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

[Jonathan Edwards]

I am not quite sure what you are recommending @DMissa . Over the years we have been through the details of methodological and interpretation problems here. Margaret is suggesting that I am dismissing things without having given them consideration and she has now been doing this for ten years despite my explaining the details on the public forums - and many others pointing out flaws I have considered. All she ever does is appeal to the authority of professors, while at the same time casting aspersions on the professors she doesn't agree with.

In other diseases there are solid facts about biology relevant the process. In MECFS I don't see anything of that sort. If there was it would be used clinically by physicians who aren't attached to a fringe private clinic.

Is there anything Margaret mentions that you would consider established biology for MECFS? Anything claimed by the people she quotes you would like to defend?

 

[Utsikt]

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?

I’d ask Klimas what she means with «inflammation».

We like to dismiss a lot of things as “handwaving” but we need to also hold ourselves to a higher standard of argument than doing the very same thing.

Because I dismissed things as «handwaving»:
What I meant is that the arguments refer to both vague concepts, and findings that have not been sufficiently established with any reasonable degree of confidence.

One response to the thread about JE’s paper at PR sums it up: JE dismissed studies that he believes are «bad». And people disagree with that, for reasons I don’t know.

 

[forestglip]

I think it would be more productive to address inconsistencies or instances of alleged misunderstanding directly, point by point.

I looked at one claim in the response, high urinary creatine as objective evidence of muscle damage in ME/CFS.

Thread 'Urinary creatine'

Yesterday at 3:27 AM

I just wanted to look at at further evidence for one claim supporting biochemical pathology from the response from Margaret Williams to Jonathan Edwards' hypothesis paper:

I mention just one more illustration: in 2001 evidence was presented by SCM Richards et al (including psychiatrist Anthony Cleare, who works with and co-authors papers on ME/CFS with Simon Wessely) at the British Rheumatologists’ Conference in Edinburgh showing that 53% of ME/CFS patients were excreting in their urine significant levels of creatine and other muscle-related metabolites including choline and...

• forestglip

• 

She cites one unpublished datapoint. Chris Armstrong's team published a paper that seems to show the opposite, but maybe @MelbME can clarify. It doesn't seem worth going through every point in detail after looking at one that looks to me to use cherrypicked data.

I'd rather she provide one claim, the most convincing one, rather than a laundry list of claims that comes close to a gish gallop.

 

[Jonathan Edwards]

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?

I don't think a non-clinician should be drawing any conclusions from what clinicians say. They need to be familiar with the facts as much as the clinicians - certainly the pathobiological facts.

And in our paper I summarize those facts - the appearance of the tissue and more specifically the imaging findings show no inflammation. I mention possible caveats and why I think they are insubstantial.

 

[wigglethemouse]

I think we have let a lot slide in this paper as it is a hypothesis paper. This seems to be the beans.

We suggest that in ME/CFS, antibodies with relatively low afnity for antigens available on an ongoing
basis contribute to disease indirectly by being taken up, together with such antigens, by high-afnity FcγRI on
gamma interferon-primed macrophages and thereby facilitating presentation of antigen to T cells

1. What evidence do we have for any "junk antibodies" in ME/CFS. I can only think of the Lipkin 1999 noting antibodies behave strange in ME/CFS. Perhaps his later B cell paper as well...

2. What evidence do we have for primed macrophages in ME/CFS? The closest we have is Hanson/Grimson writing in their immune cell transcriptomics paper that we need to study macrophages given the changes that team found in monocytes.

3. I have not seen data highlighting FcγRI receptors in ME/CFS. The papers I've seen in general seem to indicate you would see more of those receptors if they were being activated.

4. There could be an argument that there are moire activated T cells in ME/CFS but where is the evidence.

To me those are the things I would like evidence for in order to move forward with this hypothesis. The real question is how are we going to convince other researchers to start testing the hypothesis when there is so little evidence for it?

 

[Yann04]

1. What evidence do we have for any "junk antibodies" in ME/CFS. I can only think of the Lipkin 1999 noting antibodies behave strange in ME/CFS. Perhaps his later B cell paper as well...

As far as I understand this would basically be impossible to test for. There wouldn’t be one unform disease causing junk antigen, it would be a “personalised mix”, and it would be related to very slight shifts in plasma B-cell populations that wouldn’t look relevant statistically.

But I may have misunderstood the theory.

 

[wigglethemouse]

As far as I understand this would basically be impossible to test for.

