Lombardi et al 2011 - cytokine signature in CFS

[Cort]

Whether or not XMRV turns out it is good to have data on an immune signature in CFS patients. If XMRV holds up it will probably be a significant advance for the field. It is too bad that we don't have data on CFS vs XMRV with CFS vs controls...Unfortunately I can't find the immune signature info

Peterson believes the immune signature is the key....

It is good to see the WPI getting published, I agree. I think they have one more paper coming out.

 

[leaves]

hmm ive tested xmrv + and my nk function is very low, satisfy Canadian criteria, but my cytokine profile looks very different.. I dont have sudden onset tho; ive got symptoms since as long as I can remember and gradually got worse over time.

 

[Bob]

Sorry, but this paper has nothing to say about XMRV; it is all about CFS. it does not have any data for or against the idea that XMRV is real, that CFS people have it, or that it has any effect on them.

The paper compared people who have CFS and tested positive for XMRV, to people who were healthy. The healthy people were never tested for XMRV as part of this study. (Neither were the CFS patients, but they had previously been found XMRV positive as part of the previous study.)

So this study can tell us about differences between CFS who also have XMRV and healthy people, but there is no way to know if what is seen has to do with being CFS+ or XMRV+ or both.

If you ask me, this is awful experimental design. At a minimum, they should have had four groups (CFS+XMRV, CFS, XMRV, neither). That would have told us about both CFS and XMRV.

Joshua Levy

But it does tells us that there maybe a correlation between XMRV infection and a specific cytokine profile.

It's a good start with limited resources.

It is a shame that there wasn't a group of CFS patients with no XMRV infection, but as XMRV detection is at the limits of current technology and knowledge, we can't confirm that XMRV-negative CFS patients are not infected with XMRV, so to include this group might have muddied the outcomes.

 

[Bob]

Meh, probably mouse contamination...

Yes, I expect that we'll be told that it's a mouse's cytokine profile that they accidentally detected.

 

[Rrrr]

this is from an old post. i'm re-posting here, now:

Treating cytokine up/down-regulation
______

WPI & NCI Paper

"Type 1 IFN Pathyway Response to Viral Infection in Chronic Fatigue Syndrome"

Mikovits,J. Hagen,K. Peterson,D. Stephens,R. Lombardi,V.
Whittemore Peterson Institute, Reno, NV, USA. Laboratory of Experimental Immunology, National Cancer Institute-Frederick, Frederick, MD, USA.

118 CFS patients
138 Controls

Cytokines/Chemokines:

CFS:

IL-8: 1045
MIP-1a: 763
MIP-1b: 1985
IL-6: 336
TNF-a: 148
IL-1b: 500
IP-10: 98
IFN-a: 35
IL-13: 28
IL-7 160

Controls:

IL-8: 13
MIP-1a: 91
MIP-1b: 164
IL-6: 29
TNF-a: 13
IL-1b: 56
IP-10: 32
IFN-a: 60
IL-13: 86
IL-7: 60

Guide to Chemokines/Cytokines:

IL-8: RNase L & CMV activated
MIP-1a: Elevated in neurodegenerative disease
MIP-1b: Elevated in neurodegenerative disease
IL-6: Stimulates chronic inflammation
TNF-a: Stimulates chronic inflammation
IL-1b: Stimulates chronic inflammation
IP-10: Interferon response protein
IFN-a:Stimulates macrophages and NK cells to elicit an anti viral response
IL-13: Inhibits inflammatory cytokine production
IL-7: Stimulates proliferation of B & T lymphocytes & NK cells

Summary and conclusions:

Cytokine and Chemokine profiling in combination with machine logic algorythms reveals an inflammatory signature consistent with an over-expression of herpes virus and is useful for diagnosis for CFS
________

more info on cytokine and chemokines

http://www.forums.aboutmecfs.org/sh...mokine-profile&p=124292&viewfull=1#post124292

http://www.forums.aboutmecfs.org/showthread.php?5270-Antiretrovial-Trial&p=127915#post127915 (posts #401 and those after it)

 

[ixchelkali]

Sorry, but this paper has nothing to say about XMRV; it is all about CFS. it does not have any data for or against the idea that XMRV is real, that CFS people have it, or that it has any effect on them.

