Circulating extracellular vesicles as potential biomarkers in CFS/ME: an exploratory pilot study

nanonug

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COMMENT: Wondering if these extracellular vesicles are that "something" that Ron Davis mentioned is different is the blood of people with SEID. Although the sample was small, the level of significance was pretty darn good.

https://www.tandfonline.com/doi/full/10.1080/20013078.2018.1453730

ABSTRACT
Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME) is an acquired, complex and multisystem condition of unknown etiology, no established diagnostic lab tests and no universally FDA-approved drugs for treatment. CFS/ME is characterised by unexplicable disabling fatigue and is often also associated with numerous core symptoms. A growing body of evidence suggests that extracellular vesicles (EVs) play a role in cell-to-cell communication, and are involved in both physiological and pathological processes. To date, no data on EV biology in CFS/ME are as yet available. The aim of this study was to isolate and characterise blood-derived EVs in CFS/ME. Blood samples were collected from 10 Spanish CFS/ME patients and 5 matched healthy controls (HCs), and EVs were isolated from the serum using a polymer-based method. Their protein cargo, size distribution and concentration were measured by Western blot and nanoparticle tracking analysis. Furthermore, EVs were detected using a lateral flow immunoassay based on biomarkers CD9 and CD63. We found 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). Circulating EVs could be an emerging tool for biomedical research in CFS/ME. These findings provide preliminary evidence that blood-derived EVs may distinguish CFS/ME patients from HCs. This will allow offer new opportunities and also may open a new door to identifying novel potential biomarkers and therapeutic approaches for the condition.

 

Gemini

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COMMENT: Wondering if these extracellular vesicles are that "something" that Ron Davis mentioned is different is the blood of people with SEID. Although the sample was small, the level of significance was pretty darn good.

https://www.tandfonline.com/doi/full/10.1080/20013078.2018.1453730
From the results section of the paper [my bold]:

...analysis of the EV protein content may differentiate between CFS/ME individuals and controls. The content of EVs has been reported to be higher in certain CNS disorders [16 Schindler SM, Little JP, Klegeris A. Microparticles: a new perspective in central nervous system disorders. Biomed Res Int. 2014;2014:1–17. [Google Scholar]], which may serve as a biomarker in the development of new diagnostic tools for early stages of CFS/ME. In our study, a significant abundance of blood-derived EVs in CFS/ME subjects was shown by a 1.5-fold increase on average compared to HC

Authors point out benefits...

Moreover, isolation of circulating EVs coupled to our prototype for their detection by LFIA may constitute a powerful diagnostic tool, which can be performed in a single step and in minutes.

Thanks for posting @nanonug!
 

Gemini

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The report from Dr. Davis said that the 'something' was protein-sized. Vesicles sound too big, but I really don't know.
You raise a very interesting question, @Wishful. From the paper:

In fact, several proteins such as heat shock proteins, integrins and tetraspanins can be found in all EVs [2 Mathivanan S, Ji H, Simpson RJ.

Heat shock proteins are found in ME/CFS. Perhaps @JaimeS can educate us and shed some light as to whether there's a connection to Dr. Davis' findings? Also give her assessment of this paper?
 

Wishful

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From what I recall of Dr. Davis' research, they filtered the serum, removing components too big to pass through (microbes, etc), and I assume they used a second filter to pass the smaller components out. The 'something' was in the middle, which held 'protein sized stuff'.

The vesicles might contain proteins associated with ME/CFS, but they're held in comparatively big containers (the vesicles), so they should have been filtered out.

My guess is that these extracellular vesicles will turn out to be a result of ME/CFS, not a cause. Whatever is messing up our cells might be increasing the chance of vesicles forming and separating.
 

CFS_for_19_years

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https://news.cornell.edu/stories/2017/09/94m-nih-grant-funds-chronic-fatigue-syndrome-center
The second project, led by Hanson, will compare the content of extracellular vesicles between individuals with ME/CFS and controls. Extracellular vesicles are membrane-surrounded structures that contain cargos of proteins, lipids, hormones and RNAs that can influence the functions of cells when they fuse with them. These vesicles are known to be released after exercise and could be involved in cell-to-cell signaling. Hanson and colleagues will examine the proteins, small molecules and RNA content of extracellular vesicles before and after exercise, to see if inflammatory signals from the vesicles could be contributing to disease symptoms.
http://neuroimmune.cornell.edu/research/vesicles-and-signaling/
(saying more or less the same thing as above)
By analyzing, in conjunction with physiological data, metabolites, circulating inflammatory molecules, and extracellular vesicle (EV) cargo in blood samples from before and after exercise sessions, we aim to uncover markers and mechanisms of post-exertional malaise in ME/CFS. Our broad survey of possible molecular responses to exercise will include inflammatory proteins and immunogenic mitochondrial DNA fragments, targeted and untargeted metabolomics of blood serum, and a detailed proteomic and metabolomic characterization of EVs. EVs are released into the circulation during exercise and could therefore contain biomarkers or contain cargo that plays an active role in mediating the abnormal response to physical activity in ME/CFS.
Long version of grant description:
http://grantome.com/grant/NIH/U54-NS105541-01-5841
 

nanonug

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The second project, led by Hanson, will compare the content of extracellular vesicles between individuals with ME/CFS and controls.
This is going to be exciting. If they are able to get the same kind of statistical significance achieved in this pilot study, the EVs will be indeed a great candidate for a marker. The only issue would be that of specificity (for SEID), then.
 
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This shows the size of the extracellular vesicles they found. The ones in MECFS patients are smaller. (nta = nanoparticle tracking analysis)

Screen Shot 2018-04-30 at 10.44.46 AM.png


From what I read there are two main kinds of extracellular vesicles produced by cells that are not dying. The paper notes that because our ones are small and packed with protein that suggests they are Exosomses, not the other, larger kind, known as microvesicles.

Screen Shot 2018-04-30 at 10.48.26 AM.png


ANother interesting thing I learned at that link above is that you can even detect extracellular vesicles in urine. So that could be a particularly low-impact way to collect a biomarker if these EVs do prove useful.
 

alex3619

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I wonder what volume of vesicles there are in healthy controls versus patients? They were smaller but more numerous. When factoring in volume how do they compare? We almost certainly have to wait for a study looking at this to find out.
 

Gemini

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@CFS_for_19_years so good to see Hanson involved. Thanks for posting the links.

Pilot researchers note how "easy" it is to isolate circulating EVs. It would be useful if the other 3 Research Centers picked up on it given how urgently we need a biomarker.

Besides the nanoneedle, Dr. Davis said he's looking at 3 other biomarkers. Anyone know if this is one of them or if he'd be interested in looking at it? @JaimeS ?

http://forums.phoenixrising.me/inde...r-in-massachussetts-6-minute-23-of-q-a.58998/
 
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