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

[Kitty]

Charles Shepherd asked if I had a lay summary. I think that is quite tricky. The paper is really an attempt to lay out a framework for testing theories based on data that may be coming through from immunology studies, proteomics and genetics - with a best shot at a suggestion for now. It is not intended as a 'breakthrough idea' so much as a way of saying ' we may now, or very soon, be in a position to start working out what is really wrong, so let's see what we need to explain'.

I think that is the lay summary, mostly. Along with an encouragement that although it's long, it's not as difficult as papers reporting research findings.

No incomprehensible statistics, written in plain language, and you can follow the thinking without knowing anything about cell biology.

 

[Robert 1973]

That actually sounds rarer than 'unusual'.

It's not just that it can be twisted politically, although that is important. It's mostly that it isn't true. Plenty of adults recover from an illness that meets ME/CFS criteria in the first couple of years of their illness.

I disagree. Mostly means more than 50%. And from what I have seen these plenty of adults are still only a minority and not much more than 20% of all cases?

Again, I would rather not fiddle about with this because it is irrelevant to the argument being made.

I think this is covered by this section:

FWIW, I think it’s important enough to make it clearer. Off the top of my head, I think Leonard Jason’s prospective study found that the majority of people who met ME/CFS dx criteria at 6 months following mononucleosis recovered within 2 years but that recovery was rare thereafter. NB I’m saying this from memory and I may be misremembering.

Trish has quoted a different bit of the paper which makes it much clearer but I still think the earlier bit should be tweaked. If physicians are seeing significant numbers of patients recovering after meeting dx criteria at 6 months they need to know this is not unusual – and that they should not infer that anything they have prescribed has effected recovery.

 

[Turtle]

Jackie Cliff volunteered to do a diagram and then realised how tricky it would be. In my experience diagrams are mostly too vague to be helpful unless the whole mechanism is sorted out. We managed to do it for RA when we had things clear but this is not at that stage by any means.

The something in the blood I think came from the original nano needle studies that suggested an active ingredient in ME/CFS serum. Those studies never got replicated and always seemed pretty hard to interpret. Our hypothesis involves antibody populations in blood being involved, and they might conceivably be seen in that light but I don't think the original data were firm enough to revisit.

The finding of low NK numbers and function would fit with a compensatory rise in TGF beta and GDF15, as mentioned in the paper. But again, nobody is very certain how reproducible these findings ever were.

Not sure about Prusty. I don't remember that.
Edit: I wouldn't get too excited about fibronectin in serum. Serum is plasma after it has clotted and all sorts of changes to proteins like fibronectin could occur with samples after leaving the patient.

Could being low on NK-cells, mine were flatlined on the x-axis, be protective against the flu-like-PEM symptoms? No extra interferon gamma produced?

 

[Kitty]

If physicians are seeing significant numbers of patients recovering after meeting dx criteria at 6 months they need to know this is not unusual – and that they should not infer that anything they have prescribed has effected recovery.

I agree it's important they know that, but I'm not sure this paper is the place to expand on it.

It doesn't really matter in this context. There's a good chance the process gone awry is the same whether people recover or not. Recovery could be down to chance, or to genetic predisposition.

We might be able to work that out once we know what It is, but it wouldn't necessarily change the character of It.


[Edited to remove a superfluous word]

 

[Jonathan Edwards]

If physicians are seeing significant numbers of patients recovering after meeting dx criteria at 6 months they need to know this is not unusual

If physicians have any sense they will forget diagnostic criteria. Applying them via questionnaire is certainly not how medicine should work. They are a huge red herring. In the months after EBV most people improve and any decent physician knows that. We are interested in the illness that mostly doesn't. You could probably say that a diagnosis of ME/CFS is not allowed for 18 months after EBV on criteria because you have another explanation.

There is a potential for a lot of spurious precision around in this game.

 

[Jonathan Edwards]

Could being low on NK-cells, mine were flatlined on the x-axis, be protective against the flu-like-PEM symptoms? No extra interferon gamma produced?