The paper compared people who have CFS and tested positive for XMRV, to people who were healthy. The healthy people were never tested for XMRV as part of this study. (Neither were the CFS patients, but they had previously been found XMRV positive as part of the previous study.)

So this study can tell us about differences between CFS who also have XMRV and healthy people, but there is no way to know if what is seen has to do with being CFS+ or XMRV+ or both.

If you ask me, this is awful experimental design. At a minimum, they should have had four groups (CFS+XMRV, CFS, XMRV, neither). That would have told us about both CFS and XMRV.

Joshua Levy

I'm afraid I have to agree with Joshua. We've known for a long time that ME/CFS patients have a characteristic immune profile which is different from healthy people (and from people with other illnesses they've checked). I haven't yet compared these results with specifically with past studies, but I don't see that this is new information, and it doesn't seem to have anything to do with XMRV. ME/CFS patients would have this profile with or without XMRV.

Also, it doesn't appear they tested the healthy controls for XMRV, which seems odd considering that their earlier studies showed that a portion of healthy people were XMRV positive. It would be interesting to know if the immune profile of XMRV positive healthy controls would look like ME/CFS patients' or healthy people's. If being XMRV positive did make a difference in the immune profile, then having XMRV positive controls would skew the results.

I also don't see any indication that the samples were blinded in any way.

I think we need to hold the WPI to the same standards of scientific rigor that we do others, and this doesn't appear to measure up. I'm disappointed, because the abstract sounded like it was going to be something very interesting.

 

[Angela Kennedy]

Yes, I expect that we'll be told that it's a mouse's cytokine profile that they accidentally detected.

Bob nothing would surprise me lol!

 

[Angela Kennedy]

I'm afraid I have to agree with Joshua. We've known for a long time that ME/CFS patients have a characteristic immune profile which is different from healthy people (and from people with other illnesses they've checked). I haven't yet compared these results with specifically with past studies, but I don't see that this is new information, and it doesn't seem to have anything to do with XMRV. ME/CFS patients would have this profile with or without XMRV.

Also, it doesn't appear they tested the healthy controls for XMRV, which seems odd considering that their earlier studies showed that a portion of healthy people were XMRV positive. It would be interesting to know if the immune profile of XMRV positive healthy controls would look like ME/CFS patients' or healthy people's. If being XMRV positive did make a difference in the immune profile, then having XMRV positive controls would skew the results.

I also don't see any indication that the samples were blinded in any way.

I think we need to hold the WPI to the same standards of scientific rigor that we do others, and this doesn't appear to measure up. I'm disappointed, because the abstract sounded like it was going to be something very interesting.

Can I suggest you look at the paper again and note the predictive model that was used?

 

[Angela Kennedy]

But it does tells us that there maybe a correlation between XMRV infection and a specific cytokine profile.

It's a good start with limited resources.

It is a shame that there wasn't a group of CFS patients with no XMRV infection, but as XMRV detection is at the limits of current technology and knowledge, we can't confirm that XMRV-negative CFS patients are not infected with XMRV, so to include this group might have muddied the outcomes.

Yes I think that's right Bob. There is enough here to indicate more evidence for a POSSIBLE XMRV infection of CCC ME/CFS patients, and pours some more doubt on the 'contamination' theory. That should be enough to be going on with. It's the high probability that certain parties will attempt to downright poo-poo it (and stepping deeper into the regions of absurdity to do it) as related to XMRV, and downplay its significance to CCC ME/CFS (when this could be a key finding), is what I think many of us are worried about.

 

[jace]

I just posted and ran, yesterday, which was wrong of me. It does take a while to understand the significance (or otherwise) of a new paper, that's my excuse. This one, IMHO, is really important.

What it shows is a pattern in the immune system (expressions of cytokines) that predicts ME/CFS. There are also some clear pointers to help all those that fail to find XMRV. For instance:

Blood samples were drawn using green-capped vacutainer collection tubes with the anti-coagulant sodium heparin (Becton Dickinson, Franklin Lakes, NJ, USA) and processed within 6 hours of draw. Plasma samples were separated by centrifugation at room temperature, aliquoted and stored at 80 ?C until analysis. Samples were not subjected to more than 1 freeze-thaw cycle.

