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

[Jonathan Edwards]

But what do you mean by «stereotyped history of post-infective illness»?

In Reiter's the post-infective illness is quite different from the initial infection and occurs with a delay of several days. In rheumatic fever the illness is different from the original infection (sore throat) and occurs with a few days delay. The problem with rheumatic fever is that it may not strictly be post-infective because if you remove the organism it disappears, even if there may be effects of scarring years later. So rheumatic fever may be a 'secondary infective illness'.

The point of the paragraph is to indicate that although ME/CFS often appears to follow an infection the evidence for some specific triggering of an adaptive immune response is less clear than in something like Reiter's. We later come back to the idea that T cell populations may be expanded but at this point in the story I am more concerned with dismissing a knee-jerk assumption that this is some sort of antigen-specific 'triggering of autoimmunity' with all the implications about mimicry that people are so obsessed with.

I think Lidbury has either misunderstood what I am saying or has misinterpreted what he thinks he has read about symptoms appearing after 12 weeks

 

[Utsikt]

but at this point in the story I am more concerned with dismissing a knee-jerk assumption that this is some sort of antigen-specific 'triggering of autoimmunity' with all the implications about mimicry that people are so obsessed with.

Thank you! So essentially saying that although it might start with an infection, the specifics of that infection probably doesn’t have much to do with ME/CFS?

 

[Jonathan Edwards]

So essentially saying that although it might start with an infection, the specifics of that infection probably doesn’t have much to do with ME/CFS?

Yes, that is the central point.

 

[Peter T]

I am not quite sure what Lidbury is claiming. He says that 12 weeks are needed to see the appearance of idiopathic, long-term fatigue, PEM, and associated symptoms.

My personal experience was that I could not distinguish between the end of my triggering acute glandular fever (mono) and the start of my ME/CFS. As it was thirty years ago and I did not then have the concept of PEM, I can not be sure, but retrospectively the activity/crash cycle seems pretty much like PEM.

However people report such variation in their onset it makes no sense for any one to assert a definite time period for the emergence of specific symptoms. We just don’t know.

 

[Jonathan Edwards]

Thinking again about the text Lidbury thinks is 'incorrect':

“No consistent macroscopic or microscopic structural changes have been found in the brain,…”.

I think I want to stick with that. 'Consistent' can mean various things but in the context what I think I was meaning is sufficiently consistent across all ME/CFS patients for it to be likely to be part of the explanation for symptoms. In other words, what people call a diagnostic biomarker. I am pretty sure that no studies have found that - just statistical trends.

This is not an unreasonable thing to require. Research often finds statistical differences that may be of huge interest in telling us about things that are importantly, but indirectly, relevant to causal pathways. But if we are looking for something that is 'showing us what is going on behind the symptoms" it needs to be there in all cases and not in normal people - with some limited caveats.

People with ME/CFS do not consistently show any one particular change on brain imaging as far as I know.

 

[Hutan]

We have moved posts discussing the possibility that people with ME/CFS are immunocompromised to a new thread:
Are people with ME/CFS immunocompromised?

 

[forestglip]

@Jonathan Edwards, I'm not sure if you saw this response from Margaret Williams. She posted it on her website (PDF), and someone also shared it on Phoenix Rising:

DISCUSSION: Prof. Johnathan Edwards, MD: "A Proposed Mechanism for ME/CFS Invoking Macrophage FcγRI and Interferon Gamma"

A Proposed Mechanism for ME/CFS Invoking Macrophage FcγRI and Interferon Gamma Jonathan Edwards1, Geraldine Cambridge1, Jacqueline M Cliff2 Abstract Evidence bearing on possible mechanisms for the clinical syndrome of ME/CFS is reviewed. The evidence is used to argue for a hypothesis that...

forums.phoenixrising.me

First few paragraphs:

Professor Emeritus Jonathan Edwards states in his Qeios Review Article: “The absence of structural or biochemical pathology in ME/CFS has meant that definition is based entirely on symptoms and their dynamics over time” (A Proposed Mechanism for ME/CFS Invoking Macrophage FcɣRI and Interferon Gamma. 27th May 2025: Preprint Vl. CC-BY 4.0 doi.org/10.32388/8GI3CT).

With no disrespect to Professor Edwards, structural and biochemical abnormalities and impaired muscle recovery after exercise are well-documented in ME/CFS: given the sheer extent of published and “grey” evidence (eg. evidence presented at conferences) that disproves such an assertion, it is difficult to understand why Professor Edwards does not recognise this.

