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

[Jonathan Edwards]

Currently the hypothesis seems quite flexible with lots of connections not yet filled in yet. I wonder if there are any tests, observations or experiments that would not fit or refute the hypothesis?

There are observations that will test various aspects. The most obvious is a large scale GWAS study to look at the risk profile. We ill see how things pan out!

Also interested in the sentence about intravenous immunoglobulin because quite a lot of patients are still experimenting with this, so there is likely some data on it. I assume it would need to taken repeatedly in order for it to work according to the theory?

The situation for IVIg in ME/CFS is probably quite well documented now. As for most other conditions it has been tried for there are small trials suggesting some, but not very major or consistent, benefit. IVIg was never a very practical approach and from a theoretical standpoint is likely to do just that - having some, but not very major, consistent or sustained benefit. To be honest I think we know enough to say that if we think there is a theoretical basis for something of that sort it would be more sensible to manufacture a 'decoy' monoclonal antibody with an Fc binding site but no functional antigen binding site.

 

[Jonathan Edwards]

Fair enough, although I don’t understand why someone would reasonably perceive you as biased. And I’m not sure much can be done about the unreasonable ones.

We already know that a number of BPS worthies think of me as biased - the guy who wrote the NICE guideline witness report slagging off their treatments with the temerity to be 'disloyal' to medical colleagues. Judging by the Round Table Discussion the unreasonable ones are in the majority!

To anyone of the psychosomatics, I fear this will read as a suggestion of the possibility that «the people that end up with ME/CFS have learned to be sick, and the people that got better did not so they recovered. So we just have to teach pwME/CFS to stop being sick.»

Which is why I tuck it in as a trivial caveat amongst all the relevant stuff.

To be clear: I don’t think that is what you’re actually saying. Just that it’s what other might say that you are saying.

Nobody is going to quote me as having proposed this - as a lukewarm nod, compared to their trumpeting in their literature for decades. But nor can they accuse me of not considering it.

 

[Eleanor]

Successful de-escalations often involve giving one party a way to withdraw from their position without losing face. Maybe, as and when new evidence arrives, the BPS advocates will feel readier to cede some influence if they can say "oh yes, your 'neural hypervigilance' is what we were driving at all along," instead of having to take it as a humiliating defeat.

 

[JemPD]

Interesting paper. Well worth a read, even by those not interested in the biological details. Most of the paper gives an overview of what we know about ME/CFS and what interesting observations need to be addressed in a theory of ME/CFS.

If I understand the gist of it, ME/CFS shows signs of both antibody-mediated diseases (female predominance) and T-cell mediated disease (onset of a persistent illness following intracellular infection). By focusing on Fc-gamma-RI the theory offers a means to combine these two aspects.

It assumes a new subset of low-affinity antibodies that do not cause tissue damage but a 'hypervigilant' immune activation. They react with every day junk antigens such as antigens derived from gut flora or low-level persistent viruses such as Herpesviruses, and are then cleared by Fc-gamma-RI on macrophages primed by gamma interferon. This then activates T cell and a whole immune activation cascade that sensitives nerves to pain and fatigue without overt inflammation.

The special thing about Fc-gamma-RI is that it can bind to antibodies even when they are not part of an immune complex. The paper speculates that they might act like a 'nightwatchman's round' or surveillance system and that this is dysregulated in ME/CFS.

Hope I got that right?

I am not well enough to read the paper, and wouldnt be able to understand much of it even if i were, I'm sad I cant join @Sasha in her crash-course in immune biology, I'm so interested. But this summary makes sense to me even if I only vaguely know what each element means, so thanks to @ME/CFS Skeptic for that.

Just wanted to add my thanks to you @Jonathan Edwards, also to Cambridge & Cliff, for all the time & effort put into this. And for all the looooooong hours spent listening to us with an open mind all these years. It's impossible to overstate how appreciative we are.

