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

[Jonathan Edwards]

But it does mean that theories which are reliant on T cells (which we have no indication of here) are not on any higher footing

That comes in the next few posts above.

 

[jnmaciuch]

Why not raise your concerns in a review on Qeios, @jnmaciuch !! They would then be formally published.

I'd need time for polishing and citation digging, which unfortunately seems unlikely in the near future. But some deadlines may pass soon

 

[jnmaciuch]

That comes in the next few posts above.

If you're referring to DecodeME, I'll wait to see the skyscraper myself, and what the haplotypes actually do functionally. If you're referring to dynamics, I happened upon much of the same evidence, but found that it could explain a particular non-adaptive mechanism just as well as an adaptive one.

Alright, that's it for me. Time to head back to the coal mines.

 

[Robert 1973]

@Jonathan Edwards I'm only on page 11 of this thread so apologies is that has been pointed out but the link for Ref 57 in the paper (Zhang et al) is wrong:

Link in preprint: https://doi.org/10.1101/2025.04.15.253299
Correct link: https://doi.org/10.1101/2025.04.15.25325899

 

[Jonathan Edwards]

@Jonathan Edwards I'm only on page 11 of this thread so apologies is that has been pointed out but the link for Ref 57 in the paper (Zhang et al) is wrong:

Thanks.
Interesting, as this was pasted from a citation.
To be honest, I am not a great believer in citations any more. Anyone can find a paper (and the right doi) with a couple of author names.

I will edit it if I am posting a new version.

 

[Sasha]

I am not a great believer in citations any more.

I've always thought that all the different formats for citations that different journals require were a massive waste of everybody's time. The journals should have got together years ago, picked one format, and stuck to it. I wonder how many millions of hours of scientists' time has been wasted fixing the format of their citations.

 

[Utsikt]

I've always thought that all the different formats for citations that different journals require were a massive waste of everybody's time. The journals should have got together years ago, picked one format, and stuck to it. I wonder how many millions of hours of scientists' time has been wasted fixing the format of their citations.

 

[Yann04]

Do we have an oversimplified circle chart or simple message showing the mechanism. A week ago I pretty much understood it now my brain is all muddled (I hate that ME seems to have f’ed with my memory).

If I understand correctly

Junk antigens loosely bind with antibodies released from long lived plasma B-cells
->
These bind to FCgRI receptors on Macrophages.
->
This “excites” the macrophages who then interact with T-cells
->
The T-cells then release interferon gamma which produces more symptoms and also primes macrophages to be more “vigilant” thus making their reactions to junk antigens stronger
->
… repeat?

Am not looking to perfectly understand the intricacies, I don’t think I can manage that. Just get a core understanding so I don’t feel completely lost.

[I haven’t read most of the 20 pages of discussion. Reading this much especially with a lot of jargon is something I cannot do at my severity. It is too much.]

 

[Robert 1973]

I'm now on page 13 of this thread and running out of capacity to I'm going to post some comments while they are in my mind and apologise if they have been covered:

I am not sure why my paragraph is being interpreted as if I am saying that for this long term illness recovery is rare. I have simple said the mostly it does not fully recover, which is generally agreed. I have pointed out that sometimes it does. And the paragraph isn't about how often anyway. The argument being made is about the dynamic complexity.

I may review my wording a bit

I think that would be worthwhile.

In particular, can we distinguish those that go on to have ME/CFS from those that don't at an early stage?

A small proportion of people with PVF will turn out to have ME/CFS. But the great majority don't. You may not be able to tell them apart but that doesn't matter.

It cannot be the whole mechanism if it does not go on to ME/CFS. The difference between the two also needs a mechanism, surely?

Yes, and I think that has been a major confusion. Having ME/CFS symptoms does not necessarily make it ME/CFS. It may be one component of ME/CFS bin some cases but I think people have been too quick to say it IS ME/CFS. That is what Paul Garner got told and that ended up pretty badly!

I'm a bit confused about your arguments here. Until we understand the mechanism or have other some way to diagnose ME/CFS, the only way to diagnose anybody is to use some sort of criteria. If you meet a dx criteria, you have ME/CFS by that definition. Anybody who studies ME/CFS needs to define exactly what they are studying. The data seem to indicate that a significant number of people who meet the dx criteria at 6 months recover and that full recovery is rare after 2 years. We don't yet know how similar the mechanism of PVFS which resolves may be to the mechanism of ME/CFS, and we don't yet know how similar or different the mechanism may be in people who meet ICC or CCC dx criteria of ME/CFS and recover may be from the mechanism of ME/CFS which does not resolve.

If your hypothesis is that most people who meet an ME/CFS dx criteria and recover have a difference illness to people who do not recover - and that the latter have a different condition with a mechanism that is different not only in the fact that it resolves - then I think that needs to made clearer in the paper.

I'm running out of capacity and possibly not explaining myself very well but I hope you get the point I'm trying to make.

FWIW, My guess is that PFVS and ME/CFS which resolves are likely to be different illnesses to ME/CFS which doesn't resolve (at least in the vast majority of cases). I also suspect that if we had had proper physician-led services, even without biomarkers or understanding the mechanism, those physicians would have acquired enough knowledge from observation to be able to give far more accurate prognoses than is currently possible.

 

[Jesse]

Do we have an oversimplified circle chart or simple message showing the mechanism.

I liked the summary by @ME/CFS Skeptic:

Interesting paper. Well worth a read, even by those not interested in the biological details. Most of the paper gives an overview of what we know about ME/CFS and what interesting observations need to be addressed in a theory of ME/CFS.

