Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers...ME/CFS 2019, Eguchi et al

This is what the UK Cure ME team had to say about CRP in the discussion section of their paper

Source : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627354/

 

To be fair they don't state that it's helpful, they state that it has an 'impact' - which it does, a negative impact.

Depressing that they keep saying that depression is a symptom isn't it.

 

Protein containing EVs correlating with CRP does not necessarily mean that CRP is elevated. Its often not as we know. But if EV is elevated, and it further correlates with CRP so that those who do have high CRP have very high EV, then the correlation is maintained. If this is more likely in more severe patients, as suggested in one comment, then this is even more interesting. For those looking into the biochemistry, what impact might these proteins have from the established science?

 

With a bit of googling, supplementary materials :





and






and



and

 

https://en.m.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway

I have a low platelet count.

 

A question I have is why would there be EVs containing proteins that have to do with the actin cytoskeleton and focal adhesions, and what does that have do with ME/CFS?

Reading up on the function of these proteins, one thing that might fit with some of the ME/CFS theories is altered cell deformability.

Why would the body try to make its cells stiffer? I think that might have to do with defense against pathogens.

 

I am very severe, my CRP and ESR are non existent.

 

And/or, what are the consequences if a disease process makes them stiffer?

 

The CureME finding jives with this. They say CRP is higher mainly in mild-moderate patients, meaning severe patients would be expected to have lower CRP on average than mild-moderate patients. I'm not sure that makes this a good biomarker, but it's maybe one to watch.

 

This paper specifies skeletal muscle. Maybe the Australians were on to something with the calcium channelopathy theory. But the tie to EV escapes me. Are EVs remnants or blebs from skeletal muscle cells?

 

Reading the paper as a whole I am not very impressed. The introduction, discussion and data presentation do not have the ring of people with a deep understanding of the problem. There is no mention of blinding of samples and the way repeated cohorts have been used does not look to have been done in a way to ensure bias is avoided.

My thought is that extracellular vesicles of this sort are basically cell debris - bits of those cells that have fallen apart. The most likely cells to fall apart and give rise to vesicles in venous blood are neutrophils. I think there may be a sample handling problem that might produce systematic bias. It is also quite possible that the different patterns of activity that occur in PWME have an effect on the number of senescent neutrophils in plasma.

The number of vesicles certainly does not give a diagnostic test since there is major overlap. Most ME patients fell within a normal range constructed from controls. The data on specific proteins looks limited and I suspect was not repeated on a second test cohort.

 

Yes, I cannot see how you can get a meaningful correlation out of that plot.

 

do we know the male/ female split in this?
has the analysis been done separately re male/ females
given that we know there are differences in metabolism and expression (and the one non heriditary gene found by Chris Ponting was females only) could this be relevant?

 

No, there is no information on that (that I found).

 

I also thought the study is a bit confusing.

They start by comparing the number of circulating extracellular vesicles (EV) in several samples of ME/CFS patients compared to healthy controls. That's where they report a clear differentiation with a Area under ROC curve of 0.8.

But when they looked at ME/CFS patients versus patients with depression or idiopatic chronic fatigue there was no longer a significant difference (perhaps the sample size was too small?). So they go on to focus on the proteins within these vesicles that differ in ME/CFS versus these controls. But there are so many of these proteins its difficult what to make of this. They should probably specifiy the ones they think are abnormal and test these in another, larger sample.

 

I think there are now three groups looking at these extracellular vesicles in ME/CFS.

A Spanish group published a study about this last year (Castro-Marrero et al.) Their study was preliminary as the sample size was really small; 10 ME/CFS patients and 5 healthy controls. They reported that "the amount of EV-enriched fraction was significantly higher in CFS/ME subjects than in HCs (p = 0.007) and that EVs were significantly smaller in CFS/ME patients (p = 0.014)." https://www.ncbi.nlm.nih.gov/pubmed/29696075

Then there's Maureen Hanson's group at Cornell University. They haven't published yet but I think that in her talk at the OMF symposium in September, Hans said that there was no difference in the amount of extracellular vesicles between patients and controls but that the former did have more of the small ones. I think she also reported that cytokine associations differ in EV's of ME/CFS patients and EV's of controls.

Then there's this Japanese group. They seem to report a higher number of circulating EV's in ME/CFS patients compared to healthy controls but not compared to their small sample of patients with depression and idiopathic fatigue. They have also found some differences in the proteins EV's contain in ME/CFS and control groups. I don't think that they have confirmed that there are more small EV's in ME/CFS patients compared to controls. https://www.sciencedirect.com/science/article/pii/S0889159119307627

 

This is what it says