 

[JemPD]

This may be a total red herring in the context of this paper, if so apologies, but I always wondered about this, mainly because the effect is so stark (for me anyway)...
Does any of this modelling allow for the improvement in function/reduction in pain etc, that I & others experience with the release of stress hormones - ie what I usually call being 'adrenalined up' (although of course i dont know if its adrenaline or cortisol or some other thing that is reeased/occurs when I get angry or afraid)?

Wonder what effect stress hormones might have on the elements of the immune system being discussed? And how that could lead to temporary symptom improvement

 

[Kitty]

To anyone of the psychosomatics, I fear this will read as a suggestion of the possibility that «the people that end up with ME/CFS have learned to be sick, and the people that got better did not so they recovered. So we just have to teach pwME/CFS to stop being sick.»

They'll do that whatever is written and however it's presented. Their approach requires no logic, no grounding in reality, so they can twist whatever they like in whichever direction they choose.

All you can do in response is stick to sanity. I was taken aback at concerns over the word neuroplasticity, so I tried it out on six friends (plus a fella in a railwayman's jacket who'd been supping his pint at the bar and chipped in an opinion).

They thought it meant the brain's ability to learn new skills, though one also mentioned rewiring connections after a stroke. They couldn't talk about it much beyond that, but none thought it was to do with psychology. When I asked specifically, they were puzzled at the idea.

If people with no medical or science background have got that far, it's reasonably hopeful.

 

[wigglethemouse]

I've been puzzling what is special about antibodies/IGG in ME/CFS vs normals that facilitates the hypothesis of this paper. I'm reminded of an Ian Lipkin story. Could it be relevant? If not what sort of evidence in past research should we be looking for that might tie in?

A few years ago I watched a research update from Ian Lipkin for their NIH ME/CFS center and in the Q&A at 27-28mins he described in mid-1990's finding high antibody levels to a wide range of "things" in a swedish cohort while working on a project to look for Borna virus.


Here is the video transcript:

My first engagement in this field was in the mid-1990s when we were asked to look at whether or not a virus called borna might be implicated and in those days we went back we used pcr we used uh antibody tests and we found no evidence for borna virus infection but i was impressed at that point as were my colleagues by the observation that people with mecfs in the swedish cohort had very high levels of antibodies to a wide range of things some of them that you don't even encounter in nature so at the tail end of our paper we said we find no evidence that this particular virus is important in mecfs but we do find evidence of abnormalities in the immune system suggesting that this is a biologically based disorder

I think this is the 1999 Lipkin CFS paper regarding the work he mentioned in his talk.
Absence of evidence of Borna disease virus infection in Swedish patients with Chronic Fatigue Syndrome

I thought this text in the discussion section maybe key:

Although serum immunoreactivity to BDV proteins observed in Swedish CFS patients by ELISA may reflect infection with related microbial agents that induce cross-reactivity with conformational determinants on BDV proteins (Kliche et al, 1996) and b-galactosidase, the serologic findings are also con-sistent with nonspecific polyclonal B-cell activa-tion.

I'm also aware of a more recent unpublished pilot study using a modern array technology antibody panel (ELISA like) that found elevated antibodies vs healthy controls. Most of the results did not stand up when more robust wet lab techniques were used for verification. Something must have caused the false readings, much like in Lipkins 1999 study.

 

[wigglethemouse]

And a follow up question, if there is something about antibodies/IGG in ME/CFS that is different vs healthy controls the hypothesis hints at, why aren't they hoovered up by other parts of the immune system, one example being KIR+ CD8 cells. Could there an upstream disease process that allows these antibodies/IGG to hang around in ME/CFS.

 

[wigglethemouse]

Gamma-delta T cells have been highlighted by the Selin group in their recent video (increased numbers I think). They seem to be a strange type of immune cell that bridge innate and adaptive immunity and according to Google AI produce more IFN-γ.

