Is ME an immunological disease?

Marshall-Gradisnik's group does small studies, releases PR posts that say they've found 'the answers to ME' (with a heading titled First Proof CFS/ME is a Real Thing!) and moves on to another small study without ever returning to validate the first.

I think her group's work is fine, and I have a hard time faulting them for 'following the money' when funding for ME research is so devilishly hard to secure. But with no validation or replication, it's impossible to tell if these were non-findings when they expanded their pool, or if they didn't try again, or if they tried to get funding for larger studies and were denied.

I don't think we're wrong to be looking into immune function! However, their work is not proof of T cell involvement. I know others who are doing T cell work, and hope that they are able to replicate with larger numbers of patients.

 

Wenzhong had a lot to say on this. I don't want to derail this convo, which is about ICC vs SEID, so I will just drop the link here.

https://twitter.com/user/status/1046128391500365824


Click on the second tweet to see the thread.

 

The IOM discussed the following but were criticized even in 2015 for missing key studies:
1. impaired immune funnction with a highlight on NK cell function

"The committee’s literature review yielded data demonstrating poor NK cell cytotoxicity (NK cell function, not number) that correlates with illness severity in ME/CFS patients and could serve as a biomarker for the severity of the disease, although it is not specific to ME/CFS. More research is needed to address cytokine abnormalities and their potential use as bio- markers of possibly distinct subgroups of ME/CFS."​

2. immune activation - said the most consistent studies are with pro-inflammatory cytokines but said findings are varied, inconsistent, in small studies, and generally not replicated. It also noted "fewer peer-reviewed papers report on functional studies of other aspects of immune function, and these studies yielded less consistent findings." This includes "reports of Immunoglobulin G (IgG) subclass deficiencies, diminished T and B cell response to mitogens, and abnormalities of neutrophil and macrophage functions. However, the subjects studied were limited to small series, and there are no replication studies"

3. Emerging areas including reports of autoimmunity and systems biology approaches to look at "immune endocrine/ neuropeptide homeostatic balance"

 

Hm, that looks pretty thin.

Recently the CureMe team at London School of Hygiene working with the best basic NK research unit in the UK failed to find anything of note in NK cells in ME. This is personal communication but I think public knowledge. This did not surprise me since other groups have been unable to find anything and even Nancy Klimas's group was said to have problems repeating their findings. And anyway it is very unclear what low NK function test results mean in terms of health.

The cytokine research has not really yielded anything one could make anything of clinically. They say the most consistent findings were pro-inflammatory cytokines - but these were inconsistent. My reading of the literature is that the cytokine that came up most often was TGFbeta, which is anti-inflammatory - and that was pretty inconsistent too. There are a few studies that look as if they did find some differences, like the one Mady Hornig reported, but even so the changes are not dramatic and might be due to all sorts of confounding factors relating to being ill and at home and having disturbed sleep.

Number 3 seems to be more about approaches to research rather than findings.

None of this is enough to be sure that ME is based on ongoing immune dysfunction.

 

AFAIK, others have replicated the findings, although I have heard one researcher who did not.

The IOM report said quite a bit about NK cell function and even recommended it in the clinician guide as a potential test to aid diagnosis clinically, although admittedly not specific to ME.

Regarding its meaning in terms of health...I understand that NK cells have an important role in killing cells infected with viruses and in detecting and early signs of cancer. If so and the function is low, I'd think that they'd have significant health implications

 

I think there is a publication bias problem here. Moreover, the story has been pretty unstable from the start. I gather it was suggested that NK numbers were down. Then that got changed to numbers being normal but function tests giving low readings. The some people have suggested it is a particular subset that is abnormal. Then others have suggested that the NK cells are fine but affected by a serum factor. This does not sound like a solid science story to me.

There have been some replications from the original group and a group that worked with the original group as I understand it. However, even Nancy Klimas has been unable to repeat her original findings sufficiently to take the story any further. The two groups I know best in the UK could not repeat the findings. And there are others. Presumably Ron Davis would have got his immunology friends to look at NK cells even before T cells and we have heard nothing from that group as far as I know.

There are several problems with NK cell function tests. The first is that it is all too easy ta low result - just have to be uncareful or maybe just unlucky when preparing your target and killer cell preparations. So blinded simultaneous controls are essential. From what I have of results from commercial path labs relating to ME I would not take any notice of what they send out on NK. The quality control is not there.

