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Hornig/Lipkin cytokine study out now - press release

Daisymay

Senior Member
Messages
754
Peter White said:

"Only one out of the 51 immune proteins studied was elevated in all cases compared with controls, something that could happen by chance alone."

This is a red herring from Professor White.

Hornig et al were not basing their conclusions on one cytokine, they reported finding a pattern of many cytokines being activated and problems with regulatory networks:

Hornig et al:
"Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks."

Yet instead of addressing the findings in total Professor White chose to ignore them and instead just talk about this one cytokine which was elevated in all the patients and that this could be due to chance.

So what?

Please Professor White address the full findings of the paper and their implications for your view of ME/CFS as a behavioral disorder.
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
CD40L finding, B cells and autoimmunity
One of the most interesting findings is about a small cytokines called CD40L (immunologists name molecules with flair) that plays a crucial role in B cell development. It's one of two cytokines that was actually lower in the short illness group, and is a lot lower too:

upload_2015-2-28_15-33-4.png


(see full image Fig 1 in the original paper)

But it wasn't just lower levels in the shorter duration group. The study also found that while levels of CD40L were strongly correlated with the levels of other cytokines in the control and long duration group ('drives' cytokine levels), that correlation was almost missing in the short duration group. CD40L had become 'uncoupled' in some way. The authors think this could be important:

Mady Hornig et al said:
CD40L plays an important role in B cell maturation (49). There is indirect evidence that B cells play an important role in ME/CFS (50), although not all studies have found abnormalities of B cell phenotype or function (51, 52). Most studies indicate a higher frequency of autoantibodies in the illness (53), and a randomized trial of a monoclonal antibody that targets B cells has demonstrated symptom improvement in some patients (54).
 

wdb

Senior Member
Messages
1,392
Location
London
Daily Mail
Proof at last that 'yuppie flu' is a real illness: Study finds chronic fatigue commonly seen among professionals is not just in the mind
The debilitating condition once derided as ‘yuppie flu’ is a genuine illness, researchers say. Controversy has raged for nearly 30 years as to whether the symptoms of chronic fatigue syndrome are real or all in the mind. Now a study shows the condition, also known as myalgic encephalomyelitis or ME, does trigger a distinctive immune response in the body.
The discovery paves the way for treatments that, given early enough, could prevent years of ill health....
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,232
Location
Cornwall, UK
I agree, it raises more questions than answers. On first blush, it's interesting to think about how many symptoms of ME are the same as those of certain cytokines administered in excess (fatigue, fevers, sickness behavior, tachycardia, cognitive dysfunction, etc.) but that doesn't explain why people sick > 3 years would continue to have these same symptoms if their cytokine levels drop below that of healthy people.

Sorry if someone has already said this - I don't seem to have read all the enormous number of messages in this thread yet - but CCL11 (eotaxin), CSF2 (GMCSF), PDGFBB and CD40L are raised in long-term patients. I am not familiar with these, but hope to find out more!
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,232
Location
Cornwall, UK
I can only imagine what they must do behind the scenes and am sure others will inform me. Is there anything comparable to this center in the U.S.? I am still trying to put it into some kind of context to figure it out!

Maybe not yet, but I seem to recall a thread that suggested that the SMC were putting out feelers towards the USA with a view to setting up a centre/center there. :eek:
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,232
Location
Cornwall, UK
It does, and it also sheds light on a lot of other studies that seem to have contradictory findings, with some finding a certain cytokine high and another finding the same cytokine low. All future research into this disease is going to have to take length of illness into account now.

Other factors may also be important, but I think some of these were controlled for in the new study. Erica Verrillo refers to cytokine fluctuations here.

E.g.
Natelson’s meta-analysis, entitled “Evidence for the Presence of Immune Dysfunction in Chronic Fatigue Syndrome,” examined 79 studies of immune function in CFIDS patients. Natelson found that that there was no consistent immune dysfunction. Some studies indicated that there were increased pro-inflammatory cytokines, others found increased anti-inflammatory cytokines.

Given the fact that one of the hallmarks of CFIDS is waxing and waning symptoms, this should not have come as a surprise. The immune dysfunction that characterizes CFIDS is that it both under- and over-responds. This is the ultimate outcome of the loss of homeostasis which lies at the heart of the illness.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,232
Location
Cornwall, UK
I vaguely remember @Simon mentioning that displaying results in this way can make them seem more significant than they are? (I need to take the time to understand this stuff better).

Again, sorry if others have already cited this, but:
Short-duration versus long-duration ME/CFS versus controls GLM comparison of short-duration ME/CFS cases (≤3 years, n = 52), long-duration ME/CFS cases (>3 years, n = 246), and controls (n = 348) (with and without sex and age included in the models) showed significant differences for more than half of the 51 cytokines (tables S4 to S6).

(My bolding)

HTH
 

Scarecrow

Revolting Peasant
Messages
1,904
Location
Scotland
There is no power on earth that can stop the Daily Mail from saying 'yuppie flu' in every single article about ME that it writes.

:bang-head:
Other negatives:
  • 'not just in the mind' also in the headline
  • features a feel good story: yet another talented lovely attributes her recovery after only a short time ill to a change in diet and yoga.
Positives:
  • generally well balanced.
  • the journalist is either wise to the SMC or doesn't know they exist.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,232
Location
Cornwall, UK
We patients are clearly telepathically conspiring to force the immune system to dysfunction according to precise patterns in our attempt to emotionally communicate our repressed childhood traumas while faking illness unbeknownst to ourselves.

Fortunately there are geniuses such as Wessely, White, and Chalder who can see through our deceptions and save us from ourselves.

