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

[Jonathan Edwards]

If ME/CFS pathology is mainly in the nervous system where we can hardly measure or influence it at this point, then trying to influence or reset it with immune therapies might be worth considering?

Yes but to me the logical approach would be keeping the cytokine well down for a good while.

 

[Kitty]

Why should this not happen as part of ordinary infections?

And in a proportion of pwME/CFS, the opposite happens: they feel much better with a viral infection. Whatever's causing their normal symptoms appears to be reduced, neutralised, or involves a process that can only do one thing at a time.

 

[ME/CFS Science Blog]

Why should this not happen as part of ordinary infections?

Just speculating here but perhaps it has to be a certain kind of infection, like a severe viral infection, that ME/CFS patients are less likely to get because of social isolation.

Yes but to me the logical approach would be keeping the cytokine well down for a good while.

But most cytokines already seem normal or low in ME/CFS while the symptoms signal runs full strength. So perhaps what is needed is an increase in cytokines that would normally cause the same symptoms, hoping that feedback mechanisms set in that help weaken the signal.

All a bit speculative and far-fetched I admit.

 

[Jonathan Edwards]

But most cytokines already seem normal or low in ME/CFS while the symptoms signal runs full strength.

But normal may be enough if the nervous system is oversignalling.
Normal probably involves quite significant cytokine signalling locally in places like gut.

 

[V.R.T.]

But most cytokines already seem normal or low in ME/CFS while the symptoms signal runs full strength.

Do we have good evidence that is also the case during PEM? And I thought the signalling could be happening outside of blood anyway.

So perhaps what is needed is an increase in cytokines that would normally cause the same symptoms, hoping that feedback mechanisms set in that help weaken the signal.

Surely this carries a pretty good risk of amplifying the feedback loop, making people sicker and perhaps even more severe long term.

I see what you mean though, it's sort of like when some people feel better after an infection? It's maybe reset the system to normal, at least temporarily.

If we were going to either raise or lower the cytokine level in MECFS as a therapeutic experiment in MECFS, what kind of people would we need to get on board? Is this something that could be set up quickly if we thought it was a good idea?

 

[V.R.T.]

Yes but to me the logical approach would be keeping the cytokine well down for a good while.

Would this be dangerous e.g. by leaving people immunosuppressed?

 

[V.R.T.]

I suppose my questions stem from the fact that if we think there is a reason to do an experiment like this, either MECFS Sciences idea or JEs, and it is relatively safe, it could tell us one way or the other whether certain cytokines are involved in a signalling loop in MECFS, and potentially get us straight to a treatment that could help people get out of dangerous, potentially life threatening situations with their health or with care or lack of it. Even if it wasn't 'the treatment' that is rolled out in the long term. I am thinking particularly of people stuck in hospital.

If nothing else a positive response in a trial like this would very quickly prove MECFS is real which would change all of our lives.

So if it were safe and relatively quick to set up then perhaps it should be a priority.

Edit: I suppose you would have to do both experiments to conclusively rule out a particular cytokine - both raising it and keeping it low for a while in different groups of pateints. Obviously you would also need a placebo group.

 

[V.R.T.]

Just speculating here but perhaps it has to be a certain kind of infection, like a severe viral infection, that ME/CFS patients are less likely to get because of social isolation.

But when MECFS patients do get severe viral infections, yes some report feeling like they dont have MECFS while sick but many also get worse for a while or permanently.

 

[Jonathan Edwards]

Would this be dangerous e.g. by leaving people immunosuppressed?

I am not necessarily espousing blockade - but we have quite a lot of backgound data on that. Blocking one cytokine tend to be fairly safe unless you have undiagnosed TB. Blocking more than one is often problematic with infections.

I was thinking more in terms of maybe just keeping the person away from infections and maybe irritant foods as the logical thing to do. Not really suggesting there is an avenue to pursue here.

 

[Jonathan Edwards]

If nothing else a positive response in a trial like this would very quickly prove MECFS is real which would change all of our lives.

I am not sure it would do that. Lots of cytokines might make a person with MECFS feel worse but that does not tell us what and where the signaling problem is or even if it is 'real' over and above what we already know from experience.

 

[V.R.T.]

I am not sure it would do that. Lots of cytokines might make a person with MECFS feel worse but that does not tell us what and where the signaling problem is or even if it is 'real' over and above what we already know from experience.

I think the original proposal was that it might break the signalling loop and make the patients feel better.

 

[Jonathan Edwards]

I think the original proposal was that it might break the signalling loop and make the patients feel better.

OK, that way around, even then I am not sure it tells us what mediates the illness. Another cytokine might simply feed in to the pathway from the side.

 

[V.R.T.]

OK, that way around, even then I am not sure it tells us what mediates the illness. Another cytokine might simply feed in to the pathway from the side.

But it would give us a vital clue and show you could make people feel much better than any GET or CBT approach can from an immune treatment. Which would help our cause a lot. To say nothing of the fact you would have a treatment (unless there were problems giving it long term), which would be huge.

 

[butter.]

Just speculating here but perhaps it has to be a certain kind of infection, like a severe viral infection, that ME/CFS patients are less likely to get because of social isolation.


But most cytokines already seem normal or low in ME/CFS while the symptoms signal runs full strength. So perhaps what is needed is an increase in cytokines that would normally cause the same symptoms, hoping that feedback mechanisms set in that help weaken the signal.

All a bit speculative and far-fetched I admit.

I believe, the symptom signal runs full strength more likely because neurological (network) changes have occurred, a different equilibrium with different setpoints has emerged, and not necessarily because of some messenger gone awry chronically.

 

[Nightsong]

An unexpected result:

IFNγ-induced memory in human macrophages is sustained by the durability of cytokine signaling itself (J. Exp. Med, February 2026)

Sticky memories of an activated macrophage (associated commentary)

 

[Jonathan Edwards]

So it seems that IFN gamma can hang around on macrophage surfaces after the party is over.
I wonder whether this could also apply to dorsal root ganglion neurons.

 

[Hutan]

AI

While Heparin sulphate is a major binder, studies have shown that in certain tissues (like arterial walls), chondroitin-6-sulfate (C6S) in the ECM is particularly effective at binding IFN-γ.

Is C6S found on the surface of neurons?

Yes, chondroitin-6-sulfate (C6S) is present on the surface of neurons, primarily as a component of the extracellular matrix (ECM) known as perineuronal nets (PNNs) that condense around specific types of neurons.

Yes, chondroitin-6-sulfate (C6S) is present on the surface of dorsal root ganglion (DRG) cells, particularly in association with Schwann cells, which produce and carry these molecules in the extracellular matrix

 

[Jonathan Edwards]

AI
Is C6S found on the surface of neurons?

So we are back to the Writing on the Wall hypothesis.

 

[bobbler]

AI

Is C6S found on the surface of neurons?

Does the heparin bit mean a possible loose link there to the decodeME gene that’s related to ferritin homeostasis?

I’m getting possible complex links between this and iron regulation but risk it could be nonsense because on one bullet it say heparin can act as as strong an inhibitor as Hepcidin for iron, then another bullet notes heparin-iron complexes are being developed as novel approaches to anemia. Ok it seems it suppresses hepcidin so that’s how both could logically make sense.

 

[Jonathan Edwards]

Does the heparin bit mean a possible loose link there to the decodeME gene that’s related to ferritin homeostasis?

It might be heparan sulphate rather than heparin. I doubt there is any link.
Googling quickly suggests that there isn't a heparin sulphate.