Cytokine signature associated with disease severity in chronic fatigue syndrome patients

[jimells]

From 1997...

https://www.researchgate.net/publication/14131133

Elevation of Bioactive Transforming Growth Factor-beta in Serum from Patients with Chronic Fatigue Syndrome

ADRIENNE L. BENNETT, CHUN C. CHAO, SHUXIAN HU, DEDRA BUCHWALD, LAURA R. FAGIOLI, PETER H. SCHUR, PHILLIP K. PETERSON, and ANTHONY L. KOMAROFF

The current finding that TGF-beta is significantly elevated among patients with CFS supports the
findings of two previous studies examining smaller numbers of CFS patients.

In conclusion, TGF-beta levels were significantly higher in CFS patients compared to patients with various diseases known to be associated with immunologic abnormalities and/or pathologic fatigue.

These findings raise interesting questions about the possible role of TGF in the pathogenesis of CFS.

----
TGF-beta has been found to be expressed constitutively in a variety of cells, including
platelets, macrophages, neutrophils, and lymphocytes. Almost all of the TGF-beta produced by these cells is released in a latent high molecular weight complex form.

The bioactive form of TGF-beta, which was measured in the present study, is 200-fold more active than the latent form. The cellular source(s) of TGF-beta in the serum and the physiologic mechanisms of its activation are presently unknown.

I keep digging through the headline hype with my manure fork trying to find the pony, but so far it seems the study only tells us what we already knew. How can it be that 20 years later we *still* don't know the source of the TGF? Why has no one tried to answer this obvious question?

The new study doesn't even mention the "200-fold more active" observation, or even reference the 1997 study. Is this a red herring? I am particularly intrigued by this because the 1997 study lists Komaroff as a co-author, and he reviewed the new study.

Two decades of torturing cytokine data has resulted in NO treatments, treatment targets, or management strategies. Time to move on?

 

[Demepivo]

The Blundell et al 2015 paper quoted by Alan Carson is a QMUL special..amongst the authors is Peter Denton White

https://www.ncbi.nlm.nih.gov/pubmed/26148446
Brain Behav Immun. 2015 Nov;50:186-95. doi: 10.1016/j.bbi.2015.07.004. Epub 2015 Jul 3.
Chronic fatigue syndrome and circulating cytokines: A systematic review.
Blundell S1, Ray KK2, Buckland M3, White PD4.
Author information

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-β) 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.

==========================================================================

The full paper is on Sci Hub

http://sci-hub.cc/10.1016/j.bbi.2015.07.004

 

[msf]

@msf, I think you mean 20st century? 1991

I feel like something is being lost in translation. I was pointing out that the studies you quoted were from the 20th century, and asked if there was a study from the 21st century that you are enthusiastic about, which is the question I asked but I´m not sure it was the one you were answering.

 

[msf]

Anyway, don´t worry about it. I was just trying to point out that you often seem to have a pessimistic view of studies´ importance, which in this case I do not share. It seems to me like a very important study that will lead to the discovery of the pathophysiology of the disease.

 

[PracticingAcceptance]

Hello, it's my first time on this section of the forum. I'm delighted to see how you all are dissecting the research. I love seeing the variety of responses - hope AND scepticism because of what you've seen before. It helps me to put things into context.

I've only been suffering for about 10 months. This is the first research that has come out about ME that I've been aware of. It gives me hope to see that research is currently happening.

It makes me wonder how long it will take to put any of this research into practical action for us patients.

It does interest me that they've separated out mild, moderate, and severe. Even if this particular research doesn't make all the difference, maybe this approach will help with future studies. And as other people have said on here, looking at how things happen over time could help, too. Maybe this isn't a new approach though?

I'm starting to understand the politics around ME/CFS. One day, it won't be like this any more. We will have an understanding based in science - it won't be trial and error, and a load of societal prejudice, which leads to all this political discussion. Maybe it will be another 50 years. But this period is surely a phase in history that will pass.

The thing is, most people on here know or probably think this study is at best a tiny step in the journey to a biomarker or diagnostic test.

Yes - a small step - but it's still a step. Part of the problem with ME/CFS is being misunderstood. So, we need culture change. Culture change happens slowly with many small steps. Media helps. This news coverage helps. I mean, there's some crappy suggestions because of journalists' lack of sensitivity/knowledge, but it's better than nothing. More awareness of ME/CFS = more funding = more research = we get ever closer to treatment that works.

What positive action can we take, to make more research happen, or use the research that's out there? What can we practically do with this study? Doesn't look like we can all go out and test our cytokine.

 

[msf]

I don´t think it´s a small step at all. Cytokine levels correlate with severity, therefore it is very likely that something else that cytokine levels correlate with ´causes´ the degree of severity, if not the cytokine levels themselves. Either way, the next step is finding out what causes the correlates with the cytokine levels. The number one suspect, at least for me and I would hope Maureen Hanson, would be LPS, which is sometimes referred to as a ´super-antigen.´ That would be fairly easy to test. If it turns out to be something else, then we have Davis´s Big Data approach to find the culprit.

