Understanding the Pathogenesis of Accelerated Atherosclerosis in Systemic Lupus Erythematosus: A Role for T cell Dysregulation
Wade, Nekeithia Shiana
Patients with the autoimmune disease systemic lupus erythematosus (SLE) have an increased risk of developing premature cardiovascular disease, most notably atherosclerosis. While the mechanisms behind this increased risk are currently unknown, it is widely thought that immune dysregulation and inflammation contribute to SLE-accelerated cardiovascular disease (SACVD). Our laboratory recently developed a model of SLE-accelerated atherosclerosis. This model uses a triple congenic mouse model harboring three lupus susceptibility loci derived from the NZM2410 mouse strain. Each locus confers phenotypes associated with SLE pathogenesis. Sle1 is associated with chronic lymphocyte activation and anti-nuclear antibody production. Sle2 is mainly associated with B cell hyperactivity while Sle3 mediates CD4+ T and antigen presenting cell hyperactivity. While having one or two intervals leads to various phenotypes associated with SLE, mice with all three intervals display an SLE phenotype similar to human disease. We demonstrated that radiation chimeras of SLE-susceptible B6.Sle1.2.3 and low density lipoprotein receptor-deficient mice (LDLr.Sle1.2.3) have increased atherosclerosis, associated with increased T cell burden in lesions. In the current study, we take advantage of this mouse model in order to understand the mechanism of SACVD, specifically the role of T cells in mediating disease. Our data reveal that the increased atherogenesis observed in LDLr.Sle1.2.3 mice is independent of high fat diet feeding and that these mice have T cell phenotypes commonly observed in SLE patients. We find that transfer of individual lupus susceptibility loci associated with T cell hyperactivity (Sle1 and Sle3) is not sufficient to accelerate atherosclerosis; however, adoptive transfer of CD4+ T cells that contain all three lupus susceptibility loci into immunodeficient mice enhances atherogenesis. Moreover, we observe that an imbalance in regulatory and inflammatory T cell populations potentially contributes to disease pathogenesis. Taken together, our results indicate that T cells significantly contribute to SACVD and that their role is multifaceted. Furthermore, these studies enhance our scientific knowledge of how immune dysregulation mediates disease progression in autoimmunity and atherosclerosis and will hopefully facilitate the development of therapeutics designed to treat both diseases.