γδT cells are present in muscle and are involved in injury repair. Could physical PEM be related to the interaction of activated γδT cells interacting with macrophages in muscle per this hypothesis. It is an environment where we don't necessarily need a viral/bacterial antigen to see stimulation. I'm not sure if there is any evidence for increased IL-17 in ME/CFS which might be expected if this were the case?

I'm just throwing some mud against the wall to see if anything that is not needing antigen presentation for this hypothesis can stick.

 

[Stuart79]

If I’ve understood the hypothesis correctly, PEM would be a downstream side effect of cellular debris triggering immune activation as opposed to a protective mechanism of some kind as many others have speculated. If that’s the case, would this hypothesis potentially allow for ME/CFS without PEM?

 

[Jonathan Edwards]

I've been puzzling what is special about antibodies/IGG in ME/CFS vs normals that facilitates the hypothesis of this paper. I'm reminded of an Ian Lipkin story. Could it be relevant? If not what sort of evidence in past research should we be looking for that might tie in?

Yes, like the mechanism of viral malaise, this is something with wider implications for immunology that I don't think we understand enough. Women make more 'error antibodies' but have the same amount of antibody and probably the same number of B cells. It reminds of the song "It ain't what you do, it's the way that you do it".

Jo Cambridge has been looking at antibodies to 'all sorts of things' using a large commercial antigen array and finds differences in ME/CFS and also in severity grades. Hopefully that can be published soon. As in the Sato and Ryback papers there is a suggestion that B cells are going about things a bit differently.

 

[Jonathan Edwards]

And a follow up question, if there is something about antibodies/IGG in ME/CFS that is different vs healthy controls the hypothesis hints at, why aren't they hoovered up by other parts of the immune system, one example being KIR+ CD8 cells. Could there an upstream disease process that allows these antibodies/IGG to hang around in ME/CFS.

The idea is that whatever is different about these antibodies is only relevant in the context of FcRI. KIR+ CD8 cells engage via antibody and FcRIII (CD16) mostly. Again, the way to probe this might be shot-term co-culture experiments, this time in the presence of antibody. The antibody would then function like the 'something in the blood' that people have thought they found previously.

 

[Jonathan Edwards]

If I’ve understood the hypothesis correctly, PEM would be a downstream side effect of cellular debris triggering immune activation as opposed to a protective mechanism of some kind as many others have speculated.

I don't think we are suggesting a need for cellular debris. Whether or not the process is seen as a 'protective mechanism' I think probably distracts from focus on trying to work out the specific mediators. We haven't really committed ourselves to a PEM mechanism because there look to be various options. We have really only tried to suggest that a T cell signalling process might allow for explanations of delayed and prolonged PEM. We have suggested that antigens involved my be non-specific 'junk' present all the time even in normal people but not necessarily that more junk is available after exertion.

 

[hotblack]

I’ve mainly been in recovery and digest mode. Looks like discussion is moving fast here, I need to catch up. But a couple of thoughts.

As it fits in with and expands on much of what we’ve been talking about here in a clear framework, perhaps it’s unsurprising that I really like it.

It’s an interesting explanation for how little shifts in multiple different areas could come together to cause an over-reactivity to a bunch of everyday stuff around the body without there being any clear individual signal. And hopefully gets people thinking about where we could look for evidence.

Presumably we’re now hoping for more proof of these or similar contributory factors to show up in genetic signals?

My main initial and broad question is how, beyond DecodeME, do we build on this with more ideas and experiments, what are the tyres that need kicking? That seems to be the direction and motivation here, here’s what we do/don’t know, here’s one potential mechanism, get thinking.

 

[Simon M]

We already know that a number of BPS worthies think of me as biased - the guy who wrote the NICE guideline witness report slagging off their treatments with the temerity to be 'disloyal' to medical colleagues. Judging by the Round Table Discussion the unreasonable ones are in the majority!

