Preprint A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma, 2025, Edwards, Cambridge and Cliff

[Utsikt]

It isn't a matter of brute fact, the conclusion one draws depends entirely on how the evidence is intrepretated. Evidence is not some objective entity that points towards one true conclusion, evidence means something because a mind interprets it as changing a point of view. If these disagreements were matters of brute fact there would be no need for evidence and no need for debate.

My (limited) understanding is that the majority of the uncertainty in science lies in how accurately the evidence is able to capture the underlying reality, and not in how the evidence is interpreted.

So the caveat is mostly «if A is correct, B must be true», and B is just given by logic.

The problem we’re discussing here is that for the studies mentioned by MW, if A is true, any one of B to Z could be true. Yet MW claims that A definitely means that G is true, and ignores the various other meanings that are equally supported or made possible by evidence A.

There is also the issue of how we might not be able to imagine all of the possible explanations for A, and therefore wrongly believe that A supports B, and only B. Essentially an issue of unknown unknowns.

As for your last point - you can’t assume that all people are perfectly rational. And you’d still need evidence to establish something as a fact, regardless, otherwise it would be an opinion.

 

[wigglethemouse]

To test for women having more 'junk antibody' activity you might need a special assay using FcR1 but if it were just a shift in Kd you could probably do it with standard ELISA technology.

But the idea of testing female sera for more low affinity activity seems to me a very nice experiment if one could persuade someone to fund it. Maybe Audrey could do it - she has already shown some odd things about MECFS Igs.

Thank you for taking the time to respond in such detail.

In 2020 I took part in a very small unpublished pilot study that found "low level" connective tissue disease antibodies (sjogrens, lupus, dermatomyositis etc) vs healthy controls using a modern ELISA like array in a research lab. I think the results changed with longitudinal sampling, and did not hold up when tested with standard clinical test for autoimmunity or gold standard wet lab for most participants. Is this the kind of result you would expect to see?

That researcher moved on and I recently heard that another researcher did another similar pilot project with the same research test lab. I think on the whole both researchers did not know what to make of the results except to confirm that it might fit the picture of non-specific B cell clonal activation. Would that description seem relevant to your hypothesis?

 

[Jonathan Edwards]

In 2020 I took part in a very small unpublished pilot study that found "low level" connective tissue disease antibodies (sjogrens, lupus, dermatomyositis etc) vs healthy controls using a modern ELISA like array in a research lab. I think the results changed with longitudinal sampling, and did not hold up when tested with standard clinical test for autoimmunity or gold standard wet lab for most participants. Is this the kind of result you would expect to see?

That researcher moved on and I recently heard that another researcher did another similar pilot project with the same research test lab. I think on the whole both researchers did not know what to make of the results except to confirm that it might fit the picture of non-specific B cell clonal activation. Would that description seem relevant to your hypothesis?

I guess these were studies of people with ME/CFS? As indicated, our theory does not propose yo would find anything different in ME/CFS populations - but it does require a difference in women.

Jo Cambridge has been working with a commercial assay that looks at hundreds of antigens. Maureen Hanson published on something similar. There are lots of ways one might approach it but very careful attention needs paying to the thermodynamics of the binding events and to having a relevant read-out. I doubt that any of the commercial arrays would be set up right, but maybe they would pick something up. Jo is the technical expert on this sort of thing. She has been looking at antibody profiles in ME/CFS for several years now. There are findings but not so far published.

 

[Jonathan Edwards]

If I were to hand you some respirometry and extracellular acidification traces, plus some background reading, I could not expect you to apply anywhere close to the depth of understanding and accuracy of interpretation that I have developed by years of experience. And it would make perfect sense for you to seek my advice, particularly if there was something you did not feel confident in drawing conclusions about.

