidney / chemistry
  • Kidney / pathology
  • Liver / chemistry
  • Liver / pathology
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Knockout
  • Myocardium / chemistry
  • Myocardium / pathology
  • NF-E2-Related Factor 2
  • Oligonucleotide Array Sequence Analysis / methods
  • Oxidative Stress / physiology
  • Phenotype
  • Trans-Activators / deficiency*
  • Trans-Activators / genetics

Substances

  • Autoantibodies
  • DNA-Binding Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Trans-Activators
  • 8-Hydroxy-2'-Deoxyguanosine
  • Deoxyguanosine