Abstract
Patients with systemic lupus erythematosus (SLE) have a significant increase in cardiovascular (CV) risk although they display a preserved number of circulating angiogenic CD3+CD31+CXCR4+ T cells (Tang), a subpopulation of T cells which promotes repair of damaged endothelium. This happens due to the concomitant expansion of a Tang subset with immunosenescent features, such as the loss of CD28. Therefore, the aim of this study was to elucidate the interplay between Tang subpopulations and endothelial cells in a group of young SLE patients without previous cardiovascular events. Twenty SLE female patients and 10 healthy controls (HCs) were recruited. Flow cytometric analysis of endothelial progenitor cells (EPCs) and Tang subsets were performed and serum levels of interleukin (IL)-6, -8, matrix metalloproteinase (MMP)-9 and interferon (IFN)-γ were measured. Human umbilical vein endothelial cells (HUVECs) proliferation and pro-inflammatory phenotype in response to subjects’ serum stimulation were also evaluated. Results showed that the percentage of Tang and EPC subsets was reduced in SLE patients compared with HCs, with a marked increase of senescent CD28null cells among Tang subset. SLE disease activity index-2000 (SLEDAI-2K) was inversed related to Tang cells percentage. Furthermore, IL-8 serum levels were directly correlated with the percentage of Tang and inversely related to the CD28null Tang subsets. We indirectly evaluated the role of the Tang subset on the endothelium upon stimulation with serum from subjects with a low percentage of Tang CD3+ cells in HUVECs. HUVECs displayed pro-inflammatory phenotype with up-regulation of mRNA for IL-6, intercellular adhesion molecule (ICAM)-1 and endothelial leukocyte adhesion molecule (ELAM)-1. Cell proliferation rate was directly related to IL-8 serum levels and EPC percentage. In highly selected young SLE patients without previous CV events, we found that the deterioration of Tang compartment is an early event in disease course, preceding the development of an overt cardiovascular disease and potentially mediated by SLE-specific mechanisms. The overcome of the CD28null subset exerts detrimental role over the Tang phenotype, where Tang could exert an anti-inflammatory effect on endothelial cells and might orchestrate via IL-8 the function of EPCs, ultimately modulating endothelial proliferation rate.
Highlights
Systemic lupus erythematosus (SLE) is a polymorphic systemic autoimmune disease, burdened by a significant cardiovascular (CV) risk [1,2,3]
Since anti-phospholipid antibodies (aPL) antibodies are additional CV risk-factors, we investigated the percentage of angiogenic T cell (Tang) and endothelial progenitor cells (EPCs) among SLE patients positive for aPL; our analysis showed that there was no significant difference in the percentage of circulating Tang and EPC subpopulations
This work further unveils the complex interplay between Tang and EPC subsets, even though we acknowledge that future studies exploiting more sophisticated experimental approaches are needed to gain mechanistic insights into the crosstalk between Tang and endothelial cells
Summary
Systemic lupus erythematosus (SLE) is a polymorphic systemic autoimmune disease, burdened by a significant cardiovascular (CV) risk [1,2,3]. The overall prevalence of vascular events ranges between 10 and 30%, with a 50-fold higher risk of myocardial infarction among young lupus women compared to age-matched controls [4]. The presence of anti-phospholipid antibodies (aPL) represents an additional CV risk-factor in patients with SLE, as aPL trigger thrombotic events and exert a direct role in the atherosclerotic process via the induction of endothelial activation [9]. Given such important vascular morbidity and mortality, it is essential to investigate the mechanisms responsible for the increased CV burden in SLE
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