Cardiovascular disease, the leading cause of death in the US, results from a chronic inflammatory disease called atherosclerosis. Autoimmune diseases (AD) including systemic lupus erythematosus (SLE) affect up to 8% of Americans. Pre-clinical and clinical evidence suggests that atherosclerosis and SLE are interrelated, with heavy involvement of the immune system in atherosclerosis and increased atherosclerosis risk in SLE patients. Regulatory B cells (Breg) suppress autoimmunity, like SLE, by inhibiting T cell-mediated inflammation through IL-10, an antiatherogenic cytokine. Evidence suggests that Breg in AD may be dysfunctional. We propose 2 aims to investigate Breg as a potential mechanistic link between AD and atherosclerosis.
In Aim 1, we will examine the function of Breg in B6.Sle1.2.3 mice (B6.Sle), a model of lupus-like disease. Preliminary data indicate that more B6.Sle Breg produce IL-10. Despite this, inflammation is increased and lupus-like disease persists, suggesting possible Breg dysfunction. We will examine Breg function by isolating Breg and T cells for coculture assays. Inflammatory cytokine production and proliferation by T cells will be examined to determine if the suppressive capacity of B6.Sle Breg is equal to B6 controls. In addition, expression of the IL- 10 receptor on B6.Sle T and B cells is increased. Given that suppression by Breg occurs through IL-10, a defect in the IL-10 pathway is possible. To explore this possibility, we will examine immune cells for phosphorylated Jak1, STAT1 and STAT3, all indicators of IL-10 pathway activation.
In Aim 2, we will examine the role of Breg in atherosclerosis and in lupus-accelerated atherosclerosis. We believe IL-10 production by Breg confers an atheroprotective role to Breg and that, in a setting of lupus, their ability to control atherosclerosis is reduced. To determine the role of Breg in atherosclerosis, we will transfer Breg from B6 and B6.Sle into LDLr-/- mice and evaluate atherosclerosis. To determine how Breg function in a setting of lupus and atherosclerosis, we will transfer Breg from B6 and B6.Sle into LDLr.Sle mice and evaluate atherosclerosis and AD. We will also be able to determine if B6 Breg can suppress autoimmunity and/or atherosclerosis in LDLr.Sle mice. Collectively, the proposed studies will allow us to determine the role of Breg in two disease processes, atherosclerosis and AD, providing an important step towards understanding how atherosclerosis and AD are related.
Cardiovascular disease (CVD) is the leading cause of death in the US and patients suffering from autoimmune diseases such as systemic lupus erythematosus (SLE) have an increased risk of CVD and myocardial infarction (MI). While this is a significant health problem, the mechanism behind accelerated atherosclerosis in SLE is unclear. In this proposal, we will test the hypothesis that Breg play an important role in both autoimmunity and atherosclerosis and that dysfunction in Breg from autoimmune mice results in a reduced ability of these cells to suppress T cell-mediated inflammation, along with reduced ability to control atherosclerosis.
|Wilhelm, Ashley J; Rhoads, Jillian P; Wade, Nekeithia S et al. (2015) Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/- mice. Ann Rheum Dis 74:778-85|
|Covarrubias, Roman; Wilhelm, Ashley J; Major, Amy S (2014) Specific deletion of LDL receptor-related protein on macrophages has skewed in vivo effects on cytokine production by invariant natural killer T cells. PLoS One 9:e102236|