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

[Kitty]

I am struggling to find a better term but my sense is that over-responsiveness may at least be better than hypervigilance?

Maybe an option would be 'immune over-responsiveness, targeting the nervous system and mediated...'

.

Agree about the hypervigilance, though probably only because of the particular history of ME/CFS. Maybe spelling it out in a sentence like this would help? It’s plain language and doesn’t add too many clunky words.

 

[Sasha]

For me it’s been absolutely fine with flu but terrible with the covid ones. So I assumed it’s more complex and related to specifics of antigen rather than just severity or anything which stimulates immune activity.

Similar issue for me.

 

[hotblack]

Maybe an option would be 'immune over-responsiveness, targeting the nervous system and mediated...'

Is it over responding? That would imply lots of something being produced, but it sounds like the point is, there isn’t. It is more an over-reactivity or sensitivity or hypersensitivity to particular things isn’t it? Overt readiness? Primed immune response?

“Immunological and potentially neurological sensitivity to…”
“Increased probability of reaction to…”

 

[Karen Kirke]

If you are referring to the seronegative spondarthropathies mentioned below, then no, because the HLA risk gene is different for them (B27 or C6)

OK. Are there other conditions that your proposed mechanism would predict would be more common among relatives of pwME?

I'm replying here to your post above only so that we understand each other better, but this is a peripheral point and I don't want it to distract from the discussion of your paper.

Suggestions that ME/CFS can be diagnosed at 3-4 months is to stop idiot doctors from saying that they cannot diagnose and advise patients about ME/CFS until 6 month have passed. For schoolchildren in particular this is a breach of human rights. But what an intelligent doctor should be doing is ignoring the criteria and saying that if someone is disabled by fatigue-type symptoms for three months then there is a significant possibility that in a year's time they will be understood to have ME/CFS. But if they get better at 5 months then I personally would say that they did not have ME/CFS in any useful sense, especially if the fatigue followed a viral infection because we already have another useful category for such people - post viral fatigue.

This is not about criteria for me. My point is that if someone is disabled by fatigue-type symptoms for three months following an infection, then it’s much more likely that in a year’s time they will be well than that they will be understood to have ME/CFS. As currently written, the reader may well think that the person is more likely to be sick than well if they're an adult, at least until they get to p.4. I perhaps have less faith than you do that the reader is an intelligent doctor!

I think resolution in the early months and years is at least as important a point to get across than a distinction between those under and over 20. Van der Werf et al. 2002
reported 2-3 times as much improvement and recovery in those ill for less than 2 years compared to those ill for more than 2 years.

I agree with you that what we’re trying to solve is the long-term illness. However, I would say that ME/CFS is, in post-viral cases, simply PVFS that lasts or recurs – I think they are more likely to be the same thing than different things. And I don’t think a cut-off of 6 months separates PVFS from ME/CFS well at all.

In this sentence…

Spontaneous improvement or even resolution may occur, chiefly with onset before the age of 20[20].

…I wonder did you mean to reference Bell et al. 2001 rather than Bansal? I may have missed the bit you were referring to, but this is all I could find in Bansal:

The prognosis in children is significantly better with 80 % returning to normal health or much improved with mild persisting disability [9]

where 9 is Bell et al. 2001. But what Bell et al. 2001 found is quite different: 37% reported recovery, but only 26% reported “minimal, if any, symptoms”. I liked Katherine Rowe’s study – she found

The mean duration of illness was 5 (range 1–15) years in the 50% who reported recovery. By 5 years 38% and by 10 years 68% reported recovery. At 10 years the mean functional score was 8/10 (range 2–10) with 5% scoring <6.

Regarding the vigilance vs responsiveness point, I didn't get the sense that the mechanism you were describing was particularly vigilant. It sounded more misguided or dysfunctional to me. But I may not understand it well enough yet!

 

[Jonathan Edwards]

OK. Are there other conditions that your proposed mechanism would predict would be more common among relatives of pwME?

Not until we have a clearer picture of the relevant genes. I think the Zhang study must be pointing us roughly in the right place but it may pick up on particular genes that are not very relevant.

 

[voner]

Jonathan, you missed my previous qustion? Here it is again.

@Jonathan Edwards ,

I was trying to understand some of your statements with only having a hotdog bun education (at best) in this area….

in the “myalgia not arthralgia" section you say,

"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".

and you reference the 2017 paper by Mark Davis and others…

https://www.pnas.org/doi/epdf/10.1073/pnas.1710519114

I took a look at this 2017 paper and I don’t see where it shows raised serum levels in gamma interferon. The charts I looked at seemed to show a rising gamma interferon that correlated with increased severity. In mild patients it was below the healthy controls and in moderate patients it was about the same as healthy controls and in severe patients it was elevated over healthy controls.

am I interpreting this information incorrectly?

