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

[Jonathan Edwards]

Would this theory align with ME/CFS-like symptoms after brain injury?

It probably would if we make the very vague proposal that shifting neural circuit balance in someone with a genetic predisposition to an ME/CFS type process could be an adequate triggering event. We emphasise that we think that infection as a trigger is probably doing something nonspecific. The theory as presented in the paper focuses on the immune side but if neural signalling responsiveness is an important element then a neural trigger is plausible too.

I am hoping that DecodeME will test some of these aspects of the model .

 

[Jonathan Edwards]

So could that responsiveness also directly cause symptoms on exertion (feeling depleted), rather than it being delayed like in PEM?

Yes, sorry, @Jesse, to answer your original question, I think it would fit. The immediate reaction is the smoke alarm in the barn going off. PEM might be the T cell nightwatchman saying 'not the bloody smoke alarm again, when I've had my tea I will drag myself over there and re-set it'. Except that the nightwatchman has got the wrong glasses on and keeps re-setting the sensitivity even higher.

 

[ScoutB]

Hi all, long time lurker, love this thread and the paper.

This really confuses me. Surely I can, under normal circumstances, tell my body what to do at the macro level, even if I can't directly order my macrophages about. Are you suggesting that I can't decide (assuming I'm not exhausted) to raise my arm? Or that I haven't decided to type this message?

A fun example of something like this is when we're stretching and feel that we've reached the limit. It *feels* completely physical -- like a bungee chord stretched to its maximum amount -- but actually that sensation of a limit is caused by a inhibitory neural feedback loop. AFAIK without this "false" limit your muscles and tendons could indeed stretch further (and eventually get badly hurt). Sometimes I kind of want to ask the BPS folks to please mind-over-matter this arguably purely functional limitation to doing the splits...

 

[Sasha]

Welcome to the forum, @ScoutB!

 

[Utsikt]

Hi all, long time lurker, love this thread and the paper.

A fun example of something like this is when we're stretching and feel that we've reached the limit. It *feels* completely physical -- like a bungee chord stretched to its maximum amount -- but actually that sensation of a limit is caused by a inhibitory neural feedback loop. AFAIK without this "false" limit your muscles and tendons could indeed stretch further (and eventually get badly hurt). Sometimes I kind of want to ask the BPS folks to please mind-over-matter this arguably purely functional limitation to doing the splits...

Welcome!

Power lifters do just that. They are able to completely tear their muscles when doing max lifts. And lots of sports injuries are not caused by contact - someone just went beyond their physical limits. But I suspect adrenaline is involved in making it easier to override those limits. And that’s the exact opposite of that the BPS people preaches.

 

[Jonathan Edwards]

Sometimes I kind of want to ask the BPS folks to please mind-over-matter this arguably purely functional limitation to doing the splits...

You are not I hope encouraging people to undergo grievous bodily harm.
Surely the witches' ducking stool would be enough?

 

[ScoutB]

You are not I hope encouraging people to undergo grievous bodily harm.
Surely the witches' ducking stool would be enough?

aah yeah I was imagining it was impossible, good point about the body builders though @Utsikt

 

[Jesse]

Yes, sorry, @Jesse, to answer your original question, I think it would fit. The immediate reaction is the smoke alarm in the barn going off. PEM might be the T cell nightwatchman saying 'not the bloody smoke alarm again, when I've had my tea I will drag myself over there and re-set it'. Except that the nightwatchman has got the wrong glasses on and keeps re-setting the sensitivity even higher.

No worries, we do seem to be getting there. That's a fun analogy, happy to hear it fits theoretically!

I'm still very curious on the involvement of the sympathetic nervous system when trying to push through:

I'm usually able to push it (hard as it is), which would trigger a huge stress response in my body (hr/bp going up, sweating, GI upset, frequent urination, overstimulated brain, restlessness). When trying to rest afterwards I get stuck in tired but wired state and get insomnia. Then PEM starts the next day.

what happens if we push through this, and in my experience the activation of the sympathetic nervous system. Is there a mechanism that makes sense there?

@Jonathan Edwards any idea how that could work?

 

[Hoopoe]

Exertion beyond a certain limit does seem to increasingly cause "sympathetic nervous system activation" during the same day. This can also be caused by being upright for too long or too much socialising. It feels like tired-but-wired and returning to a relaxed resting state is impossible. The same night, sleep quality will be poor. The next day, I will wake up feeling unrefreshed, more symptomatic and less able to function.

I suspect that the experience of PEM without warning may be due to being unaware of the SNS activation or even experiencing it as not unpleasant state of excitement.

The SNS activation may also favor overactivity because of its stimulating effect.

I wrote "sympathetic nervous system activation" because I'm not certain what it really is, but it seems to be the closest concept in terms of how it's experienced.

 

[Jonathan Edwards]

@Jonathan Edwards any idea how that could work?

I don't have any specific suggestion. The trouble with the nervous system is that it is very complicated and predicting how it will behave, beyond very simple reflex events, is hard.