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

[Jonathan Edwards]

Would exertion result in an increase of these same 'everyday junk’ antigens thus causing stronger symptoms? And would that fit with all types of exertion (physical/cognitive/emotional)?

Not sure. Extra junk might be produced after muscle use but that would not cover PEM from mental exertion. In general my thought is that the level of junk probably does not change much. The change in severity relates to the T cell and neural responses.

Your questions are very relevant. I am not sure I have clear answers yet.

 

[hotblack]

One thing I learned in my reading is that in addition to neurotransmitters, T cells and other immune cells express receptors for neuropeptides for communicating.

Yes, I’ve got a whole load of papers from reading and searching on this area, I’m sure others have. I’m not sure what the best way of us sharing them all and understanding if they’re any good/relevant is. Maybe we should set up a thread for it? Would that be useful?

But the general idea of signalling between neuronal and immune cells, and even impacting expression of FcgRI, seems very plausible. Add in some neurotransmitter interactions and bingo. Perhaps a bit hypothetical right now but still…

 

[hotblack]

In general my thought is that the level of junk probably does not change much. The change in severity relates to the T cell and neural responses.

I got the impression that expression of FcgRI was a factor? In response to activity the expression increases, which strengthens the loop. Is that the case in your theory? What would be the timescales involved, presumably macrophage lifespan?

 

[Jonathan Edwards]

I got the impression that expression of FcgRI was a factor?

In response to T cell gamma interferon, yes. FcRI levels might shift over hours or days but the macrophage might also undergo a longer term maturation shift to continued expression.

 

[arnoble]

Are there any direct PET tracers for IFN-γ or other markers upregulated by IFN-γ? To see where IFN-γ is occurring?

 

[Jonathan Edwards]

Are there any direct PET tracers for IFN-γ or other markers upregulated by IFN-γ? To see where IFN-γ is occurring?

I think the concentration is going to be too low. Looking for gamma interferon using staining of tissue sections is feasible but at least as difficult as 'Where's Wally' to actually find your staining unless you know in advance where it is going to be. At low magnification (resolution of about a tenth a millimetre) you see nothing. PET has a resolution around Icm I guess.

 

[hotblack]

In response to T cell gamma interferon, yes. FcRI levels might shift over hours or days but the macrophage might also undergo a longer term maturation shift to continued expression.

Thanks. I haven’t really got a good understanding of the timescales of the different factors involved in the proposed feedback loop. On how long it takes for things to respond or be modified and how long they then hang around for. Could you or perhaps someone else give a rough idea or is it all a bit ‘it’s complicated and depends’?

Macrophages
- FcγRI (receptor)
- IFNGR (receptor)
- MHC/HLA (for presenting)

T-cells
IFN-γ produced by them
Transcription factors too?

B-cells
- BCRs
Antibodies produced by them

 

[Jonathan Edwards]

Could you or perhaps someone else give a rough idea or is it all a bit ‘it’s complicated and depends’?

It is very complicated but if macrophages and T cells are going to set up a mutual conversation that is likely to develop over hours. I am thinking of the B cell and antibody side being a fairly constant factor over months (except perhaps immediately after an initial triggering infection).

 

[Kitty]

I think the concentration is going to be too low. Looking for gamma interferon using staining of tissue sections is feasible but at least as difficult as 'Where's Wally' to actually find your staining unless you know in advance where it is going to be.

So if after DecodeME and further debate we think there's a good chance the theory stands up, is the best approach to test it with a medication rather than look for something we might not be able to see?

 

[Jonathan Edwards]

So if after DecodeME and further debate we think there's a good chance the theory stands up, is the best approach to test it with a medication rather than look for something we might not be able to see?

I think there is a chance that you can see what is going on by taking T cells from blood, dividing them into subsets and putting them in short term culture with macrophages. In that situation you can put individual cell clusters under a microscope and see things in detail.

Testing with a therapy may turn out to be the way to go but it seems hard to believe that whatever immune signalling is going on it is completely invisible.

 

[Kitty]

Testing with a therapy may turn out to be the way to go but it seems hard to believe that whatever immune signalling is going on it is completely invisible.

That sounds positive. The trouble with finding a therapy that offers benefit is presumably that you're not always sure what it's doing. Which doesn't help those for whom it offers no benefit.

 

[hotblack]

It would be great if we could test and see what is going on. I’ve been thinking about all the different places that things could be up or down regulated or vary in different ways contributing to this cycle (basically like my list above). It sounds like @Jonathan Edwards has a narrower idea of where to look.

If we’re looking along the lines of getting the T cells to unlearn whatever bad habits they’ve picked up (I think it was something like this that was mentioned). Are we then talking about getting rid of just activated/memory T cells, leaving naive ones alone? Is this even possible?

 

[arnoble]

I think the concentration is going to be too low.

