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Inflammation and COVID-19: the HLA-G immune checkpoint under surveillance

In a study published in Viruses, a team of researchers from SRHI and the University of Ferrara (Italy) showed that the soluble form of HLA-G may contribute significant anti-inflammatory properties via its role in controlling the adhesion of neutrophils to endothelial cells and thus improve disease outcome in patients with COVID-19. 

Published on 11 January 2022

In late 2019, COVID-19 became pandemic, spreading across the globe and causing more than 370 million cases and 5.6 million deaths as of the beginning of February 2022  (1). This disease results from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and manifests as a range of more or less severe symptoms. In mild forms of COVID-19, these symptoms include fever, coughing, fatigue and a loss of taste (ageusia) and smell (anosmia). In its severe forms, the disease is associated with acute respiratory distress, multi-organ failure and resultantly very poor prognosis.

Intense research has brought great progress to the understanding of the mechanisms underlying COVID-19's clinical manifestations. For example, it has been shown that the activation of endothelial cells (those lining the blood vessels) plays a central role in the pathogenesis of respiratory distress and multi-organ failure in patients with COVID-19  (2,3). In patients with severe COVID-19, that endothelial activation contributes to an increased infiltration of immature and/or defective neutrophils into the tissues (notably those of the lungs), which, in turn, may provoke an overly strong inflammatory response called a "cytokine storm." However, the molecular mechanisms specific to that endothelial activation are currently poorly identified.

HLA-G is a protein most-widely known for its role in maternal-fetal tolerance and inflammatory & infectious responses. It does however also have antiangiogenic properties mediated by its interaction with the CD160 receptor expressed by endothelial cells. Specifically, the interaction between HLA-G and CD160 induces apoptosis in endothelial cells, inhibiting angiogenesis (the formation of new blood vessels) via the negative regulation of fibroblast growth factor 2 (FGF2). Moreover, HLA-G is also a powerful inhibitor of neutrophil adhesion to endothelial cells.

It was thus in this setting that the Immuno-Hematology Research Unit (SRHI), contributed its 30-plus years of knowledge on the HLA-G protein (4), to a collaborative work carried out with the University of Ferrara in Italy. In its study, published in Viruses, the team set its sights on understanding the immune and inflammatory mechanisms of these clinical manifestations of COVID-19 to empower the identification of potential therapeutic targets. The work was the first to show that hospitalized COVID-19 patients with respiratory failure had higher levels of soluble HLA-G (sHLA-G) in their plasma samples than did control patients who were either healthy or hospitalized with respiratory failure unrelated to COVID-19. Also, the team observed a correlation between those elevated sHLA-G levels and favorable disease outcome.

To investigate any link between sHLA-G and endothelial cell activation, the researchers studied two biomarkers involved in the latter: E-selectin and ICAM-1. These two proteins participate in the adhesion of neutrophils to endothelial cells, easing their passage into the tissues during inflammatory responses.

That investigation showed that the plasma level of sHLA-G was inversely correlated with those of ICAM-1 and E-selectin in patients with COVID-19.

In vitro experiments on activated (by inflammatory cytokines) endothelial cells confirmed sHLA-G's ability, via its interaction with CD160, to diminish ICAM-1 and E-selectin expression. The team noted that the efficacy of the reduction of neutrophil adhesion to endothelial cells was comparable to that obtained by the use of anti-ICAM-1 or anti-E-selectin antibodies in the same in vitro model.

Similar results were obtained in plasma samples taken from patients recovering well from COVID-19 and presenting high levels of sHLA-G. The inhibition of neutrophil adhesion obtained in the plasma from those COVID-19 patients was significantly reduced by the use of anti-CD160 antibodies, suggesting a role for the sHLA-G/CD160 interaction in the regulation of neutrophil-endothelial cell adhesion. By diminishing the expression of the ICAM-1 and E-selectin adhesion factors in endothelial cells, fewer neutrophils attach to and pass through the layer to the tissues and thus the risk of harmful inflammatory reactions is diminished.

In sum, the results provided by the Franco-Italian team suggest that soluble HLA-G may have significant anti-inflammatory properties. The protein appears to control the adhesion of neutrophils to activated endothelium, an action which, in the setting of COVID-19, appears to improve disease outcomes. It is therefore possible that high blood sHLA-G may be a novel biomarker of good prognosis for patients with that disease. Further research is needed to assess the mechanisms by which HLA-G controls ICAM-1 and E-selectin expression in activated endothelial cells and how it acts upon neutrophil adhesion

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