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

[Nightsong]

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)

 

[Hutan]

See this thread for the pre-match discussion:
Notice about a forthcoming paper: A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma

 

[Kitty]

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.

 

[Sean]

‘A little more T cells …’

Anon

ME/CFS is an acquired illness, with subjects healthy prior to onset, even if, rarely, that occurs under the age of 10.

I think these are two observations that we need to keep an open mind on. In particular the possibility that there might be a long pro-dromal phase for many, and that some may never progress beyond that phase while still experiencing a subtle and unrecognised but still practically significant reduction in health status.

Symptomatic benefit from corticosteroids suggests that symptoms may involve pathways used in inflammation, even if steroids have wide effects on gene expression and the benefits in ME/CFS appear short-lived and modest[45].

I had a two month course of prednisolone some years back (starting dose 40mg daily, reducing by 5mg per week) to try damping down a general allergy response, and there was a substantial improvement in my overall health status (both physical and cognitive) during that time.

The benefit faded away once I stopped taking it. But it was a very interesting experience, and more than a little frustrating.

However corticosteroids are a drug of absolute last resort as they have horrible effects on your whole body, particularly when taken on a sustained basis, and so are not even close to a therapeutic option for us. But my experience seems to support that point in the paper.

 

[Robert 1973]

Until recently, treatment for ME/CFS has tended to focus on rehabilitative programs that encourage patients to undertake physical exertion of the sort that triggers symptoms. It is now clear that this approach not only has no valid theoretical basis but produces no useful benefit and often leaves patients more unwell[16][64]. If activity triggers non-specific immune signals that fuel further macrophage-T cell interaction, this is hardly surprising.

Nicely put.

 

[ChronicallyOverIt]

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….

 

[V.R.T.]

. In particular the possibility that there is a possible long pro-dromal phase for many, and that some may not progress beyond that while still experiencing a subtle and unrecognised but still practically significant reduction in health status.

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.

 

[Sean]

ME/CFS is an acquired illness, with subjects healthy prior to onset, even if, rarely, that occurs under the age of 10.

I think these are two observations that we need to keep an open mind on. In particular the possibility that there might be a long pro-dromal phase for many, and that some may never progress beyond that phase while still experiencing a subtle and unrecognised but still practically significant reduction in health status.

Which might, in part at least, explain why there seems to be a low rate of onset in the first 10 years of life.

 

[Hutan]

Thank you to the authors for caring enough to put this together. There's lot in it and I'm going to need to read it a few times before I can understand it enough to make substantive comments.

In the meantime, I have gratitude for things like the paragraph Robert1973 quoted above, some quibbles around the edges - my usual ones, and some questions.

ME/CFS has a variable course. Spontaneous improvement or even resolution may occur, chiefly with onset before the age of 20[20]. Otherwise, it is a long-term fluctuating illness, in some cases with progressive deterioration. Adult-onset illness mostly never fully resolves.

There are people who meet ME/CFS diagnostic guidelines at 4 months after an acute disease, 6 months, even a year or so who go on to recover. We have evidence that suggests this is common, even in adults. Suggesting otherwise helps build up these people who recover from a relatively short term illness (at least 'short' relative to life-long ME/CFS) as special. Hence we get Garner and other evangelical sellers of various forms of pseudoscience claiming to have special knowledge. I'd really like to see an 'established' qualifier in there, e.g. 'established adult-onset illness, that is ME/CFS that has been present for more than three years, seems rarely to fully resolve'.

I think shaky epidemiology is sometimes accepted a bit too readily to bolster ideas. Sean has noted a couple of issues. I'd add the second peak of the twin peaks story. Also the idea that new ME/CFS onset is rare in the elderly population. (I have a 94 year old aunt, who is quite certain that she has suffered a permanently substantially reduced capacity for exertion after a Covid-19 infection. She mentions crashes that sound like PEM to me. I doubt that she nor her doctor would even begin to consider adding an ME/CFS diagnosis to her medical record.). I think though that the ideas can still work, even if some of the epidemiological ideas don't turn out to be true.

One of the questions I have is about the mention of t-cell clonal expansion. I remember that we got excited about this idea for a while, but I thought that it was found not to be present in ME/CFS. Do I have that completely wrong? Would we not expect to see the clonal t-cells in blood samples if they are part of ME/CFS? If t-cell clonal expansion isn't present, do the ideas still hang together?

It's great to see the ideas for trials of treatments.

 

[forestglip]

This might also be relevant to the finding that cytokine and lymphocyte population shifts in ME/CFS appear to be more pronounced in the first 3-5 years after onset compared to the longer-term situation[56][5].

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)

Furthermore, the expression of IGHV3-30-3 was inversely correlated with disease duration (Spearman r = -0.377, p = 0.02, Fig. 2B), indicating that upregulation of IGHV3-30-3 is a feature of relatively earlier disease-stage. [IGHV3-30 was p=.06]

Furthermore, the disease duration in most patients with an increased PB [plasmablast] frequency was within 10 years (Fig. 3E), indicating that the upregulation of PB might be a hallmark of severe, relatively earlier stage ME/CFS.

