Endothelial Cell–Activating Antibodies in COVID‐19

Abstract

Objective While endothelial dysfunction has been implicated in the widespread thrombo‐inflammatory complications of coronavirus disease‐19 ( COVID‐19 ), the upstream mediators of endotheliopathy remain for the most part cryptic. Our aim was to identify circulating factors contributing to endothelial cell activation and dysfunction in COVID‐19. Methods Human endothelial cells were cultured in the presence of serum or plasma from 244 patients hospitalized with COVID‐19 and plasma from 100 patients with non‐COVID sepsis. Cell adhesion molecules (E‐selectin, VCAM‐1, and ICAM‐1) were quantified by in‐cell ELISA. Results Serum and plasma from patients with COVID‐19 increased surface expression of cell adhesion molecules. Furthermore, levels of soluble ICAM‐1 and E‐selectin were elevated in patient serum and tracked with disease severity. The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID‐19 serum to activate endothelium. Depletion of total IgG from antiphospholipid antibody‐positive serum markedly restrained upregulation of cell adhesion molecules. Conversely, supplementation of control serum with patient IgG was sufficient to trigger endothelial activation. Conclusion These data are the first to suggest that some patients with COVID‐19 have potentially diverse antibodies that drive endotheliopathy, adding important context regarding thrombo‐inflammatory effects of autoantibodies in severe COVID‐19.

Mediators of Obesity Do Not Influence SARS-CoV-2 Infection or Activation of Primary Human Lung Microvascular Endothelial Cells In Vitro

“…In line with these findings, we found that incubation of endothelial cells with COVID-19 patient plasma containing a mixture of cytokines including IFNa, adipokines and other mediators did not alter ACE2 expression and also not result in endothelial activation. In contrast to our findings, a recent study by Shi et al using serum from a large cohort of COVID-19 patients found that the surface expression of E-selectin, VCAM-1 and ICAM-1 were around 2, 4 and 3-fold increase in HUVEC compared to control serum (40). However, the response of the serum on endothelial cells was very heterogenic with a large sub-population of patient samples not inducing endothelial activation.…”

“…In contrast to our findings, a recent study by Shi et al. using serum from a large cohort of COVID-19 patients found that the surface expression of E-selectin, VCAM-1 and ICAM-1 were around 2, 4 and 3-fold increase in HUVEC compared to control serum ( 40 ). However, the response of the serum on endothelial cells was very heterogenic with a large sub-population of patient samples not inducing endothelial activation.…”

“…However, the response of the serum on endothelial cells was very heterogenic with a large sub-population of patient samples not inducing endothelial activation. We used plasma and flow cytometry to determine the surface expression of the endothelial activation markers, whereas Shi et al., used serum and quantified the expression of surface endothelial markers using in-cell ELISA ( 40 ). These distinct techniques may account for the differences found between these studies.…”

Persistent Antiphospholipid Antibodies Are Not Associated With Worse Clinical Outcomes in a Prospective Cohort of Hospitalised Patients With SARS-CoV-2 Infection

“…In addition, injection of IgG purified from COVID-19 patients accelerated venous thrombosis in two mouse models ( 15 ). Recently, the same group found that serum samples from COVID-19 hospitalised patients were able to activate endothelial cells compared with those of sepsis patients and healthy controls ( 22 ). Interestingly, aCL and aPS/PT from COVID-19 patients strongly correlated with markers of endothelial cell activation and modestly with those of NETs/thrombo-inflammation including C-reactive protein, D-dimer and calprotectin ( 22 ).…”

COVID-19-induced latent relapsing hypercoagulable state in the absence of persistent viral infection

“… 11 Recent data have also suggested that some patients with severe COVID-19 may develop diverse autoantibodies that activate the endothelium, driving endotheliopathy and thrombo-inflammatory effects. 12 According to this theory, it is possible that discontinuation of IV steroids after 8 days of treatment may have allowed the inflammatory process to rebound, leading to endothelial reactivation and recurrent thrombi formation. Interestingly, the tPA therapy did not help improve respiratory function in the long run, as shown in a case series by Wang et al 13 Furthermore, data have shown that the use of anti-IL-6 therapy has risks of secondary bacterial and viral infections, delayed viral clearance, and reinfection from the COVID-19 virus, 14 but, in the above clinical setting, we decided to go for the anti-IL-6 therapy for the second time to control the inflammatory surge.…”