Abstract 477: The Genetic Interval Sle1 is Sufficient to Accelerate Atherosclerosis in LDLr-/- Mice
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by T and B cell activation and increased circulating autoantibodies. While kidney disease and infection are common causes of early death, patients surviving more than a year after diagnosis have a strikingly increased risk of atherosclerosis resulting in heart attack or stroke. Despite identification of this increased risk more than 40 years ago, mechanisms for SLE-accelerated atherosclerosis remain elusive. The B6.Sle1.2.3 mouse model of SLE contains three genetic loci that confer SLE susceptibility: Sle1, Sle2 and Sle3. We have shown that bone marrow transplant from B6.Sle1.2.3 into LDLr-/- mice results in increased atherosclerosis accompanied by more CD4+ T cells in the lesions, pointing to T cell dysregulation as a contributing factor. While all three loci are necessary for fully penetrant lupus nephritis, whether one particular interval is responsible for accelerated atherosclerosis is unknown. We have shown that Sle3, the interval associated with T cell dysregulation, is not adequate to accelerate atherosclerosis. Therefore, the purpose of the current study was to test the hypothesis that Sle1, which is linked to chronic lymphocyte activation, is sufficient to modulate atherosclerosis in LDLr-/- mice. LDLr-/- mice were irradiated and received bone marrow from Sle1, Sle3 or Sle1.2.3 mice. Following a 16 week recovery period, mice were placed on Western diet for 8 weeks. At sacrifice, spleens were collected for flow cytometry and atherosclerotic lesion area in the aortic root was evaluated. LDLr.Sle1 and LDLr.Sle1.2.3 mice exhibited similar increases in the percentage of splenic CD4+ T cells and activated T cells compared to LDLr.Sle3 controls. Interestingly, both LDLr.Sle1 and LDLr.Sle1.2.3 mice had a 30% increase in atherosclerotic lesion area compared to controls, along with increased numbers of CD4+ T cells in the lesions. These changes were independent of serum cholesterol and triglyceride levels. Our results indicate that the genetic interval Sle1 is sufficient to cause accelerated atherosclerosis in LDLr-/- mice and that this increase is related to aberrant lymphocyte homeostasis and activation.
Author Disclosures: A.J. Wilhelm: Research Grant; Modest; NHLBI/NRSA. J.P. Rhoads: Research Grant; Modest; T32 training grant NIH. A.S. Major: Research Grant; Modest; NIH/NHLBI R01, Lupus Research Institute Grant.
- © 2014 by American Heart Association, Inc.