As probably most people know, COVID is associated with a number of complications including thrombosis but, more broadly speaking, endothelial cell dysfunction and blood vessel dysfunction leading to leaky blood vessels with release of plasma and fluid into spaces in the lung causing all kinds of problems. So there have been certainly suggestions that some of this might be caused by antibodies directed towards endothelial cells which cause them to be dysfunctional. So that is what we looked at.
We found, using cultured endothelial cells in a dish from human umbilical veins, that about 20% of the COVID IgG samples purified from patients with acute COVID, about 20% of these caused endothelial cell activation in this culture system. What that was characterised by was increased expression of cell adhesion molecules that allow inflammatory cells such as neutrophils, monocytes, to bind to the endothelial cell and possibly migrate across the endothelial cell layer. We also found that these endothelial cells expressed elevated levels of tissue factor which stimulates blood clotting and a protein called TMEM16F. We didn’t actually look at the protein, we looked at the RNA from the protein. TMEM is responsible for maintaining the surface of the endothelial cell in a certain structure such that there’s not negatively charged phospholipid on the cell surface. So when TMEM16 was upregulated it would suggest that there’s more negatively charged phospholipid material on the endothelial cell surface that would further promote coagulation.
We found that a lot of the IgG that was causing this, we haven’t fully characterised it yet but at least some of it was in the form of immune complexes which contain both the IgG as well as multiple components of the complement pathway that can cause further inflammation after an antibody binds to its target. So that’s where we sit right now and we continue to work on this.
What was the study design?
The study design, it’s not a clinical trial, it’s really an exploratory study, a mechanistic study. Basically we’re comparing these COVID IgG samples which we obtained through an NIH programme, and specifically through a collaborator, Dr Wolfram Ruf, we compared their effects on endothelial cells to the effects of IgG purified from normal healthy donors, most of which had been obtained prior to the onset of the COVID epidemic, so presumably patients who had not experienced COVID. So it was really a mechanistic hypothesis-generating study to basically define what are some of the things that cause disease to be so severe in COVID and might actually be applicable to other viral infections. I consider COVID to be something we would call a viral vasculopathy, basically meaning that the virus or residual of the virus causes the vascular to become dysfunctional. We think, at least in the studies we did, this was caused by IgGs from the patient that were, as far as we can tell, these complexes didn’t actually contain any virus.
So where we go from here will require more rigorous design but this abstract is mostly hypothesis generating and exploratory. I think we have evidence that auto-antibodies may be generated as a result of COVID infection and, whether they may affect or persist, things that happen after acute COVID has resolved remains to be determined.
