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 (T_ang), a subpopulation of T cells which promotes repair of damaged endothelium. This happens due to the concomitant expansion of a T_ang subset with immunosenescent features, such as the loss of CD28. Therefore, the aim of this study was to elucidate the interplay between T_ang 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 T_ang 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 T_ang and EPC subsets was reduced in SLE patients compared with HCs, with a marked increase of senescent CD28^null cells among T_ang subset. SLE disease activity index-2000 (SLEDAI-2K) was inversed related to T_ang cells percentage. Furthermore, IL-8 serum levels were directly correlated with the percentage of T_ang and inversely related to the CD28^null T_ang subsets. We indirectly evaluated the role of the T_ang subset on the endothelium upon stimulation with serum from subjects with a low percentage of T_ang 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 T_ang 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 CD28^null subset exerts detrimental role over the T_ang phenotype, where T_ang could exert an anti-inflammatory effect on endothelial cells and might orchestrate via IL-8 the function of EPCs, ultimately modulating endothelial proliferation rate.