That’s pretty depressing, if unsurprising. Thank you for putting your head above the parapet when you know what is flying your way.

I don’t know if such trenchant opposition reinforces your view of the importance of this, or it is just part of the package?

@ME/CFS Skeptic thanks for the brilliant summary,

 

[Simon M]

I wonder how relevant neural hypervigilance is.

(If I’ve understood right, that’s the basic idea of the interception hypothesis, which a few years ago seemed to be the most popular way to add the bio to biopsychosocial. Just checking I have that right – it’s not an objection in itself.)

But it seems to be saying that the pain and fatigue we feel, which can be overwhelming, are false or exaggerated signals (edited from sensations). If that is the case, then it should be possible to push through without any real consequence. Sure, the fatigue and pain are likely to get worse in the short term, but beyond that?

My experience of pushing through is that I have a relapse - a dramatic loss of function. The pain and fatigue worsen initially, but they return to normal levels before too long. The loss of function remains.

How does that square with neural hypervigilance?

 

[Eddie]

But it seems to be saying that the pain and fatigue we feel, which can be overwhelming, are false or exaggerated Sensation. If that is the case, then it should be possible to push through without any real consequence. Sure, the fatigue and pain Are likely to get worse In the short term, but beyond that?

The biopsychosocial people might disagree, but false sensation is non-sensical. If you are having the sensation it must be real, regardless of its cause. The difference between the pain of losing a limb and neural hypervigilance (if such a thing exists) might be that pushing through the pain of a lost limb results in death, whereas pushing through the hypervigilant pain results in more pain and more pain. That is just as real and just as bad, but much harder for anyone else to have some empirical evidence of what is going on.

I am certainly not convinced of the hypothesis, but I think it is possible. The big problem for me is when people who have no idea what problem they are trying to solve, advocate for poorly evidenced treatments. Claims like pushing through the pain will make the problem better hasn't been proven at all, and there isn't a good reason to think the hypervigilance couldn't be made permanently worse by this.

 

[chillier]

Very exciting to see this paper out, thank you @Jonathan Edwards

In the model the idea is that certain T cell populations will be expanded at some point in life - probably at the time of illness onset but quite possibly earlier in a prodromal phase. All this needs to be is a shift from the 0.01% group to the 0.1% group for T cells that happen to be a nuisance in the relevant genetic and antibody population context. Since we all have clones at both 0.01 and 0.1% levels there is nothing to see. The shift might turn out to be more easily identified but it is hard to say. In the diseases where we are pretty sure that T cell populations are causing pathology there has been pretty little evidence for clonal expansion as far as I know. I am thinking of Reiter's and psoriasis again. Reiter's is problematic because there ought to be a rise in clones recognising the trigger microbe anyway in these people. I have seen suggestion that in psoriasis T cells are recognising a melanocyte antigen but I have not read up about that in enough detail to be sure it is reliable and replicated - or indeed that clonal expansion has been shown.

Would you expect though, that many clones at a lowish level - as opposed to very low levels - would show up as a decreased repertoire diversity overall. The Dibble/Ponting study @Hutan referenced did not see differences in diversity. Or is it more likely that relevant, once expanded clones are now hidden amongst the many other "0.1%" group of T clonotypes that every human will have such that diversity metrics wouldn't be able to spot it? I should also say about the Dibble/Ponting study that they may have been slightly hampered by things by low sequencing depth.

The pathological nature of these clones would be given by their target specificity is that right? Is it the same logic as with the antibody: that high affinity towards an eg viral peptide also have low/medium affinity towards all sorts of other inoffensive material.

You talk about positive feedback loops in disease at one point. Have I understood correctly that the positive feedback loop that might be relevant here is IFNg -> +IFcgR1 -> MHC -> T cell stimulation -> +IFNg. Would this mechanism also explain fatigue associated with IFN therapy (though this happens with both IFNg and IFNa).