I expect they are working on this right now. In fact I think I read some stuff a few weeks or months ago suggesting that they were trying to work out how our emotional state could alter levels of cytokines or possibly other molecules.
 

halcyon

Senior Member
Messages
2,482
They say:
Network diagrams of intercytokine correlations revealed unusual regulatory relationships among cytokines in the short-duration ME/CFS group that were not apparent in either the long-duration case group or healthy controls
Right, but how would the short-duration cytokine profile looks compared to someone with HIV, hepatitis C, or some other chronic infection?
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,232
Location
Cornwall, UK
greeneagledown said:
Why isn't C-Reactive Protein and/or sed rate elevated in short-duration patients if they have so much cytokine inflammation? Makes me wonder if maybe these two tests don't measure inflammation as effectively as has traditionally been thought

These are two of many markers. I haven't seen a list since I was at uni but its much longer than that. Its just these are two that are clinically useful in a wide range of conditions.

Any ideas, @Jonathan Edwards?
 

Scarecrow

Revolting Peasant
Messages
1,904
Location
Scotland
@MeSci, this is from the recent CDC PCOCA thread

This is around the 35 minute mark. Dr Montoya stated that for many years ME/CFS was viewed as a disease lacking in inflammation because ESR (which he refers to as Sed Rate) and CRP are most often normal in ME/CFS. He then goes on to say:
"However, Sed Rate and CRP are primitive and very limited indicators of inflammation. Our cytokine data [I think that is the word] contradicts the erroneous conclusion that ME/CFS is not an inflammatory disease and supports that not only an inflammatory state exists in these patients but it also opens the door for the use of anti-inflammatory drugs or biologics, as it has been done for other inflammatory diseases whose aetiology is still unknown, including in rheumatoid arthritis and systemic lupus erythematosus."
 

Jonathan Edwards

"Gibberish"
Messages
5,256
It's worth bearing in mind also that buried amongst these averaged findings will be PWME whose illness didn't follow from a viral infection.

It's also clear (to me anyway) that the post 3 year findings suggest that the immune pattern seen prior to that are not necessary to sustain the symptoms. Stating the obvious of course but it does all point to the glial hypothesis. I don't see 'immune exhaustion' as a likely explanation for the change in pattern.

That was exactly what I was going to say - all four bits - but much more concise!
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Scatter charts sound like they could be very interesting, presumably they already have all the data they would need to do a scatter of level vs years ill. Do you think there is any possibility they could be persuaded to produce these or even release the raw data so that others could ?

Asking fellow scientists to present their data in another format is a bit a man asking his wife to re-iron all his trousers but with the crease at the side instead of the front. I am not going to ask Mady to redraw all her slides. On the other hand you never know who is reading PR and seeing some scatter plots at IiME in May would be so neat!!

I note with interest the bit Simon flagged up about log transformed data being normal. If these data really are 'unimodal' as this suggests then scatter plots may not help us much. I am not familiar with these transformation techniques but I have to say my intuition is that there ought to be at least a hidden bimodality in here - for the reason A.B. raises. Hidden in the early patients should be some 'early converters' and some 'late converters', in the sense of conversion to the >3yr pattern. But if conversion time shows a Gaussian variation I guess you may still end up with a normal distribution under appropriate transform. I have to say I believe my eye much more than my understanding of statistics here. I think the brain has better algorithms for identifying unlikely patterns than statistics textbooks do.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
The HPA might follow the same pattern as the cytokines - high activity in early stages followed by lower activity in later. Of course, leptin also inhibits the HPA, fitting the hypothesis of high leptin levels in advanced stages of ME/CFS.

Yup, one thing I started toying with was that this swathe of cytokine shifts in the early stage might reflect poor HPA control as much as anything. The question then is what is going on later and I cannot work that out.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,232
Location
Cornwall, UK
NO. Five years is the MINIMUM for new treatments. It could be much longer. However, as Klimas recently discussed, older drugs (and hence cheaper) that are already approved, and have a great safety record, could be used off label after only phase 2 clinical trials. This reduces the timespan to only 3 years, but that is 3 years after the study starts. Adding startup times might mean the time frame is 4-6+ years, presuming of course that this research is robust.

It is the case though that particularly aggressive and daring doctors could start such treatments, off-label, very soon, for existing drugs. However there are no guarantees, and I doubt any insurance anywhere would cover it.

I doubt if all of us here are prepared to just sit back and wait, even while lobbying/funding for more research. We are going to be researching ourselves to see what drugs and supplements - perhaps even foods/diets - have been shown to alter cytokine levels in the required direction.

Some of us have already tried various anti-inflammatory supplements, but this study has shown that at least one I've tried may be unsuitable (turmeric/cumin which, as I have reported in a blogpost, can reduce TNF-alpha and IL-1) as these do not seem to be increased, at least in late-stage ME. It seems to have helped some with some symptoms though.

Now we have a better idea of what to look for...

EDIT - although of course we don't know if all the abnormalities are pathogenic - some may be (necessary) responses to pathology, so it will have an element of trial and error as usual, as of course does (much) formal research.
 

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,232
Location
Cornwall, UK
[I also have to admit to wondering whether it would be possible to temporarily induce this newly discovered cytokine profile by artificial means to see if doing so could briefly bring on ME/CFS symptoms in otherwise healthy individuals. Sort of like Barry Marshall swallowing a Petri dish of h. Pylori for science. Do I see any volunteers among the "it's all in their head" crowd in the audience?:)]

I doubt the latter, but the first victims will probably be innocent lab animals, which will tell us nothing.
 
Messages
40
Professor Edwards
Regarding these findings, does it assist with the rituximab trial? For example, people who have been ill less than 3 years or more than three years? Or, does it have no assistance to the rituximab trial?
 
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