 

[user9876]

Agreed, which is why my first concern was around this. Correcting for FDR is a base requirement IMHO but is not sufficient in and of itself.

However, grouping by severity looks to my untrained eye as being one of the first ways one would split the data rather than some of the other studies like the one (Peterson?) that only got to statistical significance by creating a whole new category of 'atypical' that included such gems as 'got it on holiday' (I paraphrase, but only just). Correlating by severity is analogous to doing a dose-response curve so doesn't feel like the data has been tortured too much to give p<0.05. It's also consistent with previous and upcoming longitudinal findings so I think it's worth giving the benefit of the doubt.

It is the obvious thing to look for severity but I don't think it is obvious to form severity categories rather than a more continuous measure. Then there is a question of category boundaries. Even if you just ask are you mild, moderate, severe then its up to patients to interpret severity. However we shouldn't make the mistake of assuming severity can easily be summarised in a linear scale either.

 

[user9876]

I think it´s quite likely that cytokine levels are depressed from where they ´should´ be, i.e. patient´s immune systems adapt to the constant stimulation of higher levels of LPS by downregulating inflammatory cytokines, but in severely ill patients the levels of LPS are so high (as reported by KDM, who first reported the raised levels of LPS established by Hanson) that even with the downregulation the levels of inflammatory cytokines are still above controls. As I suggested in my blog, I think research will eventually show that measuring both these factors after exercise will show a much clearer separation between patients and controls.

Is there any evidence that cytokine levels get depressed as a result of immune system stimulation?

 

[msf]

Yup, but I am too lazy to find it. They get depressed after chronic stimulation with LPS, for one.

 

[ljimbo423]

Is there any evidence that cytokine levels get depressed as a result of immune system stimulation?

Hello user9876- Mady Hornig found what she calls immune exhaustion in this study-

Possibly, as occurs with pancreatic β cell production of insulin in type 2 diabetes (42), or in chronic infections (43), the exuberant stimulation of cytokine-producing cells seen in the first 3 years of the illness leads to an “exhaustion” of the cytokine-producing cells thereafter.

studies that control for duration of illness may provide additional clarity as to the potential contribution of mechanisms of immune exhaustion to the immune changes observed later in the course of ME/CFS.

LINK

Maybe they should be looking at the low cytokines as well as the high ones?

Jim

 

[jimells]

Is there any evidence that cytokine levels get depressed as a result of immune system stimulation?

I'm not sure if this answers your question, but TGF-beta "inhibits the production of pro-inflammatory cytokines", according to Bennett 1997 (cited in my previous post):

Perhaps of greatest relevance to CFS are the effects of TGF-beta on cells of the immune and the central nervous systems.

Although TGF-beta is known to have both anti-and pro-inflammatory activities, it is primarily an immunosuppressive cytokine, downregulating the inflammatory response by inhibiting the production of proinflammatory cytokines (such as IL-1, TNFa, IL-6, and IFN), suppressing T-cell and monocyte cytotoxicity, and suppressing B-cell antibody production.

There is accumulating evidence that TGF-beta may play a role in autoimmune and inflammatory diseases...

Conceivably, the findings of immune dysfunction in some immunologic studies of CFS patients could be ascribed to overproduction of bioactive TGF-beta.

On the other hand, elevated levels of serum TGF-beta could reflect a response of an activated immune system. This view would be consistent with previous reports that CFS patients have increased numbers of T lymphocytes that bear antigens indicative of a state of immune activation
or of differentiation in vivo...

Both the beta-1 and the beta-2 isoforms of TGF-beta are produced by astrocytes and microglial cells, and an increasing body of evidence indicates that TGF-beta affects the growth, differentiation, and function of brain cells...

Hopefully, as more is learned about the biology of TGF-beta, both in the peripheral circulation and in the central nervous system, its role as a potential mediator or neuroprotective cytokine in the pathogenesis of disorders such as CFS will be better understood.

Hmmm, we are still left with the question of whether TGF is "the cause" or a downstream effect. We really, really need to know what cells are producing this stuff.

 

[Murph]

Cytokine levels correlate with severity, therefore it is very likely that something else that cytokine levels correlate with ´causes´ the degree of severity, if not the cytokine levels themselves.

I appreciate this. The complexity is stripped out and the issue becomes easier to see.

If the cytokine correlation findings are true (and 17/51 with the same pattern is certainly suggestive) Then either (1) cytokines are reacting to something that is causing symptoms, or (2) some other situation exists that mean cytokines - even inside normal range - can produce symptoms.

(1) I do like the idea that our bodies are producing tgf-beta like crazy to try to reduce cytokine production (quelling the inflammatory response to factor x) but in severe patients this is like pouring a garden hose at a fire and it doesn't do enough. So severe patients have high tgf beta and high cytokines (and probably high factor x).

• Presumably, ramping up tgf beta has side effects. These would manifest as symptoms common to severity classes.
  