The second problem is that NK cell is a very strange and poorly understood process that depends on recognition of the target cells as 'self'. N cells are supposed to be 'self-policing'. But the target cells used in traditional assays are not self. They have on a line called K562, which is a of a tissue type that is unlikely to be self. My understanding is that results with these tests have always been found to vary greatly from person to person. So it is very hard to say any result is significantly abnormal.

The third problem is that we do not actually know what these tests mean in terms of healthy immune function. We know that people with severe immunodeficiencies including NK cells have zero function on the tests. But in other situations where NK cell function seems to be lower than average it is very unclear if this means anything in terms of immune deficiency.

So no, we do not know if these tests have any implication for health.

The more I see of this the more it seems likely that at some point someone thought maybe ME is like AIDS except with low NK function leading to susceptibility to infection instead of low CD4 T cells. There is really nothing to support that. PWME do not get opportunistic infections like pneumocystis or Kaposi or disseminated zoster or JC virus etc. And whereas all people with AIDS and infections have low CD4 counts the NK cell findings in ME are extremely variable and, as indicated above may actually turn out not to be real findings.

The first report of NK cell abnormalities in ME was thirty years ago. Over that time no consistent findings have emerged. If there was something to find why have the people who originally reported it not worked out the detail? If there was a serum factor it would be very straightforward to take serum from cases with low function tests and demonstrate its action on highly standardised NK cell/ target cell assays, and then fractionate to find the molecule responsible.

 

I see it can be understood like that.
CBT/GET and BPS are not about science or helping patients or understanding. It's about power. That needs to be addressed differently - it's another game with other rules. That's why they don't stick to scientific principles, in my view.

I think we have to be cautious to call everything crap, and too fast. For example: The NK cell studies aren't all crap - they're maybe not consistent. Lack of consistency or reproduction is not the same as crap. I think it would be more accurate to say "We don't know - we should look closer". We don't have deep analyses, with very few exceptions. That something isn't reproduced doesn't mean it's crap - it could be there was no money, or researchers realized they don't have the technology, or they find the topic not promising enough (again money). I also think, if it is looked at the immune system, this should happen at several points of time.

In the meantime, people with an ME diagnosis might find they have NK cell abnormalities. To say these are crap is denying part of reality, and maybe a person's reality. Obviously, there are people with ME who probably have these abnormalities, and others who don't. Does that mean the entire topic is crap? No. For some NK cells might play a role, for some they don't. Maybe we don't have the technology to know.

If we get down to it, we know only one thing for certain: There are sick and disabled people, whose disease was once called ME - it's not important if that name is correct, you could have chosen the name XYZ or KaKa - and other people tried to describe that symptom complex as best as they could. Some here say they were biased, seems everyone around ME was biased. Biased or not, sadly, that wasn't improved over time - which is the normal way - it was worsened by those who claimed the symptom complex is fatigue, by those power people.

All this doesn't get better with adding more and more names and more and more criteria. The ICC/CCC has one advantage: Many "experts" in the field agreed on them. That's quite an exception in the ME world. This could be further developed.

Imagine you all would have to describe your disease. How would you do it? How would you decide that another person has the same disease? In order to find out what's going on, you need to find people who resemble your disease as best as possible, not "a little". You can look at those separately to find if they share the same pathomechanism or another one, which would be quite enlightening.
I think that would be interesting.

Every human a new world.

 

I think you were the person who called things crap @Inara!

Just to get this straight. The lack of reproducibility of the NK findings is nothing to do with lack of money or not having technology or not finding the topic promising. The School of Hygiene, with the best NK unit in the UK thought the topic was important enough to get a $2M grant from NIH to see if they could reproduce the finding. And they found no abnormalities as far as I have been told. For the various reasons I posted it looks likely that this will turn out to be a spurious finding originally that we should forget about.

 

I was going to respond, but Jo answered this faster and better than I could.

 

I've understood the evidence for NK cell dysfunction differently. Articles in 1987 and 1990 by two different groups both found low function. And at least one other group has replicated those fundings since then. I have not heard that NK cells are fine but a serum factor is the problem. But the test needs to be run within 24 hours and I think I remember only on unfrozen samples so that limits its commercial viability and thus its use by clinicians at large. I think someone at CDC might be investigating this issue but not positive.

