Cytokine signature associated with disease severity in chronic fatigue syndrome patients, 2017, Montoya et al

Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Jose G Montoya, Tyson H Holmes, Jill N Anderson, Holden T Maecker, Yael Rosenberg-Hasson, Ian J Valencia, Lily Chu, Jarred W Younger, Cristina M Tato, Mark M Davis

Published: July 31, 2017

[Line breaks added]

Significance
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) devastates the lives of millions of people and has remained a mystery illness despite decades of research. It has long been suspected that inflammation is central to its pathogenesis.

Although only two cytokines were found to be different (TGF-β higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity. Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years. Only CXCL9 (MIG) inversely correlated with fatigue duration.

Abstract
Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible.

To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding.

On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls.

Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α.

Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

Link | PDF (PNAS) [Open Access]

 

Links on PMC page for this study:

See letter "Cytokine signature in chronic fatigue syndrome" on page E9435.

See "Reply to Roerink et al: Methods for recruitment, serum separation, and storage were the same for patients and controls" on page E9436.

See "PNAS Plus Significance Statements" on page 8923.

See commentary "Inflammation correlates with symptoms in chronic fatigue syndrome" on page 8914.

 

Was this ever replicated or followed up on?

Apologies for confusingly quoting it, brain fogged today and my formatting is suffering

 

The paper mentions that TGF-B was elevated in 5 of 8 previous studies. From memory this is the largest study to date. So in a way it replicates previous findings. It is my understanding that there have been efforts to do a follow up and larger cohort cytokine study with disease comparisons and updated technology, for example 71 PLEX, but there has been no funding for that one despite having collected samples.

 

That is absolutely criminal. If that follow up had been done we might have had a head start on understanding ME and therefore long covid by 2020.

 

Ah there mustn't have been a thread for this afterall. The paper stood out to me yesterday and I couldn't find a thread for it (when I made the other post about cytokines, I did indeed have this paper in mind)

 

Dr Jose Montoya presented the results at the 2017 CMRC conference - see video starting at 16:36

https://www.youtube.com/watch?v=CgAxsHn9njA

He spends some time discussing the upwards trends of a subset of cytokines. i.e. those cytokines that increase with severity.

 

There is a post on PR here for this paper if you are interested in peoples thoughts on it. It was published before s4me existed and has some comments by people who now post on s4me.

 

thanks, I didn't know PR pre-dated s4me. I had actually forgotten about it since I haven't really looked there very much

 

It is somewhat nostalgic to see that PR thread, with most of the posters being those us who moved camp because you were not allowed to use the word 'quack' there. Looking at the profile of cytokines I think it makes quite good sense in the context of what has panned out since. I think at the time I was a bit sceptical that the study methodology was robust but it may stile the best picture we have.

 

If this replicates previous findings and gels with the emerging picture as @Jonathan Edwards says, is there a way to get the ball rolling on the larger cohort cytokine study? Is it something patients could crowdfund? What about charities? Or wealthy donors?

It seems like it could be important and there are I believe TGF-B inhibitors that could be trialed, not to mention other drugs that target some of these cytokines (at least I assume so). Or perhaps it would tell us something vital or just finally be a solid puzzle piece to point the way.

 

There is a paper this week on here looking at tgf-b inhibitors when people catch covid. So yeah it gives that sense if that has any effect on LC or indeed on covid itself and how people fare with that

 

Good spot! Almost needs its own post (but with that twist added into the thread title)

 

I'd just like to bump my question from a few days back considering possible tgf-beta link in the fibro paper from today and general tgf b talk that's going on atm.

To put it more clearly than I did above, is there a way of pushing for a larger cytokine study that could replicate this paper, if as @wigglethemouse says there are already samples that have been collected? Either by lobbying institutions for funding or, if its not prohibitively expensive, charities patients and wealthy donors?

If there's already an effort going on I'd be really interested to hear that.

 

There have already been several studies looking at TGF-beta, so the question would be what could such a study achieve? I'm not sure how much simply being larger would accomplish as the study is already relatively large. In the above paper they only report the mean values. Perhaps someone that has access to the data can plot it so have a better look at how things look like. Even with the rather large sample sizes, it might still be interesting to ensure that things aren't just driven by a handful of outliers on either side of the spectrum. Perhaps then it will be easier to know whether or not a larger study makes sense.

Elevated TGF-beta seems to be one of the most consistent findings, but there have also been some negative results. There have also been studies looking at TGF-beta before and after exercise. Perhaps it makes sense to have a look at what has already been done. The above authors are also all still working in the ME/CFS fields. Perhaps it would be sensible to know why they don't seem to be following the TGF-beta story any longer? Did the results not paint a sensible picture or were there negative (unpublished) replication attempts? In a slightly larger study, by largely the same authors, it seems the results for TGF-beta are negative (https://www.science.org/doi/full/10.1126/sciadv.1400121)?

Before looking at a replication perhaps the question would be, what could slightly elevated circulating cytokines even tell you about ME/CFS?