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

which is itself a very helpful step. Up till now, it’s mostly consisted of “ Here is our finding. Here is how it could explain an aspect of the illness. Job done.”

Are you saying that there is a clear prodrome and then an event that leads to full blown? ME/CFS? I thought some people argued that Gradual on was a Slow andcontinuous process That gradually developed into the illness.

And I think we lack good data on gradual onset. Clearly it happens for quite a lot of people. But is that most people, 10%? 30%?

when I wrote the blog about “something in the blood“, I was very optimistic. Each individual study seemed quite weak, but I hope that that would change in the coming years. As far as I know, it hasn’t, and I agree that there is currently no need to accommodate this idea in a model of the illness.

I’m not totally sure that’s what it says. From my memory of numerous perspective studies, mostly after glandular fever, a large majority of patients cover before the six month threshold. Maybe half or a few more of those left recover within two years. I’m not aware We have any data beyond 2 years. If we do, I hope someone will point to it.

 

I don't feel I am in the right frame of mind to respond right now. I just don't like when I sense mocking especially when there has been a lot of suffering. I apologize if I have misinterpreted.
Whenever I think I see it I have to respond and I am sorry for that.

 

Good question. Who is 'who' and what is a what? Not an easy question.

In terms of diagnosis the intended suggestion is that the apparently higher rate of ME/CFS in women may partly be influenced by women taking more care of their health in a conscious way and getting diagnosed where men may not. I don't intend to dwell on such things, and there are of course all sorts of other uncertainties, but I think it is sensible to make clear that all possibilities need thinking about. Censoring all reference to brain function would make it much easier for BPS people to pick holes as I see it.

Neuroplasticity. The learnt is just to indicate that we are talking about 'learnt' processes in general.

I am deliberately avoiding that. The more we are seen to be defending ourselves against a BPS approach the more we will be seen as prejudiced against it. Neuroplasticity is a perfectly legitimate scientific concept and may well be important in ME/CFS, at least in some cases. I think it is better that we raise these things than reviewers come up with them - "They just think it's T cells and completely dismiss neuroplasticity. Typical Cartesian dualism.".

 

Thank you for reassuring me. I get really upset easily about things like this.

 

Thank you anyway for your concern, @AliceLily! It was a joke in good part which I enjoyed and those buns got me a really long way. I recommend the book (though others here think it a bit inaccurate).

 

Haha, I mean, we could… Not using the pipeline I’ve setup though. I’m not sure it’s something I’d want to invest the time in to but… in theory yes we could. Voice cloning has got scarily good.

 

Could this explain severity. Like perhaps a mild person will have 0.05% while a very severe 0.2%. And maybe continued overexertion can trigger feedback loops that make these specific antibody recognising T-cells proliferate?

[Note I haven’t read this whole thread and at the rate this is balloning I might never be able to. Sorry if this has already been asked or mentioned.]

 

I’m not sure I follow here. Who «sees» us, and why would we be trying to please them?

Yes, but it’s also being used very wrong, on everyone, and as the basis for supposedly curative interventions with great potential for harm.

I’m not suggesting that we don’t raise them, just that it is done in a way that is also less open for misinterpretation. Although I guess it could be argued that pseudoscience doesn’t follow logic, so they are going to end up at their favoured conclusion regardless of which starting point we give them..

 

I think you are right. I don’t feel comfortable sending a copy of this to my caregivers precisely because I know they will see words like “plasticity” and think that means I should be meditating and make them dig into BPS stuff.

 

I’m not either, because they don’t have the experience to quickly sniff out the pseudoscience elsewhere. If it sounds credible or familiar, to them, it’s probably partially true.

 

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?

 

Would be good to have a reference for this. Anorexia nervosa probably has a high female predominance and depression and anxiety also affect about 2 times more females then men if I recall correctly.

 

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?

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 'we' is the authors and as authors we do not want to pull back from mentioning things like neuroplasticity, not to please anyone but to avoid being assumed to be taking a biased view.

But that isn't a reason not to mention it if it is possibly part of the reality, surely. As you say, there is nobody we are 'trying to please'.

I am not clear why the manuscript is particularly open to misinterpretation. If I remember rightly we simply point out that there are possibilities that cannot be excluded but for which there is no particular grounding.

 

To be honest it had not crossed my mind that this paper would be passed to caregivers. It is a discussion of theoretical models for the benefit of those interested in such things.

 

I think Anorexia nevrosa is probably underdiagnosed in young men, and I wouldn’t trust any estimates on depression or anxiety given it’s frequent use as a catch-all for any complaints from women by practitioners that should know better. How many of e.g. the 10 % of women with endometriosis have been dismissed as anxious or depressed?

We also know how flawed the questionnaires are..

 

Yup.

 

I didn't find the sort of 3:1 or 4:1 female dominance when I searched through psychiatric conditions but anorexia nervosa might be in that area I guess. I do not have a specific reference for the general statement.

 

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.

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.»

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.