0/0 studies tend to handle their samples less rapidly, I have read that some freeze at -30C and also that their samples have been put through multiple freeze-thaw events.

I haven't got my head round the Random Forest Algorithm that was used, but I do know that they fed their raw data in, and the program then predicted with amazing accuracy which samples were ME/CFS XMRV+

we utilized the Random Forest data mining software package using patient status as the target variable and the cytokine and chemokine values as the predictive variables .... The final model accurately identified 128 out of the 138 controls (93% specificity) and accurately identified 113 out of 118 patients (96% sensitivity) (Table IV).

So in other words, this test randomizes the results and then picks out the sick people by analysing the cytokine profile.

The conclusion, in proper qualified scientific speak

Although the determination of XMRV infection is presently not a definitive stand-alone diagnostic tool for neuroimmune diseases or malignancies, a combination of XMRV and cytokine/chemokine analysis may prove to be a reliable diagnostic strategy and may assist in monitoring the success of treatment

In science, there is no "proof". The concept of certainty is anti-science. True scientists always allow for new information to change their view of reality. True science evolves.

The exciting thing is that this may be an objective tool to test how well treatments work. That is hugely important, and I am super excited about it.

 

[currer]

Hi,
I haven't read the whole paper yet, but I remember JM saying somewhere that the cytokine signature was the best way to distinguish sub-groups of CFS patients. So maybe this research is looking specifically at this subgroup with this specific cytokine signature, and the XMRV correlation.

It is rather hard to see how otherwise, among a very variable cohort of "CFS" diagnosed patients, one would pick out a specific subgroup to study. How can you diagnose "CFS"?

Haven't we all been complaining about cohort selection before?
Where do you start in defining your study group? I accept it could have been a bigger study with more and different sub-groups, but this is a start at correlating physiological markers with infection.

 

[Angela Kennedy]

I just posted and ran, yesterday, which was wrong of me. It does take a while to understand the significance (or otherwise) of a new paper, that's my excuse. This one, IMHO, is really important.

What it shows is a pattern in the immune system (expressions of cytokines) that predicts ME/CFS. There are also some clear pointers to help all those that fail to find XMRV. For instance:



0/0 studies tend to handle their samples less rapidly, I have read that some freeze at -30C and also that their samples have been put through multiple freeze-thaw events.

I haven't got my head round the Random Forest Algorithm that was used, but I do know that they fed their raw data in, and the program then predicted with amazing accuracy which samples were ME/CFS XMRV+



So in other words, this test randomizes the results and then picks out the sick people by analysing the cytokine profile.

The conclusion, in proper qualified scientific speak


In science, there is no "proof". The concept of certainty is anti-science. True scientists always allow for new information to change their view of reality. True science evolves.

The exciting thing is that this may be an objective tool to test how well treatments work. That is hugely important, and I am super excited about it.

Nice explanation Jace. Thank you.

 

[Snow Leopard]

How do we know the controls were new controls, not those tested and found XMRV negative? (I'm genuinely asking here).

The paper states that the controls were:

One hundred and thirty-eight control plasma samples were
provided by a local medical practice, under University of Nevada,
Reno IRB approval, also with a female to male ratio of
approximately 2 to 1. Control subjects donated blood during a
routine health check-up and were determined to be healthy at the
time of their visit.

Unfortunately they did not have a XMRV negative CFS control group, so the results of this study may merely reflect having CFS and have nothing to do with being XMRV+.

 

[anciendaze]

There is a new paper on the dynamics of immune response which may help clear up some of the confusion which is all over the field. Too much emphasis has been on levels, (which admittedly make for convenient clinical tests,) and too little concern for context and timing. Immune systems are examples of complex dynamical systems, par excellence.

 

[alex3619]

Gamma delta T cells are chemical watchdogs. They look for strange chemicals and react fast to stimulate the immune system. They are very sensitive to biological molecules including amines, but also possibly lipopolysacharides and many others. It occurs to me they could explain all kinds of chemical sensitivities.

They are adaptive. Those stimulated can multiply I think (tons more reading to do) and so we become MORE sensitive to those chemicals. Sound like anything you know? (Rhetorical question in case there is doubt.)

Bye
Alex

 

[In Vitro Infidelium]

In science, there is no "proof". The concept of certainty is anti-science. True scientists always allow for new information to change their view of reality. True science evolves.