89Zr-PET seems capable of at least lighting up tissues where IFNg is gathered: https://pmc.ncbi.nlm.nih.gov/articles/PMC10735274/ (admittedly in mice). I know nothing about imaging, but maybe some useful techniques are just around the corner. I was interested to see just how much has already been done with
89Zr‑PET imaging in humans: https://www.researchgate.net/publication/354366903_89Zr-PET_imaging_in_humans_a_systematic_review

 

[Jonathan Edwards]

89Zr-PET seems capable of at least lighting up tissues where IFNg is gathered:

Well it might at least give us some idea which tissues there is a bit more of whichever interferon in - and maybe provide some useful negatives at least. Radioimmunolabel imaging was not that good in the days I was doing that sort of thing but it may have moved on significantly.

 

[RedFox]

Thank you to the authors for taking the time to write your thoughts in this paper. You have an interesting and novel hypothesis. As a non-expert, it seems as plausible as any other model of ME/CFS I've seen thus far.

I don't think the wording on topics that could be confused with BPS is terrible. The entire paper makes it very clear the authors don't have a BPS view whatsoever. The only thing I wish was clarified would be this

In this context, we cannot rule out the possibility that the higher rate of diagnosis of ME/CFS in women is in part due to a greater ‘health vigilance’ in women – of central nervous origin.

It could be worded to explain patient's behaviors directly instead of making it sound "psychosomatic", for example "We cannot rule out the possibility that the higher rate of diagnosis of ME/CFS in women is in part due to a greater likelihood for women to seek medical care and diagnosis".

You explain concepts like scientists should, but don't unfortunately. Nowadays everything is wrapped in jargon and buzzwords. It seems more about trying to impress the audience than laying out a logical argument. There's a lot of common sense in this paper. Using the epidemiology to suss out possible causes is pretty clever because epidemiology is one of the few things we know reasonably well, compared to all the biochemical studies, that mostly find subtle abnormalities that don't explain much in terms of causation. I'm also glad you're upfront about the lack of certainty behind your ideas, unlike a lot of scientists who try to argue they found it when they haven't, or only found preliminary evidence. It's all solid reasoning.

I can't really speak too much about the specifics of the model, but you manage to explain most of the observed features of ME/CFS, like the predominance in women, ages of onset. And there's a lack of obvious test results because it's a potentially local signalling problem. I don't know if it's specifically a problem with FC gamma receptors, but the idea it's caused by a signaling problem in the immune system, inducing something akin to chronic sickness behavior (but without activating all the pathways you get with a cold or flu), makes a lot of sense.

 

[Jonathan Edwards]

Thanks @RedFox.

I am negotiating some changes in the txt (minor) with the other authors and the paragraph you don't like is likely to go. I thought it might be useful to make it clear that we are aware of other possible interpretations of the sex difference in diagnosis rates but I now tend to think that if there is anything to say on this, it is obvious to anyone, hard to support with any evidence, and off the main track.

 

[RedFox]

Thanks @RedFox.

I am negotiating some changes in the txt (minor) with the other authors and the paragraph you don't like is likely to go. I thought it might be useful to make it clear that we are aware of other possible interpretations of the sex difference in diagnosis rates but I now tend to think that if there is anything to say on this, it is obvious to anyone, hard to support with any evidence, and off the main track.

I don't dislike the whole paragraph. It just needed a little rephrasing. It's true that women in our culture are somewhat more likely to be conscientious about their health. (It's probably not enough to explain a 2-3x difference in prevalence though.) But you're right, that point isn't essential to your argument. I also appreciate you working with forum members on refining your paper. Accepting feedback can be hard but making improvements based on it will only make your paper more robust.

 

[Sean]

Thanks @RedFox.

I am negotiating some changes in the txt (minor) with the other authors and the paragraph you don't like is likely to go. I thought it might be useful to make it clear that we are aware of other possible interpretations of the sex difference in diagnosis rates but I now tend to think that if there is anything to say on this, it is obvious to anyone, hard to support with any evidence, and off the main track.

Thank you (and to your co-authors) for taking this issue seriously. It isn't just us being hyper-sensitive snowflakes. Unfortunately, as we have learned the hard way, the language and politics of it all matter very much and have to be taken into account. We have all seen and experienced many examples of the words we use being co-opted and twisted to mean something very different, and the consequences of that. Pacing (or 'pacing up'), for example, having now become the term BPSers use for GET-lite.

 

[Deanne NZ]

I was thinking about the female prevalence in MECFS & the discussions in this thread and wondered if there has ever been a study that looked at the differences in severity levels between the sexes.
Is it possible that although there are fewer males, they are more often at the severe end of the spectrum.

The only other health condition I am really familiar with is Type 1 Diabetes. It has a male prevalence of 1.8:1 and yet around 30% of females go on to develop 1 or more other autoimmune conditions (Hashimoto's or Graves being the most common) but only around 15.8% of males do.
https://pmc.ncbi.nlm.nih.gov/articl...study of adults,disease being the most common.

 

[Holinger]

Testing with a therapy may turn out to be the way to go .

I would sign up to that kind of research in a second if it was going on in Australia. Obviously that kind of therapy could do some harm but hopefully the Qeios article will start some deep conversations and get the ball rolling. Thanks.