Serum of Post-COVID-19 Syndrome Patients with or without ME/CFS Differentially Affects Endothelial Cell Function In Vitro

Abstract

A proportion of COVID-19 reconvalescent patients develop post-COVID-19 syndrome (PCS) including a subgroup fulfilling diagnostic criteria of Myalgic encephalomyelitis/Chronic Fatigue Syndrome (PCS/CFS). Recently, endothelial dysfunction (ED) has been demonstrated in these patients, but the mechanisms remain elusive. Therefore, we investigated the effects of patients’ sera on endothelia cells (ECs) in vitro. PCS (n = 17), PCS/CFS (n = 13), and healthy controls (HC, n = 14) were screened for serum anti-endothelial cell autoantibodies (AECAs) and dysregulated cytokines. Serum-treated ECs were analysed for the induction of activation markers and the release of small molecules by flow cytometry. Moreover, the angiogenic potential of sera was measured in a tube formation assay. While only marginal differences between patient groups were observed for serum cytokines, AECA binding to ECs was significantly increased in PCS/CFS patients. Surprisingly, PCS and PCS/CFS sera reduced surface levels of several EC activation markers. PCS sera enhanced the release of molecules associated with vascular remodelling and significantly promoted angiogenesis in vitro compared to the PCS/CFS and HC groups. Additionally, sera from both patient cohorts induced the release of molecules involved in inhibition of nitric oxide-mediated endothelial relaxation. Overall, PCS and PCS/CFS patients′ sera differed in their AECA content and their functional effects on ECs, i.e., secretion profiles and angiogenic potential. We hypothesise a pro-angiogenic effect of PCS sera as a compensatory mechanism to ED which is absent in PCS/CFS patients.

Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity

“…These patients were referred to as PCS/ME/CFS and the others as PCS/non-ME/CFS ( 5 ). Mechanisms of PCS remain poorly understood, but some first evidence point to both immune and vascular dysregulation ( 8 – 13 ). Prothrombotic autoantibodies (AAB) against anti-phospholipid and anti-type I interferon were among the first to be described in acute COVID-19 patients ( 14 – 16 ).…”

Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses

“…Implications of endothelial damage have long ago been proposed as a component of ME/CFS pathology that drives symptom manifestation [ 170 ], but is only now starting to receive due attention. The idea of endothelial dysfunction driving ME/CFS seems more plausible after acknowledging such pathology in Long COVID [ 58 , 198 , 210 , [221] , [222] , [223] , 226 , 228 ]; not to mention the evidence of endothelial dysfunction in ME/CFS [ 24 , 45 , 166 , 209 , 210 , 229 , 233 , 236 , 335 ]. Further exploration of the vasculature, cardiac functioning, and coagulation system in ME/CFS is therefore warranted.…”

“…These are characteristics that can exaggerate any pathological impact on the endothelium. It is known that ME/CFS plasma induces endothelial dysfunction in healthy cells [ 209 , 210 ] – further analysis is required to determine if fibrinaloids are largely responsible for this phenomenon.…”

“…Similarly, another study that exposed ME/CFS sera to healthy endothelial cells reported the release of molecules that inhibit nitric oxide pathways, as well as the downregulation of endothelial activation markers [ 210 ]. The researchers also revealed an increase in autoantibody binding to endothelial surfaces in the ME/CFS group, which they sought to investigate due to evidence of autoimmunity in ME/CFS [ 230 ].…”

Efficacy of traditional Chinese exercises in patients with post-COVID-19 chronic fatigue syndrome: A protocol for systematic review and meta-analysis

“…[33] Since viral infections are frequently the cause of CFS, also since about 30% of individuals who don't fully recover from the acute phase of COVID-19 suffer from the condition known as the post-COVID-19 syndrome, which is characterized by fatigue intolerance, persistent fatigue, insomnia and anxiety. [34][35][36] TCEs are painless therapies inherited from China and have high safety. It has been proven in a randomized controlled trial that TCEs can relieve fatigue and insomnia in CFS, but no systematic review of TCEs for post-COVID-19 CFS is currently available.…”