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The bm12 Inducible Model of Systemic Lupus Erythematosus (SLE) in C57BL/6 Mice
Published on: November 1, 2015
Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice
Jiang Li1, Thor D Stein, Jeffrey A Johnson
1School of Pharmacy, University of Wisconsin, Madison 53705-2222, USA.
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.
Insights
Mice lacking the Nrf2 gene, which controls antioxidant defenses, developed a disease similar to human lupus. This suggests that impaired detoxification and oxidative stress can trigger systemic autoimmune disorders.
Area of Science:
- Immunology
- Toxicology
- Genetics
Background:
- Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune complex deposition affecting multiple organs.
- While oxidative stress and apoptosis are implicated in SLE, the precise etiological factors remain unclear.
- The role of specific transcription factors in regulating detoxification and antioxidant pathways in autoimmunity is not fully understood.
Purpose of the Study:
- To investigate the role of the transcription factor Nrf2 in the development of autoimmune disease.
- To determine if Nrf2 deficiency leads to conditions resembling human SLE.
- To explore the link between oxidative stress, detoxification, and systemic autoimmunity.
Main Methods:
- Generation and analysis of mice lacking the nuclear factor, erythroid-derived 2, like 2 (nrf2) gene.
- Assessment of autoantibodies (anti-dsDNA, anti-Smith), immune deposits (IgG, IgM, C3), and organ pathology in nrf2 knockout mice.
- Measurement of oxidative damage markers (8-hydroxydeoxyguanosine, malondialdehyde) in liver and kidney.
- Analysis of gene expression profiles in liver and spleen, focusing on antioxidant, detoxification, cytokine, and immune cell-specific genes.
Main Results:
- Aged female nrf2 knockout mice developed autoantibodies and immune complex deposition in kidneys, liver, heart, and brain, mimicking human SLE.
- Increased oxidative damage, indicated by elevated 8-hydroxydeoxyguanosine and malondialdehyde, preceded autoimmune antibody and organ pathology.
- Gene expression analysis revealed decreased antioxidant/detoxification genes in the liver and altered cytokine and immune cell gene expression in the spleen of nrf2 knockout mice.
Conclusions:
- Deficiency in the Nrf2-controlled detoxification and antioxidant system can lead to the development of systemic autoimmune disease.
- Increased oxidative stress is a key factor in the pathogenesis of nrf2-deficiency-induced SLE-like disease.
- These findings highlight the critical role of Nrf2 in preventing autoimmunity by maintaining cellular redox homeostasis.
