Differences in Endothelial Activation and Dysfunction Induced by Antiphospholipid Antibodies Among Groups of Patients With Thrombotic, Refractory, and Non-refractory Antiphospholipid Syndrome

Abstract

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by pregnancy morbidity or thrombosis and persistent antiphospholipid antibodies (aPL) that bind to the endothelium and induce endothelial activation, which is evidenced by the expression of adhesion molecules and the production of reactive oxygen species (ROS) and subsequent endothelial dysfunction marked by a decrease in the synthesis and release of nitric oxide (NO). These endothelial alterations are the key components for the development of severe pathological processes in APS. Patients with APS can be grouped according to the presence of other autoimmune diseases (secondary APS), thrombosis alone (thrombotic APS), pregnancy morbidity (obstetric APS), and refractoriness to conventional treatment regimens (refractory APS). Typically, patients with severe and refractory obstetric APS exhibit thrombosis and are classified as those having primary or secondary APS. The elucidation of the mechanisms underlying these alterations according to the different groups of patients with APS could help establish new therapies, particularly necessary for severe and refractory cases. Therefore, this study aimed to evaluate the differences in endothelial activation and dysfunction induced by aPL between patients with refractory obstetric APS and other APS clinical manifestations. Human umbilical vein endothelial cells (HUVECs) were stimulated with polyclonal immunoglobulin-G (IgG) from different groups of patients n = 21), including those with primary (VTI) and secondary thrombotic APS (VTII) and refractory primary (RI+), refractory secondary (RII+), and non-refractory primary (NR+) obstetric APS. All of them with thrombosis. The expression of adhesion molecules; the production of ROS, NO, vascular endothelial growth factor (VEGF), and endothelin-1; and the generation of microparticles were used to evaluate endothelial activation and dysfunction. VTI IgG induced the expression of adhesion molecules and the generation of microparticles and VEGF. RI+ IgG induced the expression of adhesion molecules and decreased NO production. RII+ IgG increased the production of microparticles, ROS, and endothelin-1 and reduced NO release. NR+ IgG increased the production of microparticles and endothelin-1 and decreased the production of VEGF and NO. These findings reveal differences in endothelial activation and dysfunction among groups of patients with APS, which should be considered in future studies to evaluate new therapies, especially in refractory cases.

Asymmetric Dimethylarginine Is a Marker of Endothelial Dysfunction in Thrombotic Antiphospholipid Syndrome Patients

“…The role of NO is also the inhibition of platelet adhesion and aggregation, leukocyte adhesion and migration, and smooth muscle proliferation. Therefore, the impairment of NO production leads towards a prothrombotic phenotype [ 30 ]. In PAPS patients, aCL antibody titers inversely correlate with urinary NO levels.…”

An update on inflammation in antiphospholipid syndrome

“…Another collection of recent studies evaluated endothelial activation and dysfunction in cultured endothelial cells exposed to various serum factors from APS patients [33 ▪▪ ,34,35]. One study found that IgG isolated from patients with different disease phenotypes (primary APS, secondary APS, APS refractory to treatment, and obstetric APS) resulted in the differential expression of markers related to endothelial activation and dysfunction [33 ▪▪ ]. For example, polyclonal IgG from refractory APS patients increased the production of microparticles, reactive oxygen species (ROS), and endothelin-1 while reducing nitric oxide production.…”

In Vitro Assessment of Poly-N-Vinylpyrrolidone/Acrylic Acid Nanoparticles Biocompatibility in a Microvascular Endothelium Model

“…These changes lead to a reduction in vascular integrity, an increase in the expression of adhesion molecules and cytokine production propagating inflammation, and an enhancement of human leukocyte antigen (HLA) molecules [ 31 ]. The increase of adhesion molecules, including ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), and E-Selectin, facilitates the adherence of leukocytes on the endothelium and their subsequent transmigration to the sub-endothelium [ 32 , 33 ]. In addition, the production of cytokines, including interleukins and tumor necrosis factors, regulates the immune response [ 31 , 33 ].…”

“…The increase of adhesion molecules, including ICAM-1 (intercellular adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1), and E-Selectin, facilitates the adherence of leukocytes on the endothelium and their subsequent transmigration to the sub-endothelium [ 32 , 33 ]. In addition, the production of cytokines, including interleukins and tumor necrosis factors, regulates the immune response [ 31 , 33 ]. The above enhances the risk of thrombocytic events [ 33 ].…”

“…In addition, the production of cytokines, including interleukins and tumor necrosis factors, regulates the immune response [ 31 , 33 ]. The above enhances the risk of thrombocytic events [ 33 ]. Therefore, a thorough investigation of nanoparticles with the endothelium is an obligatory step in NPs’ biocompatibility evaluation.…”