 

[Jonathan Edwards]

However, I would say that ME/CFS is, in post-viral cases, simply PVFS that lasts or recurs

I used to think along those lines but I no longer think it is a useful way to look at it. We are crucially interested in the process that distinguishes them. As I say I have had post-viral fatigue for six months from EBV and post-Covid fatigue and I don't think my experience is close to what people with ME/CFS describe. One thing that I think tends to get forgotten is that you need to be significantly disabled to qualify for ME/CFS. Just having similar symptoms and maybe sort of PEMish episodes isn't enough.

And the different time profiles do require different explanations.

 

[Jonathan Edwards]

It sounded more misguided or dysfunctional to me.

I was working on the basis that adaptive immunity is inherently a vigilance in respect to microbial dangers and that hypervigilance would imply something more that was indeed misguided or dysfunctional.

 

[Karen Kirke]

I used to think along those lines but I no longer think it is a useful way to look at it. We are crucially interested in the process that distinguishes them. As I say I have had post-viral fatigue for six months from EBV and post-Covid fatigue and I don't think my experience is close to what people with ME/CFS describe. One thing that I think tends to get forgotten is that you need to be significantly disabled to qualify for ME/CFS. Just having similar symptoms and maybe sort of PEMish episodes isn't enough.

And the different time profiles do require different explanations.

I'm influenced by my own experience of [what was labelled] PVFS in the aftermath of viral meningitis. I was told I "wouldn't feel like myself" for 6 months, but it was more like 14 months. For the following 5 months I slowly introduced the less vigorous end of vigorous exercise and it seemed to be going fine until SPLAT, I relapsed, with the exact same symptoms as before. The only difference thereafter was that instead of slowly improving, it slowly deteriorated. To me, it would make no sense to say that I had PVFS first, and that ME/CFS started on day SPLAT. It was all the same. Same symptoms, same effect on functioning, just more tenacious.

At the time, I too read what people with "ME" reported, and thought, that sounds different and worse compared to what I have. It wasn't. I just had mild ME/CFS, a pace-able life, and often, rather than clearly defined crashes, I had bad patches of just feeling worse and being able to do less for weeks on end. Not recognising that contributed to a lot of unnecessary uncertainty and mismanagement. You don't hear much from those with mild ME/CFS on forums because they're off struggling to do normal-ish things with difficulty and don't have any spare energy.

I also find the 50% reduction in functioning to quality for ME/CFS a bit daft. If someone improves from moderate to mild or very mild ME/CFS such that they're functioning at more like 70-90% of normal, but they still feel crap much of the time and still can't do plenty of things that normal people can do, they still have ME/CFS in my book.

We won't know if the mechanism of the two is the same or different until we figure out the mechanism of one and see if the other set of people have it too. And maybe we will find out that the ones who stay sick or end up relapsing do have an entirely different mechanism right from day one. But I don't think we can assume that now.

 

[Utsikt]

I also find the 50% reduction in functioning to quality for ME/CFS a bit daft. If someone improves from moderate to mild or very mild ME/CFS such that they're functioning at more like 70-90% of normal, but they still feel crap much of the time and still can't do plenty of things that normal people can do, they still have ME/CFS in my book.

In my opinion, this is why we can’t measure functioning is ME/CFS in terms of what you can do. We have to measure it in terms of the consequences of any given actions. Like what FUNCAP tries to achieve.

If you can do a fair few of normal things, but feel terrible after, you can’t properly do them.

 

[Jonathan Edwards]

To me, it would make no sense to say that I had PVFS first, and that ME/CFS started on day SPLAT.

Sure, and that will be the way things go for people who turn out to have ME/CFS.
These diagnosistic categories are not 'separate diseases' in popular terms. The situation is a bit like that for species in ecology. In technical terms people think that 'species' is both a synchronic and a diachronic concept when it can only be a synchronic concept. There is no formal meaning to the question whether a chaffinch 100,000 years ago was the same species as one now. Illness categorisation plays with our intuitive ideas about categories in a different way. W assume that we have a robust way of categorising but that is illusory. Which is why when doing research it is always better to establish exactly what group of people you want to ask what question about and forget the official names as much as possible.

A small proportion of people with PVF will turn out to have ME/CFS. But the great majority don't. You may not be able to tell them apart but that doesn't matter.

