The IMMENSE Study: The Interplay Between iMMune and ENdothelial Cells in Mediating Cardiovascular Risk in Systemic Lupus Erythematosus

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)-g 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.