Hard to say much more until the London group published the data that you are referring to.

Regarding the serum factor - the only example of that that I've heard is for studies with the nanoneedle. Is that what you are referring to?

The discussion may need to be moved to a separate thread as its veering into another topic.

 

Trouble is, thirty years is a long time ago and if this is the key immunological abnormality in ME why have we heard so little. I agree that one group found something similar, although not actually the same, in the last ten years. But I am aware of four groups who have not found anything.

The first I heard of this was from a collaboration involving Nancy Klimas, although I have never seen it published. The research could not repeat the initial findings but concluded that this was because cells had been washed and low function returned with ME serum. What is a bit odd about this is that one would have expected the original studies to have been done on washed cells. More recently there was a presentation in Scandinavia- I think someone possibly from Karolinska, who claimed to have shown that it was indeed a serum factor causing reduced function. But again there is no publication.

People have been talking about a serum factor for at least four years. This is not related to Ron Davis's findings with cell impedance. Of course it could be the same serum factor in both but I have not yet been able to work out quite what Davis thinks he is measuring beyond just impedance itself - which could be affected by a thousand pathways.

I think there is likely to be a major problem with publication bias here. I have heard of at least four failures to replicate, none of which have come through to publication yet - but that is typical. I might also add that in the 1980s there were probably two publications on low NK cell function in pretty much any chronic disease!

'Needs to be run within 24hrs' and 'does not work on frozen cells' may be legitimate issues but these things are often used to explain inconvenient negative findings. The labs I am aware of know a lot about cell handling for NK function assays. And if the effect is due to a serum factor there is no problem because ME serum can be tested in standardised conditions on very fresh cells obtained from healthy volunteers.

And these considerations do not seem to have limited commercial viability and use by clinicians. On the other forum we used to have regular reports of patients having NK function tests. I suspect the tests were lousy but they were being sold. I think the limiting problem is more likely to be that you have to run patient cells against groups of controls (say ten) every time because the assay is so variable - it certainly was when we did it in our lab. Maybe that was done in the old studies but practical constraints like this tend to take as much a toll on basic research as they do on routine labs.

 

AFAIK, in the US at least, patients have gotten the tests through research labs or in some cases through commercials labs when the tests can be run the same day as the draw. But I understand that in many cases, the commercial labs here take more than 24 hours to process the samples.

Edited to add:
Meant to add - thanks for the remaining information @Jonathan Edwards.

 

One advantage of SEID would be to concentrate research minds on the exertional intolerance. We'd all be able to do a bit more and have better quality of life if this could be reduced.My cognitive function is quite normal for about 15 minutes and then it declines which I think is more likely to be a signalling/ metabolic problem

 

When you have underpowered studies, non homogenous patient groups and without a very strong effect, some of those studies are necessarily going to have null results. I strongly suggest meta analysis of the NK Cell cytotoxicity and TGF Beta results will show a modest effect, the problem is that these findings are not necessarily specific to ME patients and may simply be due to different activity/sleep patterns of patients compared to controls*.

Nevertheless, I'd like to point out that these two findings along with some of the metabolic findings of lymphocytes in patients are specifically linked.
"TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway", "TGF-β Contributes to Impaired Exercise Response by Suppression of Mitochondrial Key Regulators in Skeletal Muscle." and so on.
Inhibited mTOR is central to the metabolic profiling findings of Fluge and Mella, see this thread: https://forums.phoenixrising.me/index.php?threads/metabolic-profiling-indicates-impaired-pyruvate-dehydrogenase-function-in-myalgic-encephalopathy-cfs.48446/

Of course much of the research into ME is just throwing darts at a dart board and sometimes it looks like someone has scored, only to realise they've been throwing at a different dart board. Reporting some very specific biological, often intracellular finding as a candidate to explain ME as a whole when it is often difficult to see how, even for those who have extensively studied this field.

Taking a step back, my question is, what would an overall theory of ME look like in a systematic sense - what does this theory specifically need to explain (eg kinetics of PEM, specific symptoms, the onset patterns and so on). What are all the blanks, what are the current candidates to fill those blanks, or the overall sphere of possibilities to fill each of these blanks. While speculative, I think this may be helpful in terms of showing people where research needs to be done and the areas we need to focus on in terms of building research capacity in the field.