• Presumably, suppressing cytokine production has side effects. These would be symptoms that mostly manifest in the mild.
• Presumably, having relatively high cytokine production has side effects. These would be symptoms that mostly manifest in the severe.
  
• Presumably factor x can cause symptoms too and be different in various patients.

The amazing menagerie of symptoms that characterise me/cfs could then be a complex mix of the side effects of those tgf-beta, cytokine levels and factor x.

As for hypothesis (2).

I'm wondering if high tgf-beta is a part of a hypometabolic state. A quick squiz on Pubmed suggests tgf-beta may produce hypometabolism in mice, but is in fact a thing that the C.Elegans worm uses to keep itself out of dauer.

What if everyone is hypometabolic and then severity is determined by level of immune activity? In someone hypometabolic maybe even 'high within normal' cytokines is enough to KO them.

 

[Jesse2233]

In terms of taking something actionable out of this, IFN-y had the lowest p-value of all the commercially testable cytokines correlated with disease severity. So if one wanted to track severity and responsiveness to treatment over time using the labs at a standard doctor's disposal IFN-y would seem to be a good choice.

Big caveat being it may fluctuate randomly and may not be a driver in your particular subset.

 

[dreampop]

I wouldn't read too much into individual cytokines, or develop elaborate theories for the cytokine distribution amongst severity. What I'm reading from this study is that severity tracks with the immune system. Like Younger's findings, except in disease severity, rather than symptom severity. This may reflect something in the immune system as a whole, or correlate with a specific immune problem. It's suggesting what we all have felt since we got sick - the symptoms are immune in nature.

What that is? Seems the best person to figure that out is Mark Davis. Is this his first published study on CFS?

I'm really shocked to see such widespread reporting on this as ground-breaking, and I wonder if the Stanford team feels confident they can build on this. Maybe that's wishful thinking.

Needs replication!

 

[Jesse2233]

@dreampop I'm inclined to agree. Can't wait for that Mark Davis antigen paper!

 

[slysaint]

A couple of years (?) ago a PR member posted a link to a video s/he had done showing in graphic form cytokine changes comparing year one and year three. I've tried searching for it but no joy.
Can anyone remember where it is, or who did it/posted it?

It may have absolutely nothing to do with this but it's bugging me that I can't find it to check.

Thanks.

 

[halcyon]

A couple of years (?) ago a PR member posted a link to a video s/he had done showing in graphic form cytokine changes comparing year one and year three.

 

[alex3619]

Comments are available but 2 of the 3 so far are not good.

Wrote the following -

-------------------
On point 2, the 2 day CPET has been repeatedly validated as showing a major drop in energy production.

-------------------

The CBT treatment research for CFS is under major threat, its even more bogus here than it is for asthma. If you endorse it based on PACE then you necessarily endorse the following - improper statistical analysis is good, zero improvements in physical outcomes is good; zero improvement at long term followup using subjective measures is good; patients can qualify as disabled, normal and recovered at the same time, and a formerly fit twenty year old can be considered to be recovered if they operate at the level of a typical eighty year old. Just look at the PACE trial, and the special edition of the Journal of Health Psychology that was just published. Check out Tuller's commentary on Virology Blog for a longer list of major problems, including an ethical violation.

Most of the evidence you need to overturn claims of the effectiveness of CBT and GET for CFS and ME are in the original papers themselves. Yet you have to read them to see that.

CBT is good at helping people to manage symptoms but not much more.

Imagine being told you had cancer and the only treatment available was CBT. How you you react?

-------------------
(In reply to a comment about physical symptoms without physical cause.)

No, you cannot. This is pure theory. Its never been proven.

-------------------

(On depression and deconditioning)

Only a decade's worth of research into the physiology. Deconditioning has been repeatedly debunked as a cause, as has depression. Cardiopulmonary exercising testing, CPET, can accurately identify a core problem that is not known to exist in any other disease. That problem is a marked decrease in energy production a day after activity. Sometimes its a thirty percent drop. That is major. In order to do this you have to use two CPET studies twenty four hours apart, and you need the gas analysis results to identify the anaerobic threshold. See the Workwell research, though others have replicated this over the last decade. There were very old references to this in the 80s in some reports from the pharma Hemispherx.

Moreover the highly cited paper into spectral coherence EEG shows it can separate depression from CFS.

PS All comments are waiting on moderation for now.

PPS All my comments are now live.

 

[James_B]

Today a test may be set up if one stay of D-vit & B12 for a week and take a screening of what we know
Activin, Lipin, TGF-beta, B-cell, T-cell, D-vit & B12... May show a good picture. Use a bigger net so to say.

 

[mango]

A Swedish ME/CFS center published a press release about the study today...

http://www.mynewsdesk.com/se/bragee/pressreleases/genombrott-i-forskningen-om-me-slash-cfs-2098665

Google translate, English:
https://translate.google.se/translate?sl=sv&tl=en&js=y&prev=_t&hl=sv&ie=UTF-8&u=http://www.mynewsdesk.com/se/bragee/pressreleases/genombrott-i-forskningen-om-me-slash-cfs-2098665&edit-text=