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Chronic fatigue syndrome and circulating cytokines: a systematic review

JaimeS

Senior Member
Messages
3,408
Location
Silicon Valley, CA
Chronic fatigue syndrome and circulating cytokines: a systematic review
Abstract:

Highlights

Circulating TGF was raised in CFS versus controls in most studies when measured.


No overall differences were found for any other cytokines.


There were no overall differences in cytokine concentrations after exercise.


The quality of studies published was variable and often limited.

Abstract
There has been much interest in the role of the immune system in the pathophysiology of chronic fatigue syndrome (CFS), as CFS may develop following an infection and cytokines are known to induce acute sickness behaviour, with similar symptoms to CFS. Using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a search was conducted on PubMed, Web of Science, Embase and PsycINFO, for CFS related-terms in combination with cytokine-related terms. Cases had to meet established criteria for CFS and be compared with healthy controls. Papers retrieved were assessed for both inclusionary criteria and quality. 38 papers met the inclusionary criteria. The quality of the studies varied. 77 serum or plasma cytokines were measured without immune stimulation. Cases of CFS had significantly elevated concentrations of Transforming Growth Factor-beta (TGF-) in five out of eight (63%) studies. No other cytokines were present in abnormal concentrations in the majority of studies, although insufficient data were available for some cytokines. Following physical exercise there were no differences in circulating cytokine levels between cases and controls and exercise made no difference to already elevated TGF-β concentrations. The finding of elevated TGF-β concentration, at biologically relevant levels, needs further exploration, but circulating cytokines do not seem to explain the core characteristic of post-exertional fatigue.

Keywords
  • Chronic fatigue syndrome;
  • Myalgic encephalomyelitis;
  • Cytokine;
  • Chemokine;
  • Transforming growth factor-beta;
  • Immune system;
  • Pathophysiology;
  • Systematic review
Corresponding author.
Copyright © 2015 Published by Elsevier Inc.
 

JaimeS

Senior Member
Messages
3,408
Location
Silicon Valley, CA
Did they not read the Lipkin paper? Early and late stage ME cytokine findings cancel each other out if you just combine groups without regard for duration of illness.

I've heard about P.D. White before. Is he part of the psychosomatic camp?

Also, it seems ridiculous that they put this review together and lumped early sufferers and later patients together like that. It's not sensible, given the data available....

-J
 

JaimeS

Senior Member
Messages
3,408
Location
Silicon Valley, CA
I really don't like that this seems to have been written in a direct attempt to refute Hornig's study. Doctors without a lot of time will scan this and think, "ah, I knew that was all bunk". I wish there were some magic that would make people less intellectually lazy!

In the past, I would have said 'education' was that magic, but it's really the quality of the education, not its quantity, that matters. I'm sure these guys consider themselves very learned men.
 
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worldbackwards

Senior Member
Messages
2,051
I really don't like that this seems to have been written in a direct attempt to refute Hornig's study.
It feels cheap and cynical, as much of his stuff does. But it's interesting to compare his reaction to the changing situation (denial, obfuscation, sabotage) with Wessely's (equivocation, positioning).

Of course Wessely is the consummate politician and, perhaps most importantly, has his main career outside CFS research these days - he just needs to keep on the right side of things now and, such was his ambiguous postion, no-one will much notice if he was wrong before. You can be sure no-one will pay any attention to our howls of protest.

Whereas White is absolutely embedded in CFS still - it's where he makes his money, both as a researcher and a "consultant". I suspect he won't go down without a fight and watching the death of his career in the aftermath won't be pretty.

Popcorn anyone? (accounting for allergies, obviously)
 
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Sidereal

Senior Member
Messages
4,856
I'm wading through the paper.