It doesn't seem to work though, does it? Maybe it could modulate the expression of PEM.

 

[butter.]

This paper is interesting also in the sense that it is a recommendation/invitation to pharma scouts to at very least sponsor some daratumab. It's much easier for pharma to do this with a paper like this one out.

Jackie Cliff volunteered to do a diagram and then realised how tricky it would be. In my experience diagrams are mostly too vague to be helpful unless the whole mechanism is sorted out. We managed to do it for RA when we had things clear but this is not at that stage by any means.

The something in the blood I think came from the original nano needle studies that suggested an active ingredient in ME/CFS serum. Those studies never got replicated and always seemed pretty hard to interpret. Our hypothesis involves antibody populations in blood being involved, and they might conceivably be seen in that light but I don't think the original data were firm enough to revisit.

The finding of low NK numbers and function would fit with a compensatory rise in TGF beta and GDF15, as mentioned in the paper. But again, nobody is very certain how reproducible these findings ever were.

Not sure about Prusty. I don't remember that.
Edit: I wouldn't get too excited about fibronectin in serum. Serum is plasma after it has clotted and all sorts of changes to proteins like fibronectin could occur with samples after leaving the patient.

Fwiw, I was part of a private investigation testing GDF15 levels in a small group of patients: the results showed that pwME had lower (!) GDF15 than HCs (not age and BMI matched though; unpublished).

 

[Binkie4]

I have only read bits of the paper so far but am dipping into the discussion and finding parallels with my own experience of the illness.

In the months after EBV most people improve and any decent physician knows that. We are interested in the illness that mostly doesn't. You could probably say that a diagnosis of ME/CFS is not allowed for 18 months after EBV on criteria because you have another explanation.

If I had been asked at 2 years after EBV if I had recovered, I would have said 'yes'. But I hadn't.

It took 18 months to 2 years to be reasonably functional and I called that recovered.

It was when I needed something extra eg socialising for several hours after a day at work and then lecturing the following day, that problems occurred. Colleagues did it without it being a problem but I was exhausted. I explained it to myself as being low in stamina. It wasn't. Now I think it was mild ME which had not fully cleared from the earlier EBV.

I coped like this with working 4 days a week, Ph.D registered, school age kids, running a house with a husband who travelled quite often, advocating for a child who was severely dyslexic, until I couldn't any more and I was ill health retired.

The ME diagnosis didn't come till I was 60 but it seems very obvious now that I was trying to work through the "prodromal" stage of ME. Is this right @Jonathan Edwards?
I had two major surgeries in the year before my diagnosis(at which point I couldn't leave my bed) which may have precipitated the full blown illness.

 

[forestglip]

Further, gamma interferon directly affects the metabolic function of a wide variety of cells, including bystander macrophages and immune cells, as well as skeletal and smooth muscle cells, altering their function and likely contributing to the widespread symptoms in ME/CFS.

I'm not sure if it was the intention, but this comes across as confident that IFNG is related to symptoms.

(An interesting caveat to the implication of antibody diversity in female predominance is the possibility that this diversity reflects a more general sensitivity of certain cell types to gamma interferon (which is involved in B cell follicle development) in women.

Extraneous parenthesis at the start.

 

[Hubris]

How would you explain that many patients (like me) have tried various corticosteroids and NSAIDs without any improvement?

I also tried high dose ivig (2g/kg), It made me less prone to PEM for a period but no improvements in baseline

 

[hotblack]

I’ve now had a first of no doubt many listens.

This is great. I really enjoyed it, hope others do and of course most of all hope it gets the right people interested and thinking about the topic.

Thanks to the three Jays!

 

[Jonathan Edwards]

The ME diagnosis didn't come till I was 60 but it seems very obvious now that I was trying to work through the "prodromal" stage of ME. Is this right @Jonathan Edwards?

One day I may be able to give you a confident answer!

 

[Jonathan Edwards]

I'm not sure if it was the intention, but this comes across as confident that IFNG is related to symptoms.

