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

Abstract:
Evidence bearing on possible mechanisms for the clinical syndrome of ME/CFS is reviewed. The evidence is used to argue for a hypothesis that centres on a form of persistent, inappropriate, ‘neuroimmune hypervigilance’ mediated primarily by T lymphocyte-macrophage interaction but influenced by IgG antibody binding to the gamma interferon-inducible high affinity immunoglobulin receptor FcγRI. This proposed mechanism could explain why the illness resembles post-infective T cell-mediated autoinflammatory syndromes in age of onset and time course but has a female preponderance similar to autoantibody-mediated disease.

Link | PDF (Qeios preprint, May 2025, open access)

 

It looks great.

It's an easier read for a non-scientist than I expected. Really clearly presented and doesn't have the dense concentrations of technical terms that some papers do.

We're really lucky to have a team like the Three Js working on it.

 

Nicely put.

 

Was wondering why there are anecdotal reports of rapamycin working (and hopefully positive clinical trials) and how it would fit this model. A quick Gemini deep research shows that rapamycin could be indirectly working by inhibition of IL-6 which would stop the T-cell positive feedback loop?

I try not to post AI slop (but this is just so exciting) and would love someone with more advanced input on this….

 

I've said this elsewhere on here but yes, I think the prodromal onset applies to me, if it is a thing. I have not felt healthy or well since around my 19th birthday, with all sorts of symptoms like DPDR and panic attacks and insomnia, but did not experience noticable PEM until shortly after my 26th birthday. I have noticed people on long covid forums who say they have similar symptoms but no PEM. Interestingly the symptoms people with this cluster of symptoms report often include worsened hangovers and new onset extreme bad reactions to cannabis, both of which started for me at the same time as my insomnia etc, and certaintly were not present before.


The paper itself is surprisingly intelligible to me, although I confess I have only scanned it so far. I read the possible treatments section first, I won't lie! But I have been going over bits and bobs and understanding more than I expected. I will have a more chronological pass at it tomorrow.

Thank you Jo, Jo and Jackie for all of your hard work on this hypothesis.

 

Maybe this could be another reference, though hard to know if the association is more with duration or severity.

Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome (Sato et al, 2021)

 

Shoot I think I meant IL-1 not 6

I was thinking more that this is an indirect way of how rapamycin might be working inside this hypothesis. Rapamycin could be lowering IL-1 to mediate interferon-gamma in the Tcell.

 

It's now pretty clear that this was going on for me for years before I developed full blown disabling ME/CFS.

I look back at a vacation I took about 6 years prior to onset, where I was excited and feeling great at the beginning and just kept decreasing in function over a couple weeks. I kept taking long bike rides thinking it would help the depression which was growing over the touristy activity filled days, but I got worse and worse. I had to read a book for school while there but it was incredibly difficult due to brain fog. I ended up flying home several days early because I felt so bad. (No symptoms of anything like an infection to explain it.) It's now clear the large amount of activity was probably the main factor in the bad time I had.

That's the most obvious thing I remember, and I don't recall physical activity being much of an issue otherwise. But my entire childhood was colored by mental fatigue, particulary in schoolwork and in social interactions.

Since a very young age (7ish, maybe younger but I can't remember much), I have viscerally hated and dreaded big school projects - essays, presentations, and the like - because of how mentally exhausting it is to try to be creative on cue, as well as to try to do large amounts of reading/focusing. Similarly, I have had social anxiety since a young age, and it seems to also be mainly about mental fatigue, in that it takes an incredible amount of mental effort to focus on a conversation and think of things to say, and I end up never being able to keep up, which makes for lots of awkward silence.

I don't know if I remember something like "PEM" specifically happening with these activities back then, but mental fatigue has always been an issue, and it's become much more pronounced since "ME/CFS-proper" with obvious PEM has started. I'm almost positive this is the same condition as I've always had, just much more severe.

 

I think it took me over a hour to read, must have because I got logged out of S4ME.

I have to say that I got quite emotional reading one specific part, in that it mentioned something that I always thought was involved in making me vulnerable to ME.

Thank you very much for all the listening you have done to all sufferers on the forum and taking all our experiences of ME into account @Jonathan Edwards and many thanks to Jo Cambridge and Jackie Cliff.

It's been such a long road for so many of us with ME.

 

Bloody oath. That is an understatement.

 

I feel exhausted after reading for a hour. I didn't mean to understate. I have had very severe ME. I apologize for not representing it well in expression.

 

Thank you Jonathan for putting this together. Even for patients and researchers who don't have the necessary understanding to grasp the intricacies of the immune mechanisms, the summary of the available evidence is quite useful. I could imagine it being used as a sort of framework for researchers to move past ideas of "inflammation" or "persistence" and start to tie more specific theories and mechanisms to the data we have.

While not the focus of the paper I am interested in to what extent dealing with the immune processes would address the proposed nervous system involvement. Would you think the plasticity/hypervigilance would reverse course if a suitable immune treatment was found?

In what sense is the hypervigilance state tied to the autonomic control mechanisms? If the sickness response developed to promote convalescence, what is the advantage of actually ramping up the autonomic nervous system instead of just making the subject feel bad? It is difficult for me to square my experience of hyperactive sympathetic nervous system states prior to getting sick, to my current experience with "dysautonomia" (but perhaps they are different hyperactive mechanisms).

I know finding specific mechanisms is hard in regards to neural signaling, but hopefully we find more ways to test these hypotheses.

Given that ME/CFS generally requires the absence of other diagnosis that could explain the symptoms, it would not surprise me if many in the elderly population have their symptoms ascribed to something else. For the average doctor milder symptoms of PEM, fatigue, headaches ect. could be attributed to diagnoses of dementia, COPD, diabetes unless the symptoms were to become quite severe. It could also be the case that we don't hear about elderly cases as much, but it is hard to know.

 

No no I was not criticising - I think the words you used were right. I feel exactly the same. Stuffed but happier today.