 

[Hutan]

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'm not the person with more advanced input on this, but I note from the paper:

Cytokines such as TNF may be more relevant to the killing of bacteria in a purulent or granulomatous response. Reports of systemic cytokine levels in ME/CFS have been inconsistent, but one relatively recent study found raised serum levels of gamma interferon and transforming growth factor beta but not TNF, IL-6, or IL-1[15].

I think that is right about il-6 - we haven't seen consistent reports of raised levels. So, reducing it probably wouldn't help much?

 

[ChronicallyOverIt]

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.

 

[SNT Gatchaman]

But I was a little naughty with the opening of this paper - adding a non-existent quotation to 'anon':

‘A little more T cells …’. Anon

Actually it very much is an existent quote (on S4ME, more than once even)

Onto the paper proper, and a few questions I wondered about on first read:

Nacul et al. [51] reported low creatine kinase levels in ME/CFS.

Given some evidence suggesting increased muscle capillary basement membrane thickening, there is a possibility that CK exiting muscle cells is inhibited in reaching the capillary lumen. If it slowly leaches into the bloodstream after it has ceased to be generated post-exercise the plasma levels may never get the opportunity to reach higher concentrations and may explain this lower than normal result.

See Post-COVID exercise intolerance is associated with capillary alterations and immune dysregulations in skeletal muscles (2023, Acta Neuropathologica Communications) and also this recent poster from Charité 2025.



See also Low creatine kinase is associated with a high population incidence of fainting (2009, Clinical Autonomic Research)

the long-term persistence of ME/CFS on the background of previous good health would fit most easily with an acquired T cell clonal shift that might arise from a chance combination of B and T cell receptor selection that allowed evasion of normal control signals. The relatively early age of peak incidence suggests that T cell receptor selection may be crucial since the thymus involutes in later years.

Certainly the thymus is nowhere near the size it is in infancy through to early teens, but it's probably still active throughout life.

Health Consequences of Thymus Removal in Adults (2023, New England Journal of Medicine)
Editorial The Thymus — Not a Graveyard after All, Even in Adults? (2023, New England Journal of Medicine)
Paracrine FGF21 dynamically modulates mTOR signaling to regulate thymus function across the lifespan (2025, Nature Aging)

A neural hypervigilance state of this sort might provide the basis for what is often called ‘dysautonomia’, with features such as postural tachycardia [1] in people with ME/CFS. Unlike other forms of dysautonomia, there is no indication of a failure of autonomic neuronal capacities, but rather an apparent over-readiness to respond, as for tachycardia on standing in the presence of a maintained systolic blood pressure.

I question this formulation as it somewhat recalls Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome (2022, Brain). I know this isn't to imply a conscious or in any way controllable-by-yoga hypervigilant state, but I think reference to recent OI studies on cerebral blood flow and cardiac output might be helpful to avoid misinterpretation. I recognise that they too are a work in progress.

But as I read it their evidence indicates that the requirement is to maintain cerebral blood flow with orthostatic challenge, which necessitates compensatory mechanisms which are impaired in ME/CFS. This might be due to eg endothelial dysfunction and/or reduced right atrial filling pressures per Systrom. Some of the "rescue" compensations might now even be in contention between body and brain, or at least be struggling with the loss of the normal fine-tuning of homeostasis.

 

[forestglip]

In particular the possibility that there might be a long pro-dromal phase for many, and that some may never progress beyond that phase while still experiencing a subtle and unrecognised but still practically significant reduction in health status.

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.

 

[AliceLily]

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.

 

[Holinger]

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

Bloody oath. That is an understatement.

 

[AliceLily]

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.

 

[Eddie]

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.

Also the idea that new ME/CFS onset is rare in the elderly population. (I have a 94 year old aunt, who is quite certain that she has suffered a permanently substantially reduced capacity for exertion after a Covid-19 infection. She mentions crashes that sound like PEM to me. Neither she nor her doctor would even begin to consider adding an ME/CFS diagnosis to her medical record.)

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.

 

[Holinger]

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.

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

 

[Sean]

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.

I suspect a similar story for me.

It may be that the cognitive component of ME/CFS and its consequences are dominate during a pro-dromal phase, which would skew interpretation from the start, including not even realising there is any health problem at all. Then, if it later becomes the full blown expression of the syndrome, the physical component comes more to the fore.

If so then that would open up the possibility of better and earlier diagnosis, given the right tools.

Given that ME/CFS generally requires the absence of other diagnosis that could explain the symptoms,

A requirement I have never been happy with. Not a problem for selecting a research sample, where you want the highest levels of specificity and sensitivity. But not so good for clinical level diagnosis, where the normal for all patients and conditions is to have more than one con-current condition and diagnosis.