* TGF Beta is increased after exercise (suggested as a release from muscles after mechanical loading), but we know that exercise training can reduce TGF-Beta expression. TGF Beta is associated with type I collagen production over the several days post-exercise. Finally, a background paper reviewing the role of TGF Beta in skeletal muscle.

 

There is an important difference between a disease with an immunological cause (eg RA) and one with an immunological affect (eg AIDS).

ME CFIDS by definition involves symptoms of immune dysfunction (in the sense of AIDS) but I have not seen empirical measurement of it.

This is perplexing because for me personally it is absolutely real in the form of sudden very strong allergies to grass pollen on ME onset, (tested by panel test by Prof J Brostoff), which have taken 30 years to attenuate and ongoing recurring virus (diagnosed as HSV2 multiple times by PCR) which has never attenuated and I still get between half a dozen to a dozen episodes a year interspersed with other episodes of what appear to be other viruses. ME onset (1986) was at the same time I contracted HSV2 which immediately became recurrent but this was subsequent to mononucleosis with +ve Paul Bunnel test four years earlier. The other viruses include what appear to be EBV like episodes and others fitting the description of an enterovirus like echovirus but not officially diagnosed. I know there are other people with the same kind of problem because I have met at least one other like myself in person.

Its a very concrete problem which seems to fit the TH2 shift hypothesis which Dr Paul Cheney arrived at a while ago, which is further evidence others have the same problem and I find it hard to believe that such concrete symptoms cannot be characterised and quantified for a group, which might serve to distinguish a subtype.

Even if this subtyping and gathering of evidence was possible it would not show that ME CFIDS was caused by immune disease but would show it has immunological symptoms.

So my answer to the question in the thread title depends on what you mean by immunological disease? If you asked me if it was AIDS like I would say yes, but I have no evidence it is like RA and caused by the immune system. If you asked me if it involved autoimmunity I would say probably as I have had shifting symmetrical joint pain much of the 32 years I have had ME but I would consider that as symptomatic and not causal and possibly related to too many inappropriately immortalised B cells (by EBV).

Because of my symptoms and onset conditions I believe the cause of pathology is related to viral infection and impacts the immune system among other symptoms but that does not mean the immune system causes the disease. I consider it likely that the primary symptoms of CFS are due to an immune defence pathway which changes metabolic processes to hamper virus replication, but if the virus is replicating then this is appropriate and not pathology, the pathology lies in the fact that viruses continually recur and are not cleared.

This could be due to viral immunoevasins (possibly synergising) and could involve genetic susceptibility. But if those hypothesese proved true this would not make it an immunologically caused disease in the way RA is but it could be considered a disease of the immune system itself akin to AIDS in that sense.

 

Would anyone with a little more brainpower than me care to add their thoughts on this?

Immunosignature Analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

 

IF this finding stands up to replication then it shows that we probably have a stronger anti-viral response than normal, and this to be expected from other findings, especially the RNaseL findings.

The quote about PCR is about standard PCR, not the cutting edge PCR variations that have been done. They have explicitly looked for unknown viruses. They have not found any. This is still ongoing however, they have not given up. Also the viral sequences that have been checked for include all known viruses, not just human viruses. However this latest test was on a short list of viruses for which it looks like they did some kind of quantitative PCR assay, assessing viral load. This is also different from an antibody assay.

Even an ICC or CCC ME diagnosis is probably heterogenous. It might not be, but it looks like it is to me, based on how findings split in studies with often a one third to two thirds split.

I would say there is considerable evidence of immunological abnormalities in individual cases. The problem is that there is no consistent abnormality even using ME diagnoses, though newer findings need more testing and replication and might well show such a finding ... or not.

For example, if ME is primarily metabolic then the immune system will also be impacted. There would be considerable variation I suspect, so the immune problems would vary. Also comorbidities and varying triggers might induce different immune markers.

The issue here is not that anyone considers there is no brain damage or immune damage, the issue is about quality of evidence. This is a massively under-funded area, all of ME research is. Large scale studies are very rare. Psychobabble studies are much larger than our biomedical studies. There is little funding to do otherwise. Similarly findings are not always even tested to see if they are replicable.