Yes, but this is a different context, @DMissa. If both you and I were interested in a research problem and it involved assessing extracellular acidification I would come to you and ask you to explain the details to me and after I had spent an hour asking as difficult questions as I could think of so that I absolutely understood why the results had to mean what they were supposed to mean I would likely thank you profusely for getting me up to speed. But I would not depend on your opinion about it, just mine. That is a million miles away from one person studying a problem to say 'there is lots of inflammation' and another person studying the problem saying 'OK' I take your word for it. Before I got anywhere with RA I had to get training or train myself in about six disciplines. I have had to do the same for my work on the biophysics of perception. We have to know everything about the problem we are trying to tackle

It isn't a matter of brute fact,

In reality I think it is. I see this is a 'not so open as to let your brain fall out' situation.

Someone has claimed that there is lots of inflammation in ME/CFS. That might seem to be a matter of meaning of 'inflammation', but it cannot be. There is no concept of inflammation that allows anyone on current evidence to say there is lots in ME/CFS. The original meaning is tissue physiology - no. Then you could allow surrogate biochemical markers like acute phase proetins and ESR - no. In fact the ESR is said to be unusually low in ME/CFS (doubtfully). Then you might stretch it to saying that any odd inflammatory cytokine that is raised means lots of inflammation. There are some reports of IL-8 being up but even more reports of TGF beta which is said to be anti-inflammatory. And who knows what these are doing, even if the results can be relied on?

I personally do not see how this statement can have been based on any evidence.

That is a strong thing to say but it happens all the time in biomedical circles. For years people said that RA and MS were 'TH1 diseases'. There is no concept of a TH1 disease that would allow one to say that there was clear evidence of these being it. We have physicians claiming that ME/CFS is associated with Ehlers Danlos syndrome when they don't even mean Ehlers Danlos syndrome. We have people saying it is all biopsychosocial. Enough said.

I think I am entitled to be annoyed if someone (if this is a group of people that is seriously underhand) who hides behind a pseudonym has completely misread our paper and come up with a vast list of misinformation that, as others have said, has not served anybody well. An awful lot of science is worthless, for all sorts of reasons. I don't think anything that was raised makes any difference to the negative statements I used to build a framework for what we know.

If anyone has an example let's look at it.

And it isn't just me, remember. When I chaired my first IiME colloquium I thought I would get the debate going a bit by asking the forty - odd international ME/CFS scientists what was agreed to be known in the science. The unanimous answer came back like a return from Alcaraz - nothing! Nobody working in the field really believes we have an evidence base. They have to sell research programmes but we still do not have anything solid - unless we can agree that the genetic data cannot be all noise.

 

[Hutan]

Yes, but I envisage the T cell macrophage interaction as occurring within a highly controlled microenvironment within lymph node or spleen, where bacterial products are not expected to be present at levels that would generate inflammation.

Apologies if I've posted this idea before - not sure if it ever made it out of my head - but I'm wondering if a natural experiment has already been done regarding some of the proposed treatments in this paper, that would help test its validity.

Putting those two things together, there was one case report of the removal of a spleen, and subsequent recovery from 'CFS'. It wasn't a very good case report. But, I wonder if there are any more cases of this happening.

I guess these were studies of people with ME/CFS? As indicated, our theory does not propose yo would find anything different in ME/CFS populations - but it does require a difference in women.

There are lots of ways one might approach it but very careful attention needs paying to the thermodynamics of the binding events and to having a relevant read-out.

The thermodynamics of binding events - that's an interesting thought. The core temperature of the person might affect the rate of all sorts of biochemical reactions, or even whether a reaction occurs at all. As far as I can see, the core temperature of women tends to be a bit higher than in men. Perhaps that tendency is enough to increase the chance of antibodies binding to receptors, or something else? Exercise can significantly increase core temperature (although the idea of that being significant falls down a bit if we are trying to explain why simply brushing teeth can cause PEM).

 

[Utsikt]

The thermodynamics of binding events - that's an interesting thought. The core temperature of the person might affect the rate of all sorts of biochemical reactions, or even whether a reaction occurs at all. As far as I can see, the core temperature of women tends to be a bit higher than in men. Perhaps that tendency is enough to increase the chance of antibodies binding to receptors, or something else? Exercise can significantly increase core temperature (although the idea of that being significant falls down a bit if we are trying to explain why simply brushing teeth can cause PEM).