Does this mean that Professor Edwards rejects, for instance, the evidence of structural degradation of muscle found in ME by the late Professor Wilhelmina Behan, a recognised and renowned international authority on muscle pathology? Her findings are unambiguous: “Evidence of mitochondrial abnormalities was present in 80% of the cases with the commonest change (seen in 70%) being branching and fusion of cristae, producing ‘compartmentalisation’. Mitochondrial pleomorphism, size variation and occasional focal vacuolation were detectable in 64%…Vacuolation of mitochondria was frequent…In some cases there was swelling of the whole mitochondrion with rupture of the outer membranes…prominent secondary lysosomes were common in some of the worst affected cases…The pleomorphism of the mitochondria in the patients’ muscle biopsies was in clear contrast to the findings in normal control biopsies…Diffuse or focal atrophy of type II fibres has been reported, and this does indicate muscle damage and not just muscle disuse” (WMH Behan et al. Acta Neuropathologica 1991:83:61-65).

In respect of Professor Edwards’ denial of biochemical pathology, there is clear evidence of reduced blood volume in most ME patients. A frequent clinical presentation of this is postural intolerance and persistent thirst. Professor Edwards may not be familiar with this as he does not see patients with ME. The cause is invariably impairment of the hypothalamic-pituitary-adrenal axis. Demitrack et al were the first to describe this in 1991 (Journal of Clinical Endocrinology and Metabolism 1991:73:6:1224-1234), since when there have been many papers confirming this finding. A consultant physician recently informed me that most patients he sees arrive at the consultation with a bottle of water. They then proceed to drink from this throughout the consultation. Some also have to empty their bladder half way through the consultation because of excessive urinary output secondary to the HPA axis deficiency.

 

[Utsikt]

@Jonathan Edwards, I'm not sure if you saw this response from Margaret Williams. She posted it on her website (PDF), and someone also shared it on Phoenix Rising:

DISCUSSION: Prof. Johnathan Edwards, MD: "A Proposed Mechanism for ME/CFS Invoking Macrophage FcγRI and Interferon Gamma"

A Proposed Mechanism for ME/CFS Invoking Macrophage FcγRI and Interferon Gamma Jonathan Edwards1, Geraldine Cambridge1, Jacqueline M Cliff2 Abstract Evidence bearing on possible mechanisms for the clinical syndrome of ME/CFS is reviewed. The evidence is used to argue for a hypothesis that...

forums.phoenixrising.me

First few paragraphs:

Last paragraph:

Finally, it would be helpful if Professor Edwards would be kind enough to explain for non-immunologists if his postulation disproves or substantiates the view of Professor Nancy Klimas, then Clinical Professor of Medicine in Microbiology/Immunology/Allergy and Psychology, University of Miami School of Medicine and undoubtedly one of the world’s foremost researcher-clinicians into the aberrant immunology seen in ME/CFS patients. She maintains that 80% of all ME/CFS patients – both severely and not so severely ill – have evidence ofinflammation if the correct scans are used. She further maintains that in fact, 100% of ME/CFS patients have chronic inflammation (2008: personal communication). Does Professor Edwards agree?

If I’ve learned anything from this forum, it’s that an appeal to authority and hand-waving about «inflammation» isn’t going to cut it.

And am I the only one that feels the tone is harsh, even to the point of being a bit hostile?

 

[forestglip]

And am I the only one that feels the tone is harsh, even to the point of being a bit hostile?

I don't think it's necessary to focus on. She apparently thinks Jonathan is blatantly wrong about that point, so it's understandable to sound a bit more defensive. I'm sure the writers of the "Patients with severe ME/CFS need hope..." paper consider some of the rapid responses they got harsh/hostile too.

 

[Utsikt]

I don't think it's necessary to focus on. She apparently thinks Jonathan is blatantly wrong about that point, so it's understandable to sound a bit more defensive. I'm sure the writers of the "Patients with severe ME/CFS need hope..." paper consider some of the rapid responses they got harsh/hostile too.

Fair enough.

 

[Hutan]

In respect of Professor Edwards’ denial of biochemical pathology

That's an extraordinary thing to say about a paper that proposes a disease mechanism (that involves biochemistry). I think Margaret means 'denial of existing specific evidence of biochemical pathology'.

Does this mean that Professor Edwards rejects, for instance, the evidence of structural degradation of muscle found in ME by the late Professor Wilhelmina Behan, a recognised and renowned international authority on muscle pathology? Her findings are unambiguous: “Evidence of mitochondrial abnormalities was present in 80% of the cases with the commonest change (seen in 70%) being branching and fusion of cristae, producing ‘compartmentalisation’. Mitochondrial pleomorphism, size variation and occasional focal vacuolation were detectable in 64%…Vacuolation of mitochondria was frequent…In some cases there was swelling of the whole mitochondrion with rupture of the outer membranes…prominent secondary lysosomes were common in some of the worst affected cases…The pleomorphism of the mitochondria in the patients’ muscle biopsies was in clear contrast to the findings in normal control biopsies…Diffuse or focal atrophy of type II fibres has been reported, and this does indicate muscle damage and not just muscle disuse” (WMH Behan et al. Acta Neuropathologica 1991:83:61-65).