True science sounds like true faith, and fits more closely with Poppers description of the non scientific theories which prompted his arrival at the falsifiability approach to scientific theory. To say there is no proof in science is to play a semantic game, its true that Popper does not use the term proof, but rather the condition based terms confirmation and evidence, which depending on context could both be described as forms of proof. Popper (nor anyone that has succeeded him has ever suggested proof in the form of evidence was anything other than essential to the scientific process.

The Popperian view, which is essentially concerned with theory, has limited relevance when we are concerned with real world application there are very few astrophysicists who would be willing go into space in a vehicle that had been constructed and tested on the basis that its structural integrity was conditionally established on the basis of a failure to falsify a theory of the vehicles structural integrity most would want to know that the engineering had been proved safe. Even an ardent Popperian like Stephen Jay Gould is constrained to describe as fact, that which is otherwise a Theory, albeit giving fact a particular semantic condition but still arrives at a position that amounts to a pragmatic proof my bold.

Well evolution is a theory. It is also a fact. And facts and theories are different things, not rungs in a hierarchy of increasing certainty. Facts are the world's data. Theories are structures of ideas that explain and interpret facts. Facts don't go away when scientists debate rival theories to explain them. Einstein's theory of gravitation replaced Newton's in this century, but apples didn't suspend themselves in midair, pending the outcome. And humans evolved from ape-like ancestors whether they did so by Darwin's proposed mechanism or by some other yet to be discovered.

Moreover, "fact" doesn't mean "absolute certainty"; there ain't no such animal in an exciting and complex world. The final proofs of logic and mathematics flow deductively from stated premises and achieve certainty only because they are not about the empirical world. Evolutionists make no claim for perpetual truth, though creationists often do (and then attack us falsely for a style of argument that they themselves favor). In science "fact" can only mean "confirmed to such a degree that it would be perverse to withhold provisional consent." I suppose that apples might start to rise tomorrow, but the possibility does not merit equal time in physics classrooms.

Evolutionists have been very clear about this distinction of fact and theory from the very beginning, if only because we have always acknowledged how far we are from completely understanding the mechanisms (theory) by which evolution (fact) occurred. Darwin continually emphasized the difference between his two great and separate accomplishments: establishing the fact of evolution, and proposing a theory--natural selection--to explain the mechanism of evolution.

Stephen J. Gould, " Evolution as Fact and Theory"; Discover, May 1981

IVI

 

[Snow Leopard]

I think you are perhaps misunderstanding Popper. Concepts of confirmation and evidence are inherently justificationist and therefore he does not consider them to be valid criteria for demarcation.
There is quite a difference between a strongly held belief, which is usually based on the accumulation of evidence and a scientific theory that has not yet been comprehensively falsified.

It is however true that scientists in general don't bother themselves with epistemology and many haven't bothered to read Bartley or Kuhn, or studied Bayesian epistemology for that matter. It is just as well that the beliefs and opinions of individual scientists (and all associated biases) aren't in themselves considered scientific.

 

[Sasha]

I've just spent 20 minutes searching for a comment that I thought I read earlier in response to this paper on the forums by someone saying that one element in the cytokine/chemokine signature found by the WPI only occurs in response to a retroviral infection.

If that's the case I would have thought it would be major news and a way of bypassing the whole "contamination" issue - but I haven't seen anyone pick it up. I can't remember the name of the specific chemical involved.

Sorry to be so vague - does anyone else remember the comment? Is it a big deal?

 

[fla]

I'm not in a state to read much. Can someone who read it explain how this paper relates, if at all, to the Broderick stuff we heard at the NIH state of knowledge?

 

[JohnnyD]

I've just spent 20 minutes searching for a comment that I thought I read earlier in response to this paper on the forums by someone saying that one element in the cytokine/chemokine signature found by the WPI only occurs in response to a retroviral infection.

If that's the case I would have thought it would be major news and a way of bypassing the whole "contamination" issue - but I haven't seen anyone pick it up. I can't remember the name of the specific chemical involved.

Sorry to be so vague - does anyone else remember the comment? Is it a big deal?

Sasha, You must have seen it on the other forum:

http://www.mecfsforums.com/index.php/topic,7276.msg86605.html#msg86605