What about the people that feel better during the summer or in a warm climate? I’ve heard anecdotes of it from people I know well, even though I think the norm is to feel worse during the hotter months.

 

[Jesse]

although the idea of that being significant falls down a bit if we are trying to explain why simply brushing teeth can cause PEM

Small overexertions can cause me to overheat too honestly.

What about the people that feel better during the summer or in a warm climate? I’ve heard anecdotes of it from people I know well, even though I think the norm is to feel worse during the hotter months.

Interesting point. I do very poor with both being too cold and with being too hot. But I generally get too cold way easier, than too hot. So I'm more comfortable in summer.

Then again the season doesn't doesn't significantly impact my ME/CFS. It mainly affect my mood positively (summer) or negatively (winter).

 

[ChronicallyOverIt]

As someone with very little knowledge of how these things work what are next steps towards evidence gathering of this hypothesis?

Paper gets peer reviewed then fully published, then other groups would be willing to test this hypothesis?

Who do we support, I have been donating to OMF over the years with family and friends, would they pick this up?

 

[DMissa]

Before I got anywhere with RA I had to get training or train myself in about six disciplines. I have had to do the same for my work on the biophysics of perception. We have to know everything about the problem we are trying to tackle

The point is that of the however many areas likely needed to understand what's going on, inflammation is one of them (because the word is still being used, and knowing whether it is founded on firm grounding or not is important) and all I am seeking is a bit of context to help steer me through my own learning.

There is no concept of inflammation that allows anyone on current evidence to say there is lots in ME/CFS. The original meaning is tissue physiology - no. Then you could allow surrogate biochemical markers like acute phase proetins and ESR - no. In fact the ESR is said to be unusually low in ME/CFS (doubtfully). Then you might stretch it to saying that any odd inflammatory cytokine that is raised means lots of inflammation. There are some reports of IL-8 being up but even more reports of TGF beta which is said to be anti-inflammatory. And who knows what these are doing, even if the results can be relied on?

This is helpful and the kind of thing I was originally hoping for. Thank you*.

But I would not depend on your opinion about it, just mine.

Which is why I already said that I am taking your (or others') input as supplementary to the available evidence (and not simply taken on trust, I explicitly said this) and why I was hoping for something like the foregoing reply that I just flagged (ie: an appraisal and summary of salient evidence that I can work to independently verify as a starting point). I am doing my own research and just hoping for more evidence to incorporate into my own interpretation, particularly given the disagreement over this topic (regardless of who is right or wrong or why, stumbling across a disagreement that one knows little about might warrant a clarification of the logic underpinning either side of the argument, yeah? That's all I'm asking for, which you have now delivered, so, again, thank you*).

Not looking for spoonfeeding or to recycle catchphrases. Trust me.



* :

I would likely thank you profusely for getting me up to speed

 

[butter.]

I can't read the whole thread so forgive me if this has been asked before, @Jonathan Edwards.

Can your hypothesis account for the large subgroup of patients who are highly susceptible to infectious diseases? (Many of these patients report that as their ME progressed over the years, they became seemingly incapable of running a fever and rarely—or never—contract infections.)

 

[Peter T]

I can't read the whole thread so forgive me if this has been asked before, @Jonathan Edwards.

Can your hypothesis explain the large subgroup of patients who are very prone to catch infectious diseases? (Many of these patients report that as their ME progressed over the years they became seemingly incapable to run a fever and never/rarely get infections.)

Presumably the question is that, does the model under discussion make any predictions about whether people are at higher or lower risk of catching infections, whether we respond differently if we do have a viral infection and would we expect this to change over time?

