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Published on: November 4, 2016
CD4+CXCR3+ T cells and plasmacytoid dendritic cells drive accelerated atherosclerosis associated with systemic lupus
Marc Clement1, Nicolas Charles2, Brigitte Escoubet3
1INSERM U1148, Université Paris Diderot, PRES Sorbonne Paris Cité, Paris, France.
Insights
Systemic lupus erythematosus (SLE) accelerates atherosclerosis, a leading cause of death, through immune dysfunction. This study proposes a model linking SLE-related immune responses to T cell recruitment and arterial wall inflammation, suggesting new therapeutic targets.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Rheumatology
Background:
- Cardiovascular disease (CVD) from accelerated atherosclerosis is the primary cause of mortality in Systemic Lupus Erythematosus (SLE) patients.
- Accelerated atherosclerosis in SLE is often independent of traditional Framingham risk factors, suggesting unique underlying mechanisms.
- The precise pathways driving accelerated atherosclerosis in SLE remain incompletely understood.
Purpose of the Study:
- To propose a multi-step model elucidating the mechanisms by which SLE-associated immune dysfunction contributes to accelerated atherosclerosis.
- To identify potential therapeutic targets for mitigating atherosclerosis in SLE patients.
Main Methods:
- Utilized experimental data from human SLE patients, control subjects, and ApoE-/- mice.
- Proposed a model integrating immune dysfunction (IFN-α production by TLR9-stimulated pDCs) with key steps in atherogenesis.
Main Results:
- SLE-associated immune dysfunction leads to increased circulating pro-inflammatory CD4+CXCR3+ T cells.
- Endothelial cells increase CXCR3 ligand production, promoting T cell recruitment into the arterial wall.
- This process culminates in the development of atherosclerosis.
Conclusions:
- The proposed model provides a framework for understanding how SLE promotes accelerated atherosclerosis.
- Interventions targeting plasmacytoid dendritic cells (pDCs) or related pathways may offer future therapeutic strategies for SLE-associated CVD.
Abstract:
Cardiovascular disease due to accelerated atherosclerosis is the leading cause of death in patients with systemic lupus erythematosus (SLE). Noteworthy, accelerated atherosclerosis in SLE patients appears to be independant of classical Framingham risk factors. This suggests that aggravated atherosclerosis in SLE patients may be a result of increased inflammation and altered immune responses. However, the mechanisms that mediate the acceleration of atherosclerosis in SLE remain elusive. Based on experimental data which includes both humans (SLE patients and control subjects) and rodents (ApoE-/- mice), we herein propose a multi-step model in which the immune dysfunction associated with SLE (i.e. high level of IFN-α production by TLR 9-stimulated pDCs) is associated with, first, an increased frequency of circulating pro inflammatory CD4+CXCR3+ T cells; second, an increased production of CXCR3 ligands by endothelial cells; third, an increased recruitment of pro-inflammatory CD4+CXCR3+ T cells into the arterial wall, and fourth, the development of atherosclerosis. In showing how SLE may promote accelerated atherosclerosis, our model also points to hypotheses for potential interventions, such as pDCs-targeted therapy, that might be studied in the future.
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