Then the question of how the simulated T cells cause malaise remains an open question from the perspective of this hypothesis.

 

[Hutan]

Would this mechanism also explain fatigue associated with IFN therapy (though this happens with both IFNg and IFNa).

Then the question of how the simulated T cells cause malaise remains an open question from the perspective of this hypothesis.

The interferon treatment for hepatitis is said to have caused malaise/flu-like symptoms: headache, pain, feeling of being unwell, as well as fatigue. Perhaps interferon is enough to explain PEM (and sickness behaviour)?

I'm not sure though, if interferon is acting locally, if it gets to the right places to make sickness behaviour. I wonder about it acting on a neuron, like the DRG, with the message passed to the brain?

 

[John Mac]

https://meassociation.org.uk/2025/0...-cfs-invoking-macrophage-and-interferon-gamma

MEA Comment
Thanks to Professors Jonathan Edwards, Geraldine Cambridge and Jacqueline Cliff for all the work they have put into preparing this hypothesis on possible disease mechanisms for ME/CFS. Jackie Cliff and Jo Cambridge are both involved with the ME/CFS Biobank and Jo Edwards used to be on the ME Biobank Steering Group.

As indicated, this is not a statement of firm fact as to what causes ME/CFS. It is a hypothesis that brings together some important basic facts about ME/CFS – in particular the female predominance, the role of triggering infections and the resulting immune system response – in order to produce a framework for discussion and to stimulate further research

By way of general background, the body's immune system is a bit like an orchestra in that it has a large number of different components, each having specific functions. If one component is either missing or not functioning properly then a key part of the immune response to an infection may be missing or become inappropriate. One defective component can also have an adverse effect on the way in which the whole immune system orchestra co-ordinates and responds to an infection.

Among the different components of the immune system orchestra are B cells, NK/natural killer cells, T cells, antibodies, autoantibodies, macrophages and immune system chemicals called cytokines (eg gamma interferon). Abnormalities involving all of these components, not always consistent or significant, have been reported in ME/CFS.

This hypothesis focuses on the possible role of ‘misbehaving' T cells, antibodies, macrophages and gamma interferon – whose functions are explained here:

T cells, also known as T lymphocytes, are a form of white blood cell that helps the body to fight infections – bacterial and viral – as well as harmful cancer cells. There are two main types of T cell. Cytotoxic T cells, also known as CD8+ cells, destroy infected cells and tumour cells. Helper T cells, also known as CD4+ cells, don't attack infections directly but send out signals that direct other immune system cells – B cells, cytotoxic T cells and macrophages – to co-ordinate an attack on an infection. There are also regulatory T cells which can reduce the activity of T cells when needed.

Antibodies are produced by the B cells and are proteins that circulate in the blood where they can bind to bacteria, viruses and unwanted substances in order to neutralise and eliminate them

Macrophages are another type of white blood cell that are capable of engulfing and digesting infections, cancer cells etc, They are also involved in removing dead cells and stimulating other immune system cells

Interferon-gamma (IFN-γ) is an important cytokine that is mainly produced by NK cells and CD4+ T cells. It can beef up macrophage activation, inducing high levels of what are called proinflammatory cytokines and low levels of anti-inflammatory cytokines to further promote an inflammatory response. This effect of IFN-γ is commonly referred to as priming activity, and the IFN-γ–assisted macrophage activation is called classical activation of macrophages.

Post-infective T cell-mediated autoinflammatory syndromes are a group of disorders that can develop after an infection, where the body's immune system mistakenly attacks its own tissues, leading to inflammation and organ damage. These conditions are characterized by T cell-mediated inflammation, where T cells play a central role in the development of the disease.

Autoantibody mediated diseases, also known as autoimmune diseases, are
conditions where the body's immune system mistakenly attacks its own tissues and cells.
These diseases can affect various organs and tissues, causing a wide range of symptoms. Common examples include rheumatoid arthritis and lupus.