I should have added that Jonathon hinted there would be a paper coming regarding antibodies. He also hinted we should reread the hypothesis when DecodeME is published. Perhaps there is something else.

I'm hoping when we get some additional evidence we will see some more meat in this hypothesis. I think the Hanson/Grimson lab were going to do a deeper dive on the immune cells of interest in their previous paper so perhaps something will appear there which will be helpful in the context of this paper. However, I think Cornell had their research funding frozen..........

 

[Eddie]

Yes, @EndME has it right. This isn't a matter of differences in language or interpretation. It is a matter of brute fact.

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.

Nancy Klimas doesn't even know what she means by inflammation I suspect. It is more like abracadabra or even biopsychosocial. That is the norm in biomedical research too. "All just words" as a fellow doctoral student once said to me.

Perhaps she doesn't have a specific definition, that what she means by inflammation is a cultural meme that refers to all sorts of processes. But as is the case with abracadabra and biopsychosocial, these words still mean something, even if what they mean varies more person to person than other terms. To the individual using the word it might not be clear what exactly it means. But that is all the more reason why the disagreement arises, because the terms are being used in different ways to express different and perhaps uncertain meanings. I would go even further and say that this is not just a problem with biomedical research but with all communication, a word or symbol or a gesture has as many meanings as there exists points of view. I think the only real solution is to try and help others to understand what your point of view is by explaining it in terms where agreement does exist.

 

[DMissa]

I am not quite sure what you are recommending @DMissa . Over the years we have been through the details of methodological and interpretation problems here. Margaret is suggesting that I am dismissing things without having given them consideration and she has now been doing this for ten years despite my explaining the details on the public forums - and many others pointing out flaws I have considered. All she ever does is appeal to the authority of professors, while at the same time casting aspersions on the professors she doesn't agree with.

In other diseases there are solid facts about biology relevant the process. In MECFS I don't see anything of that sort. If there was it would be used clinically by physicians who aren't attached to a fringe private clinic.

Is there anything Margaret mentions that you would consider established biology for MECFS? Anything claimed by the people she quotes you would like to defend?

Well for example what I asked about was the inflammation/Klimas issue and the response which boiled down to "the other person doesn't understand this" didn't give me much to go on.

edit: I now see another more recent reply about what was in the paper:

And in our paper I summarize those facts - the appearance of the tissue and more specifically the imaging findings show no inflammation. I mention possible caveats and why I think they are insubstantial.

This would have been a good way to avoid this. I guess the burden then falls on the other party to provide the evidence to the contrary. This was a more useful reply.

Is there anything Margaret mentions that you would consider established biology for MECFS? Anything claimed by the people she quotes you would like to defend?

I was referring more to what you'd commented about Klimas, specifically.

I don't think a non-clinician should be drawing any conclusions from what clinicians say. They need to be familiar with the facts as much as the clinicians - certainly the pathobiological facts.

Discerning what is fact without depth of experience in a particular subject is a challenge that provides more than reasonable grounds to seek advice from those with that experience. Is this not one major benefit of collaboration? Being aware of one's own, current, sphere of confident interpretation is important - as is seeking discussion to expand it.

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.

I am not seeking discussion in lieu of assessing the facts for myself - I am seeking it to provide context to help myself better discern what is or isn't fact. It is not a replacement, it is a supplement. And just like any other bit of information it would be measured and scrutinised as best can be done, and not taken on trust alone.

 

[wigglethemouse]

I think a clinician's view of ME/CFS is much broader than a researchers. Clinicians treat co-existing illnesses, some of which may have inflammation as defined by Jonathon. I think it's pretty clear by now that people throw the term "inflammation" about a lot but everyone seems to have a different interpretation of what that means.

The paper is very clear by what they term as inflammation for the purpose of this paper. I get redness and swelling as a comorbidity as defined in the paper for inflammation but I don't see this in the majority so I'm okay with what he has written vs what a clinician may say.

ME/CFS does not involve inflammation as such. No tissues show swelling, heat, or redness, even if there is pain, and magnetic resonance imaging has not shown inflammatory oedema.

A researcher is trying to find what is common and not common to a percentage of patients and present a hypothesis for that group. In this thread Jonathon and collaborators present a hypothesis that could fit the common clinical picture based on how the disease presents for the majority of ME/CFS patients.

I'd like to see more debate, reviews, and feedback on the Synthesis section of the paper to help determine if it has "legs" or not. With those contributions the hypothesis can be refined, adjusted, tested, or torn up for something new.