I wondered about that sentence but I thought I was talking within the context of the proposed model so 'likely' seemed to me to be enough to qualify it.

Extraneous parenthesis at the start.

Actually the parenthesis is intended and closes at the end of the paragraph.

 

[Jonathan Edwards]

How would you explain that many patients (like me) have tried various corticosteroids and NSAIDs without any improvement?

I think it is plausible that the cocktail of signals generated by an aberrant T cell/macrophage interaction based on FcRI and gamma interferon will produce symptoms that for some, or for some times, will be improved by these drugs and not for others. Response to NSAI when you are ill is often a bit of a toss up. Steroids tend to be more reliable but they may not impact nerve sensitisation. Not all patients with rheumatoid get major relief from steroids. The difficulty is that we cannot base predictions purely on things like flu because the cocktail there, and the feedback regulatory signals, may be a bit different.

 

[Jonathan Edwards]

I’ve now had a first of no doubt many listens.

Can you do a version using Michael Horden's voice, as in Paddington Bear?

 

[Binkie4]

One day I may be able to give you a confident answer!

Thank you. Until then, maybe I should for now add 'likely' to this very neat explanation!

 

[forestglip]

I wondered about that sentence but I thought I was talking within the context of the proposed model so 'likely' seemed to me to be enough to qualify it.

It's hard for me to read likely in that way. Wouldn't 'potentially', 'might', or 'may' make sense like these other bits that seem to be said in the same context?

'Some of these antibodies might fulfil a ‘broadly neutralising’ role'

The suggestion is that FcγRI may fulfil (amongst other things) something more like a ‘nightwatchman’s round’

'antibodies with high affinity for a virus might have a low affinity for self-components'

'Gamma interferon also contributes both to MHC Class II expression and to B cell follicle development and maintenance, which might also be relevant to continued antibody production.'

'Further, gamma interferon directly affects the metabolic function of a wide variety of cells, including bystander macrophages and immune cells, as well as skeletal and smooth muscle cells, altering their function and likely contributing to the widespread symptoms in ME/CFS.'

Actually the parenthesis is intended and closes at the end of the paragraph.

Ah, I didn't look carefully at the end because I thought nested parentheses must be a mistake. I'm not sure I've ever seen it used.

 

[Snow Leopard]

The ME diagnosis didn't come till I was 60 but it seems very obvious now that I was trying to work through the "prodromal" stage of ME

It could be, I have heard others say the same thing. There is also an often overlooked relapse-remitting pattern in some patients in the initial stages (where the remission may still not be 100%) and this unfortunately does lead to spurious claims of people being cured (by whatever they were trying just before the spontaneous remission) only to find they later relapse and don't remit the next time.

 

[V.R.T.]

To be clear, are you talking about early and late in terms of the time course of the disease or in terms of the chain of causality i.e. early being closer to the upstream mechanisms that cause it?

Oh and would this reversal be necessary for an effective treatment or just for a cure that turns off disease memory and therefore prevents recurrance?

Could I possibly draw your attention back to this message?

It would be good to have some clarity on what was meant here. Thanks.

 

[Snow Leopard]

I think it is plausible that the cocktail of signals generated by an aberrant T cell/macrophage interaction based on FcRI and gamma interferon will produce symptoms that for some, or for some times, will be improved by these drugs and not for others. Response to NSAI when you are ill is often a bit of a toss up. Steroids tend to be more reliable but they may not impact nerve sensitisation. Not all patients with rheumatoid get major relief from steroids. The difficulty is that we cannot base predictions purely on things like flu because the cocktail there, and the feedback regulatory signals, may be a bit different.

I still don't understand how the hypothesis is relevant to ME/CFS symptoms.

Is it the FcγRI binding IgG that is relevant in which tissues? How does this mediate ME/CFS symptoms? Do we only have the DRG hypothesis mentioned in the other thread?
And you are suggesting that Rituximab treatment doesn't effectively reduce this particular subset of IgG due to long-lived plasma cells?