The forums contain such variation in subjective accounts of our responsiveness to viruses it is difficult to know what the phenomenon is or even if there is a genuine immunological phenomenon. My personal subjective reporting would be there have been times in the course of my ME when I seem to get every virus going and times when I don’t catch any. But can we say this is genuine immunological issue or down to other factors? Would people who do not have ME/CFS if they have a reason to be monitoring their health report similar apparent variation? Is the potential confusion between PEM and mild or even more marked viral infections a confounding factor? Does any change in viral infection rates in ME/CFS rather reflect behavioural patterns arising from having the condition, for example because of Covid, which I have so far managed to avoid, and being largely housebound, I have now very little exposure to viruses, however some years ago when I was milder and lived next door to a pub that offered good value home cooked meals I would have pub lunches three or four times a week?

Though subjectively we feel our responses to viruses seems changed, we can not quantify this or even be certain that it is an actual immunological phenomenon? However we can ask what might this model predict and does this raise possible research opportunities?

[edited to clarify and correct typos]

 

[butter.]

Presumably the question is that, does the model under discussion make any predictions about whether people are at higher or lower risk of catching infections, whether we respond differently if we do have a viral infection and would we expect this to change over time?

The forums contain such variation in subjective accounts of our responsiveness to viruses it is difficult to know what the phenomenon is or even if there is a genuine immunological phenomenon. My personal subjective reporting would be there have been times in the course of my ME when I seem to get every virus going and times when I don’t catch any. But can we say this is genuine immunological issue or down to other factors? Would people who do not have ME/CFS if they have a reason to be monitoring their health report similar apparent variation? Is the potential confusion between PEM and mild or even more marked viral infections a confounding factor? Does any change in viral infection rates in ME/CFS rather reflect behavioural patterns arising from having the condition, for example because of Covid, which I have so far managed to avoid, and being largely housebound, I have now very little exposure to viruses, however some years ago when I was milder and lived next door to a pub that offered good value home cooked meals I would have pub lunches three or four times a week?

Though subjectively we feel our responses to viruses seems changed, we can not quantify this or even be certain that it is an actual immunological phenomenon? However we can ask what might this model predict and does this raise possible research opportunities?

[edited to clarify and correct typos]

Thanks for elaborating on it and for making my question more precise.

While I'm not certain it's an immunological phenomenon, I'm quite confident that the absence of fever in some people with ME is real. Real in the sense that it's not present when it should be (think appendicitis, sepsis, bacterial infections,...) It's a subgroup finding that may not be exclusive to ME—or even directly related to it—but the phenomenon itself is likely genuine.

The same goes for susceptibility to infections. I think there's a general tendency to dismiss such 'anecdotes' (if a clinician sees hundreds of patients making such remarks anecdotes become patterns) too readily. They could be valuable for stratifying patients. Ignoring this kind of evidence might be an overcorrection in response to the history of poor-quality research.

 

[Eddie]

In reality I think it is. I see this is a 'not so open as to let your brain fall out' situation.

Someone has claimed that there is lots of inflammation in ME/CFS. That might seem to be a matter of meaning of 'inflammation', but it cannot be. There is no concept of inflammation that allows anyone on current evidence to say there is lots in ME/CFS. The original meaning is tissue physiology - no. Then you could allow surrogate biochemical markers like acute phase proetins and ESR - no. In fact the ESR is said to be unusually low in ME/CFS (doubtfully). Then you might stretch it to saying that any odd inflammatory cytokine that is raised means lots of inflammation. There are some reports of IL-8 being up but even more reports of TGF beta which is said to be anti-inflammatory. And who knows what these are doing, even if the results can be relied on?

I personally do not see how this statement can have been based on any evidence.

Appreciate the explanation and I agree with you on the definition of inflammation and its lack of presence in ME/CFS. I think it is useful to have the evidence for inflammation spelled out at those different levels. It would be interesting to see what reasons advocates of inflammation would give in response to those points; I don't know why they think what they do. In any case, vague concepts such as this one certainly haven't made any headway into discovering specific mechanisms or treatments.