The possible biological significance of a raised TGF-β in CFS is unknown, but comparison with concentrations found in other conditions may be instructive. The mean/median elevations of TFG-β observed in all 5 “positive” papers were greater than 30 pg/ml and some were reported as high as 1ng/ml (table 5). In cancer studies, serum levels of TGF-β greater than 30pg/ml are associated with more aggressive disease and at 80pg/ml has prognostic significance (Papadopoulou et al., 2008). In juvenile diabetes, elevations of TGF- β above 400pg/ml are associated with increased risk of proliferative retinopathy (Zorena et al., 2013). In inflammatory bowel disease, where over expression of SMAD7 signalling is hypothesized (Feagins, 2010), elevations of TGF-β as high as 2ng/ml are observed in untreated ulcerative colitis (Sambuelli et al., 2000). In advanced Alzheimer’s disease significantly elevated serum and CSF TGF-β were observed in advanced disease (circa 50 pg/ml)(Chao et al., 1994). The observations therefore seem to be consistent with a biologically significant elevation in the cytokine concentration in CFS. The clinical significance of a raised TGF-β is unclear in CFS, but its associations with clinical symptoms, severity and prognosis merits further evaluation.

As an immune mediator, TGF-β has both pro- and anti-inflammatory effects. The intracellular signal transduction, following engagement of the TGF-β receptor, depends upon the cell type and context in which the cell is activated. Naïve or newly recruited leukocytes will be activated, whereas TGF-β will have an inhibitory effect on activated leukocytes. The complex nature of TGF-β makes it difficult to understand how and where it would have its effect in CFS. However, the central nervous system may be a starting point. In murine models exogenous TGF-β is associated with alterations in cerebral blood flow (Gaertner et al., 2005). In a sedentary mouse model Inoue et al (1999) showed that intracranial injection of TGF-β depressed motor activity in a dose dependent manner and that increased exercise load in rats was associated with increased TGF-β levels in the cerebrospinal fluid (Inoue et al., 1999).
 

A.B.

Senior Member
Messages
3,780
I really don't like that this seems to have been written in a direct attempt to refute Hornig's study. Doctor's without a lot of time will scan this and think, "ah, I knew that was all bunk". I wish there were some magic that would make people less intellectually lazy!

They know they can't produce robust evidence for their theories or therapies. The only thing that's left is producing a lot of bullshit while trying to maintain the appearance of good work. Sheer quantity and doubt. That doesn't work forever - eventually the biological basis of the illness is understood and they have to find some new poorly understood illness to parasitize.
 

SOC

Senior Member
Messages
7,849
I've heard about P.D. White before. Is he part of the psychosomatic camp?

Also, it seems ridiculous that they put this review together and lumped early sufferers and later patients together like that. It's not sensible, given the data available....

-J
IMO, this "study" looks less like an effort to find something, and more like a deliberate attempt to find nothing so that they can continue to claim there are no physical abnormalities in ME/CFS. They are very good at manipulating their data -- in this case by selecting the studies they use and ignoring new and significant studies -- so they get the results they want. This is not scientific research designed to uncover new information; it's propaganda designed to obscure what they consider to be unacceptable information. It's appalling that this gets published as science. I blame incestuous reviewing practices which avoid the "problem" of unbiased reviewers asking uncomfortable questions.
 
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Marco

Grrrrrrr!
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2,386
Location
Near Cognac, France
White may have inadvertently done us a favour in highlighting TGF-β and it's inhibitory effect on activated leucocytes (which include microglia).

It appears that TGF-β plays a key role in battling neuroinflammation but it's inhibitory capacities can be undermined :

LPS antagonism of TGF-β signaling results in prolonged survival and activation of rat primary microglia

We propose that LPS/TLR4 signaling interferes with key components in the TGF-β1 signaling pathway in primary microglia. As a result, the ability of TGF- β1 to exert anti-inflammatory effects is significantly reduced leading to prolonged survival of classically activated microglia. Identifying the mechanisms by which TGF- β1 signaling is targeted during microglia activation may yield novel strategies for deactivating chronically activated microglia.

http://onlinelibrary.wiley.com/doi/10.1111/jnc.12612/abstract

You would expect that microglial survival would be a good thing - not when they're inappropriately activated and neurotoxic. Is the paradoxical association of the upregulation of normally protective TGF-β with a range of 'neuroinflammmatory' disorders a compensatory reaction to blocked signalling?
 

Sidereal

Senior Member
Messages
4,856
White may have inadvertently done us a favour in highlighting TGF-β and it's inhibitory effect on activated leucocytes (which include microglia).

I would just add that TGF-β is often sky-high in CFS patients who've had it measured by certain "mold doctors" who have taken some heat here recently.