It is also important to consider the etiology of problems. The brain is highly sensitive to metabolic disturbance. However if Stanford can replicate their brain structural changes findings then there will be validated observable structural changes, showing something is substantially wrong in the brain. I hope to see those results next year.

I do support the use of modern ME definitions for research, and am not pro-SEID, but I am not sure its too far from an ME diagnosis. Its certainly better than Fukuda. Its deliberately simplified so it has a higher chance of catching a diagnosis, whereas for example the ICC is deliberately written to exclude any ME diagnosis that might not be ME, to improve research cohort homogeneity. It will fail to diagnose many ME patients, as intended by design. However some of this can be improved by relaxing exclusion criteria in a clinical setting.

Let me give an example. OI and sleep apnoea are conditions in their own right. Yet both are common in ME. Its proper to exclude sleep apnoea patients in a research cohort, its improper to necessarily exclude them (unless the apnoea explains all symptoms) in a clinical definition. This is particularly the case since apnoea does not seem to induce PEM. Also its important to realise that Orthostatic Intolerance might itself be heterogeneous, and even in ME it possibly represents different comorbid disorders. This is before considering POTS versus NMH as well.

It is critical to exclude as many possible confounding disorders as possible in a research cohort. Its not always a good idea to do that in a clinical diagnosis. I am excluded from being in a research cohort due to potential immunological confounds from diabetes. Yet my diabetes is highly atypical, and I am not sure its not just ME induced glucose intolerance.

Not having a PEM diagnostic tool is a major concern. Its so very easy to misinterpret PEM, even in an ME diagnosis. This probably results in many non-ME patients being wrongly included in research cohorts. Now the newer work on energy metabolism, and refinements of CPET, may change that, but that is work in progress. If we had a PEM diagnostic test that is easy, cheap and reliable then I think many bad research cohorts would be caught out, such as ME diagnoses that are really depression. Even if we do not have an ME diagnostic test, we still need a PEM diagnostic test.

To reiterate, there are many patients who have ongoing viral infections, demonstrated brain problems, or demonstrated immunological problems. The issue is whether these are consistent enough to be considered either a common finding or even diagnostic.

The putative molecule that Ron is looking for that disables blood cell metabolic function might even be an antibody, or some other immune factor, though its far from certain. Again that is research we are waiting on.

 

Yes, I have been trying to point that out for years. Its not science as we know it, and its promoted by political and economic issues.

 

Ron Davis has also found this issue ... and still not formally published. He is using the nanoneedle for this purpose, and the test is still being investigated without drawing hard conclusions.

 

I think what I am trying to say here is that as far as I am concerned, my symptom history provides empirical evidence to me that I have immune related disease one way or another. There is no question because my primary symptom is recurring virus and ME is secondary.

The question from my perspective is whether I have the same illness as everyone involved in the studies which are producing no results with statistical significance.

This appears to be about diagnosis and subtyping. Its a chicken and egg situation, until we have accurate diagnosis we cannot subtype, but until we can subtype correctly we cannot derive methods for accurate diagnosis.

From a perspective of enlightened self interest (or possibly more accurately a self interested quest for enlightenment) I would like to see stricter criteria used for some studies which require evidence of TH2 shift and recurring viral activity in the selection of patient subjects. I think that might provide a clearer picture of one subtype with immune dysfunction by definition and then it might be possible to identify other subtypes by isolating this subtype by molecular methods and removing it from other groups of subjects, so reducing variation in groups and making it easier to discover other subtypes with different conditions producing ostensibly similar symptoms.

At the moment I think, to extend the metaphor of comparing apples and oranges, many studies involve a bag of mixed fruit, any and all patients with unexplained chronic fatigue is far too loose a definition to pick out subtypes, some of which may not be immune disease at all, like organophosphate poisoning and some of which may be immune disease of a fundamentally different type and some of which may be misdiagnosis of other potentially recognisable illnesses like MS, Lymes, early cancer etc.

PS The alternative is to scale up sample sizes and use very broad multifactor assays plus computer analysis to try to derive subtypes from raw data. That seems to be where people are heading and what I expect is that if they have any success with this method they will eventually find that ME is being diagnosed for different diseases, some of which are immunological and some of which are not.