Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome

Abstract

Objectives Patients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS. Methods We studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells (PBMCs) were scored for expression of IFN-responsive genes. Results Endothelial progenitors from APS patients demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of APS patients (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralizing antibody. Conclusions We describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.

In Vivo Role of Neutrophil Extracellular Traps in Antiphospholipid Antibody–Mediated Venous Thrombosis

“…In terms of DNase as a potential therapeutic, this has long been considered as a possibility in patients with SLE (42–44); however, it is unclear whether sufficient and durable plasma levels can be achieved with currently available preparations. As mechanisms of NETosis become better understood, it may be possible to use agents like peptidylarginine deiminase inhibitors or neutrophil elastase inhibitors to target the process of NETosis (45, 46), or possibly anti-interferon drugs to target the downstream effects of NETs (47). In summary, we suggest that neutrophils should continue to be explored as therapeutic targets in APS.…”

Activated signature of antiphospholipid syndrome neutrophils reveals potential therapeutic target

“…Interestingly, a number of the upregulated genes have already been defined as playing a role in APS, such as TLR4 (13), the complement component 5a receptor (47), protease-activated receptor 2 (48), and Fms-related tyrosine kinase 1 (FLT1, a receptor for vascular endothelial growth factor) (49). Furthermore, TLR and IFN-mediated signaling stood out in the meta-group analysis -both are receiving active attention in APS (50)(51)(52)(53).…”

Monocyte type I interferon signature in antiphospholipid syndrome is related to proinflammatory monocyte subsets, hydroxychloroquine and statin use

“…The IFN signature is associated with endothelial progenitor cells (EPC) dysfunction in SLE2 and the recent report by Grenn et al 3 provides evidence for this link in antiphospholipid syndrome (APS) as well.…”