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

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Any questions, comments or feedback please use this separate thread so we don’t distract from discussion of the paper. Thanks.

 

A very important question. My hope is that the whole thing could be reversed from the immune end - whatever the chain of events is. Maybe doing that early would be important but maybe not. My guess is that reversal even late on is doable but may take a lot of work to find a way to do it.

I don't think we need to look for 'advantage'. If a servo system goes haywire it may produce effects way beyond what is useful. If the fridge thermostat goes dodgy you may find all your milk and lettuce frozen.

 

That is an issue, perhaps, but mature T cells have a circulatory systemic policing function so they should turn up in blood.

I am interested in the discussion of MS - is T cell clonality recognised? There is a huge amount of guff about T cell responses in MS. It seems it didn't show up in that study?

 

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?

 

My guess is that sampling problems for solid tissues are so huge that nobody will ever be able to use them effectively. We came to that conclusion with tissue samples in RA in the 1990s. My current favourite is looking at short term co-cultures of T cell subsets from blood with macrophages that can be pre-primed in vitro using ELISpot type techniques. But the lesson from RA was that you can infer what you think is going on and prove you have identified the right players with a drug therapy without ever actually observing the predicted events in tissues.

 

I doubt that will be a problem but if gamma interferon is being used locally by transient T cell passage through tissues then blood levels may be normal and even conceivably low if there is a regulatory increase in circulating TGF beta, which some studies have suggested.

 

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'.

 

correct

 

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

 

So would I.

I think the worry is justified but I think the playing field has to be kept seriously level, and not least to make it plain that nobody is intending to tilt it.

If the female nervous system is more susceptible to certain immune signals then we need to know that. Women are better at sensing odours it is claimed. Some women can see more colours than any man. Diagnostic rates may be skewed by sensible vigilance. We cannot rule out such possibilities if we want to find the right answer.

 

Haven't reviewed them in detail but, at a quick glance, there seem to be a few other errors in the references - some examples under the tag.

Spoiler: References...

This one seems wrong - can't be thousands of pages:

and this one (should be Peterson):

and this one (should be MedRxiv):

and this one (should be "Accelerated"):

and this one (should be "Taylor"):

What potentially confirmatory experimental approaches would you envisage being of most use - flow cytometry, scRNA-seq, ELISPOT, CITE-seq?

Tsuda et al (link) on IFN-γ receptor signalling in spinal microglia & its role in allodynia in a murine model may be of some additional interest.

I'm sure I'll have some more salient comments as & when I'm able to read through in detail but thanks for all your work on this; it's an extremely interesting hypothesis.

 

I think the same co-culture ELISpot type studies I suggest for ME/CFS might prove useful. The problem with acute infection though is that there may be lots of signals occurring and it may be more difficult to work out which is doing what.

 

I had that for a few years and it's the reason why I don't know if my onset was caused by covid or the vaccine. Even when my symptoms started getting really bad, it took me a few months to realise that I hadn't become I'll out of the blue, but had been symptomatic for a while. It wasn't a significant reduction in my health status though. It was so insignificant, I thought everyone was like that and it was a sign of getting older. In hindsight I think it was the first sign of cognitive exhaustion.

Ah this summarises my experience really well. I had to take a nap every day after work even though I was working remotely, but I could walk 10k steps every day or even 25k steps on holiday without issues.

 

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.