Data_Sheet_1.DOCX

Abstract

Antiphospholipid syndrome (APS) is an autoimmune disorder that is 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 decreased synthesis and release of nitric oxide (NO). These endothelial alterations are a key component 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 having primary or secondary APS. Elucidation of the mechanisms underlying these endothelial 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 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 (NR+) obstetric APS. The expression of adhesion molecules; production of ROS, NO, vascular endothelial growth factor (VEGF), and endothelin-1; and generation of microparticles were used to evaluate endothelial activation and dysfunction. VTI IgG induced the expression of adhesion molecules and generation of microparticles and VEGF. RI+ IgG induced the expression of adhesion molecules and decreased NO production. RII+ IgG increased microparticle, ROS, and endothelin-1 production and reduced NO release. NR+ IgG increased microparticle and endothelin-1 production and decreased VEGF and NO production. 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.