I do think there is a real problem with what terms refer to, but that is part of a broader point about reference/meaning and intentionality. I might post some of my ideas on the Mind Body and ME thread when I collect my thoughts.

 

[Jonathan Edwards]

what are next steps towards evidence gathering of this hypothesis?

Paper gets peer reviewed then fully published, then other groups would be willing to test this hypothesis?

Who do we support, I have been donating to OMF over the years with family and friends, would they pick this up?

The paper is published. It would be nice to have feedback on the site but the formal peer review process was never very relevant to the way a field moves forward.

The most important next step for me is to see how data from DecodeME tests the framework of the theory, which it should do. The paper was deliberately put out with that hope.

Otherwise, I think the most useful thing will be discussion, here and elsewhere, as to what predictions might be testable. These may turn out to be quite left field - like the idea of looking for low affinity FcR1-binding junk antibodies in women. Or more obvious like does daratumumab actually work. @jnmaciuch has raised the idea that type I interferons might be more important. I think that sort of discussion-bone is worth gnawing at hard because that is the sort of thing that leads to new insights into which things are really critical for a theory to work.

To be frank, the key groups I see as having the right expertise and wide-angled vision are Edinburgh and Bergen. I have to put in a plug for Jackie Cliff and the LSHTM looking at T cell subpopulations and I think Maureen Hanson and Chris Armstrong are doing good work relevant to the theory. There are others but for me these are the professionals at the coal face.

 

[Jonathan Edwards]

I do think there is a real problem with what terms refer to, but that is part of a broader point about reference/meaning and intentionality. I might post some of my ideas on the Mind Body and ME thread when I collect my thoughts.

Absolutely. It was the one bit of contemporary philosophy on my MA course that came as a real revelation!

 

[rapidboson]

but it does require a difference in women.

Does this exclude men with me/cfs from the hypothesis?

 

[Jonathan Edwards]

Does this exclude men with me/cfs from the hypothesis?

Not at all. Men get rheumatoid arthritis and even lupus, despite autoantibodies being more common in women. All adaptive immune processes involve a major random or stochastic element, so we can expect statistical shifts between sexes, but some errors to occur in both sexes.

 

[V.R.T.]

The paper is published. It would be nice to have feedback on the site but the formal peer review process was never very relevant to the way a field moves forward.

The most important next step for me is to see how data from DecodeME tests the framework of the theory, which it should do. The paper was deliberately put out with that hope.

Otherwise, I think the most useful thing will be discussion, here and elsewhere, as to what predictions might be testable. These may turn out to be quite left field - like the idea of looking for low affinity FcR1-binding junk antibodies in women. Or more obvious like does daratumumab actually work. @jnmaciuch has raised the idea that type I interferons might be more important. I think that sort of discussion-bone is worth gnawing at hard because that is the sort of thing that leads to new insights into which things are really critical for a theory to work.

To be frank, the key groups I see as having the right expertise and wide-angled vision are Edinburgh and Bergen. I have to put in a plug for Jackie Cliff and the LSHTM looking at T cell subpopulations and I think Maureen Hanson and Chris Armstrong are doing good work relevant to the theory. There are others but for me these are the professionals at the coal face.

You have said before that the 'hypothesis destroying' experiments that can total your hypothesis and help you build a better one might be drug trials in this scenario.

Without speculating on what the drug would be, how might such trials play out? I'm interested in the mechanics and organisation of this sort of experimental drug trial.

 

[Jonathan Edwards]

Without speculating on what the drug would be, how might such trials play out?

No idea, specifically, but the way Fluge and Mella have done things comes to mind.

 

[Holinger]

Response from Caroline Struthers.

Review of: "A Proposed Mechanism for ME/CFS Invoking Macrophage FcγRI and Interferon Gamma"

I am grateful to Qeios for asking me to review this article I am primarily a patient advocate and have no clinical training or expertise in ME/CFS or any other condition. I have been interested in the evidence for treatments for ME/CFS, or rather th...

www.qeios.com