That sounds like an interesting paper, I'll make a thread for it. However, it has to be said, there have been studies of ME/CFS mitochondria since 1991 that have not found mitochondrial abnormalities in ME/CFS cells. I think if the answer was as easy as 'ME/CFS mitochondria look different', we'd know that for sure by now. So, while Professor Behan may have presented unambiguous findings, the conclusion about mitochondrial abnormalities based on the totality of the literature is a lot less certain.

I guess we won't be able to convince people like Margaret who are sure that there is a great swathe of compelling evidence. But, that belief hasn't served us well. We need our advocates to be a lot more discriminating.

Edit- We already had a thread for the W. Behan mitochondria paper - link here.

 

[Peter T]

Margaret William says:

Professor Emeritus Jonathan Edwards states in his Qeios Review Article: “The absence of structural or biochemical pathology in ME/CFS has meant that definition is based entirely on symptoms and their dynamics over time” (A Proposed Mechanism for ME/CFS Invoking Macrophage FcɣRI and Interferon Gamma. 27th May 2025: Preprint Vl. CC-BY 4.0 doi.org/10.32388/8GI3CT).

With no disrespect to Professor Edwards, structural and biochemical abnormalities and impaired muscle recovery after exercise are well-documented in ME/CFS: given the sheer extent of published and “grey” evidence (eg. evidence presented at conferences) that disproves such an assertion, it is difficult to understand why Professor Edwards does not recognise this.

Though she raises many issues that any understanding of the aetiology must ultimately accommodate, she misses the point that none of these potential biomedical anomalies have yet risen to the point where they can be used as a clinical diagnostic biomarker or be used as as defining features, that currently ME/CFS is defined on the basis of symptoms. No where does @Jonathan Edwards deny the potential future relevance of such abnormalities in understanding the condition, rather he indicates that none have yet achieved the status that Margaret has accorded them.

So many of our advocates allow their enthusiasms (myself included) to take themselves beyond what current science allows us to say.

 

[DMissa]

On one hand, I see accounts from reputable clinicians saying "there is no observable inflammation" (Edwards), and on the other hand, reputable clinicians saying "there is observable inflammation" (Klimas).

So what conclusion is to be drawn here for the non-clinician on the sidelines?

Though she raises many issues that any understanding of the aetiology must ultimately accommodate, she misses the point that none of these potential biomedical anomalies have yet risen to the point where they can be used as a clinical diagnostic biomarker or be used as as defining features,

I think I said something like "there's nothing clear" in the recent webinar which I silently kicked myself for because I know people will hear it and think I'm saying we know nothing - but the point being made was what you are saying here. It's not that we don't know anything or deny a biological basis, it's that we haven't yet nailed the causal mediators or defining molecular features.

 

[Eddie]

So what conclusion is to be drawn here for the non-clinician on the sidelines?

My conclusion is that there is no universal standard of evidence that makes something convincing. What conclusion you draw is based on how the evidence fits with your prior experiences and beliefs. I think people can disagree on pretty much any issue and still be reasonable, it is just hard to see what evidence looks like from their perspective without knowing what it is like to be them.

I also think the same thing applies to the use of language. Even though a term like inflammation has a relatively specific definition, people can use that terms to mean all sorts of different things. I doubt most ME/CFS researchers are using inflammation in ways that refer to swelling and redness. Perhaps they are wrong to use the term in this way, but then again humans decide what words mean.

Given we want understand ME/CFS it is not very helpful to use a term to mean all sorts of different things. So I think if people stayed away from vague terms and said what they mean by "inflammation" that would help solve some of the problem.

 

[hotblack]

So what conclusion is to be drawn here for the non-clinician on the sidelines?

That reputable clinicians disagree on what inflammation is. Or as @Eddie says what various things mean.

I do think it’s understandable that some are responding in the way they are, we saw some of these concerns here, there have been studies that show ‘things’. But I also think it misses the point of his paper somewhat. And occasionally steps over into unfounded claims of denial of things which it doesn’t.

It’s human nature, people don’t like uncertainty or ideas that challenge and the paper is a lot about these, so they cling on to what they ‘know’.

Sorry, not a scientific argument, but tbh I don’t really feel some of these responses are, they are emotional ones with a reach for evidence.

We have no reliable repeatable evidence for causal mechanisms in the areas people bring up, so this paper tries to look at things differently. It may be wrong, but at least it’s not banging our heads against the same brick walls. Maybe there’s a clearer or more robust way of phrasing that in the paper, I guess that’s up to @Jonathan Edwards

The best arguments I’ve seen are not these but the ones like @jnmaciuch makes that challenge actual assumptions in the proposed mechanism.