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Updated: Apr 15, 2026
The bm12 Inducible Model of Systemic Lupus Erythematosus SLE in C57BL/6 Mice
Published on: November 1, 2015
T cell PKCδ kinase inactivation induces lupus-like autoimmunity in mice
Gabriela Gorelik1, Amr H Sawalha1, Dipak Patel1
1Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
Abstract:
Genetic and environmental factors contribute to the onset and progression of lupus. CD4+ T cells from patients with active lupus show a decreased ERK signaling pathway, which causes changes in gene expression. The defect points to its upstream regulator, PKCδ, which exhibits a deficient activity due to oxidative stress. Our aim was to investigate the effect of a defective PKCδ in the development of lupus. We generated a double transgenic C57BL6 × SJL mouse that expresses a doxycycline-induced dominant negative PKCδ (dnPKCδ) in T cells. The transgenic mice displayed decreased T cell ERK signaling, decreased DNMT1 expression and overexpression of methylation sensitive genes involved in the exaggerated immune response in the pathogenesis of lupus. The mice developed anti-dsDNA autoantibodies and glomerulonephritis with IgG deposition. The study indicates common pathogenic mechanisms with human lupus, suggesting that environmentally-mediated T cell PKCδ inactivation plays a causative role in lupus.
Insights
Environmental factors and a defective PKCδ enzyme in T cells contribute to lupus development. This study shows that impaired PKCδ activity in mice leads to lupus-like symptoms, suggesting a causative role in human lupus.
Area of Science:
- Immunology
- Molecular Biology
- Autoimmune Diseases
Background:
- Lupus pathogenesis involves genetic and environmental factors.
- Active lupus patients exhibit reduced ERK signaling in CD4+ T cells.
- Oxidative stress impairs Protein Kinase C delta (PKCδ) activity, affecting T cell function.
Purpose of the Study:
- To investigate the role of defective PKCδ in lupus development.
- To model lupus pathogenesis using a genetically engineered mouse.
Main Methods:
- Generated a doxycycline-inducible dominant-negative PKCδ (dnPKCδ) transgenic mouse model.
- Analyzed T cell signaling pathways, gene expression (DNMT1), and immune responses.
- Assessed autoantibody production and kidney pathology (glomerulonephritis).
Main Results:
- Transgenic mice showed decreased T cell ERK signaling and DNMT1 expression.
- Overexpression of methylation-sensitive genes linked to lupus pathogenesis was observed.
- Mice developed anti-dsDNA autoantibodies and glomerulonephritis with IgG deposition.
Conclusions:
- Environmentally-mediated T cell PKCδ inactivation is implicated in lupus pathogenesis.
- The mouse model recapitulates key features of human lupus.
- Defective PKCδ activity represents a potential therapeutic target for lupus.
