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In 2020 I took part in a very small unpublished pilot study that found "low level" connective tissue disease antibodies (sjogrens, lupus, dermatomyositis etc) vs healthy controls using a modern ELISA like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).