If I understand the gist of it, ME/CFS shows signs of both antibody-mediated diseases (female predominance) and T-cell mediated disease (onset of a persistent illness following intracellular infection). By focusing on Fc-gamma-RI the theory offers a means to combine these two aspects.

It assumes a new subset of low-affinity antibodies that do not cause tissue damage but a 'hypervigilant' immune activation. They react with every day junk antigens such as antigens derived from gut flora or low-level persistent viruses such as Herpesviruses, and are then cleared by Fc-gamma-RI on macrophages primed by gamma interferon. This then activates T cell and a whole immune activation cascade that sensitives nerves to pain and fatigue without overt inflammation.

The special thing about Fc-gamma-RI is that it can bind to antibodies even when they are not part of an immune complex. The paper speculates that they might act like a 'nightwatchman's round' or surveillance system and that this is dysregulated in ME/CFS.

Hope I got that right?

 

[Robert 1973]

Another question for which I apologise if it's already been asked:

If I contract a viral infection, I often find that my ME/CFS symptoms often seem to improve in the time between infection and the onset of symptoms of the virus. I gather that at least some other people with ME/CFS experience this too. I also find that my ME/CFS symptoms tend to improve when I have a fever, although they tend to be worse for a while following an infection, after the acute symptoms have subsided, which I have also heard others report.

@Jonathan Edwards Does your hypothesis offer any explanation for either of these observations?

 

[Kitty]

If you meet a dx criteria, you have ME/CFS by that definition.

Might it be more accurate to say you have it at that time?

I get the impression diagnosis is more of a process rather than a static state. That's one of the reasons it can take a long time—there often seems to be an element of wait-and-see built into it.

As Jonathan says, it doesn't really matter if you can't distinguish very well between PVFS and ME/CFS. One of them will go away on its own, and one won't. Wait-and-see will tell you which.

 

[Robert 1973]

As Jonathan says, it doesn't really matter if you can't distinguish very well between PVFS and ME/CFS. One of them will go away on its own, and one won't. Wait-and-see will tell you which.

Yes, but then you're saying if it goes away it's not ME/CFS - in which case the definition of ME/CFS is a disease which doesn't resolve. That is not currently a standard definition.

I also think it is exceedingly important to be able to be distinguish between the two - not least so that people like PG can't claim to have cured themselves of a disease which can't be cured by psycho-behavioural interventions.

[edit: removed double negative for clarity]

 

[Jonathan Edwards]

->
… repeat?

Yes, but it's important to rinse first.

 

[Kitty]

I also think it is exceedingly important to be able to be distinguish between the two

It would be great, but it may not be possible. If something goes away in a few months and never gets severe, it's probably PVFS, and if something lasts longer and may be severe it's probably ME/CFS, whether or not it resolves. That's all we have, and it's probably as workable a definition as other conditions have.

Diagnosis is probably never going to be precise, even if we find a treatment for some cases. There are nearly always people for whom a new treatment doesn't work, and it's not clear why.

 

[Jonathan Edwards]

I'm a bit confused about your arguments here. Until we understand the mechanism or have other some way to diagnose ME/CFS, the only way to diagnose anybody is to use some sort of criteria. If you meet a dx criteria, you have ME/CFS by that definition.

This is the fallacy of assuming that a diagnosis is a diachronic concept despite being made at time X.
I realise that this is very counterintuitive and inconvenient but those are the sorts of things I tend to turn my attention to!! If we talk of 'different illness' we have to be clear whether we are talking about cause or effect and whether it is now or how things turn out.

Diagnostic criteria are a mirage because they take none of this into account.

 

[Jonathan Edwards]

If your hypothesis is that most people who meet an ME/CFS dx criteria and recover have a difference illness to people who do not recover - and that the latter have a different condition with a mechanism that is different not only in the fact that it resolves - then I think that needs to made clearer in the paper.

I don't have a specific view on that. It isn't what the paper is about. We could write a book on all the ramifications of this but a hypothesis has to be manageable. The paper is already very long - as you point out.

 

[Jonathan Edwards]

@Jonathan Edwards Does your hypothesis offer any explanation for either of these observations?

Assuming that whenever immune cells start responding to a stimulus there are 'focusing' mechanisms that ensure a group of cells deals with one problem at a time rather than all comers I think it very likely that the proposed mechanism might get 'elbowed out' by signals telling cells to focus on something more salient. That might involve expansion of T cells that are not interested in ME/CFS, for instance. I don't have a specific proposal on this but I think our sort of model at least has a chance of providing a story where most others probably don't.

 

[Jonathan Edwards]

Yes, but then you're saying if it goes away it's not ME/CFS - in which case the definition of ME/CFS is a disease which doesn't not resolve. That is not currently a standard definition.

It is only not a 'standard definition' to the extent that the constipated minds that sit on committees that write diagnostic criteria have tunnel vision and think you have to have a list of symptoms from which you can make a full house. I think the idea that ME/CFS is a disease that does not fade away in a monophonic fashion over a period of months after an infection is widely accepted. A number of research studies require subjects to have had the illness for at least two years in recognition of the fact that monophonic resolving PVF can take nearly that long.

 

[Sasha]

I think the idea that ME/CFS is a disease that does not fade away in a monophonic fashion over a period of months after an infection is widely accepted. A number of research studies require subjects to have had the illness for at least two years in recognition of the fact that monophonic resolving PVF can take nearly that long.

What does 'monophonic' mean in this context? (Google was no help.)