 

[Karen Kirke]

I'm thinking about how your model explains the effect of exertion in ME/CFS @Jonathan Edwards :

As in acute viral infections such as influenza, this immune cell activation would sensitise nerves to pain and fatigue sensations without producing overt inflammation. Nerve sensitisation might be mediated by soluble circulating signals but might be amplified in muscle after exertion by macrophages and CD8 T cells recruited as part of normal tissue patrolling events involved in the repair of daily microdamage. Such an amplification would provide an explanation for at least some forms of post-exertional malaise, typically delayed by several hours after active exertion.

I'm interested to know whether White et al.'s 2011 study findings are consistent with your proposed mechanism? They compared controls, people with multiple sclerosis and people with CFS after a submaximal exercise challenge (which sounds very challenging: 25 mins, 70% of age-predicted maximal heart rate). They found:

Post-exercise mRNA increases in metabolite-detecting receptors were unique to CFS patients while both MS and CFS showed abnormal increases in adrenergic receptors.

See figures 2 and 3 as well; I just picked figure 4 to show as I recognised things like IL10, TNFB etc. In their discussion, White et al. contrasted the "well-regulated" sensory pathways in controls and MS with the dysregulated sensory pathways in CFS.

 

[richie]

Sure, and that will be the way things go for people who turn out to have ME/CFS.
These diagnosistic categories are not 'separate diseases' in popular terms. The situation is a bit like that for species in ecology. In technical terms people think that 'species' is both a synchronic and a diachronic concept when it can only be a synchronic concept. There is no formal meaning to the question whether a chaffinch 100,000 years ago was the same species as one now. Illness categorisation plays with our intuitive ideas about categories in a different way. W assume that we have a robust way of categorising but that is illusory. Which is why when doing research it is always better to establish exactly what group of people you want to ask what question about and forget the official names as much as possible.

A small proportion of people with PVF will turn out to have ME/CFS. But the great majority don't. You may not be able to tell them apart but that doesn't matter.

But long covid has often been declared to be ME/CFS.

 

[richie]

Both ifn gamma and CD64 are relevant to sarcoidosis too.

 

[Jonathan Edwards]

I'm interested to know whether White et al.'s 2011 study findings are consistent with your proposed mechanism?

Probably but I find findings of that sort hard to interpret. Blood cells will change after exercise for all sorts of reasons. And if the baseline situation is different the changes may be different. If this is PBMC I think it is hard to make sense of. I would like to home in on specific cell types interacting with other cells.

 

[Jonathan Edwards]

But long covid has often been declared to be ME/CFS.

Yes, and I think that has been a major confusion. Having ME/CFS symptoms does not necessarily make it ME/CFS. It may be one component of ME/CFS bin some cases but I think people have been too quick to say it IS ME/CFS. That is what Paul Garner got told and that ended up pretty badly!

 

[hotblack]

In case anyone newer to the thread missed this, audio versions of the paper are available to listen to here, now with a few fixes and a higher quality ‘Studio’ version
https://u.pcloud.link/publink/show?code=kZLPeS5ZBEzVhhjXk8hM18y29vgEGVG6zSvk

Any questions, comments or feedback please use this separate thread so we don’t distract from discussion of the paper. Thanks.

 

[Creekside]

'Further, gamma interferon directly affects the metabolic function of a wide variety of cells, including bystander macrophages and immune cells, as well as skeletal and smooth muscle cells, altering their function and likely contributing to the widespread symptoms in ME/CFS.'

Aren't IFN-g levels in the bloodstream found to be normal in PWME? If so, IFN-g's effect on cells isn't likely to be responsible for ME's body-wide symptoms. IFN-g levels at specific brain cells might have significant effects on body systems.

 

[V.R.T.]

Yes, and I think that has been a major confusion. Having ME/CFS symptoms does not necessarily make it ME/CFS. It may be one component of ME/CFS bin some cases but I think people have been too quick to say it IS ME/CFS. That is what Paul Garner got told and that ended up pretty badly!

Doesnt that depend somewhat on whether the mechinism behind short term resolving Post Viral Fatigue/ Long Covid with PEM is the same as the one behind ME/CFS?

Rather than ME/CFS is some other signalling loop or whatever happening on top of that initial post viral illness, or a totally pathologically distinct condition that initially resembles post viral fatigue?

 

[Jonathan Edwards]

Aren't IFN-g levels in the bloodstream found to be normal in PWME? If so, IFN-g's effect on cells isn't likely to be responsible for ME's body-wide symptoms.

Unless T cells are creeping in and out of tissues sensitising them with gamma interferon - either tissues like muscle or the nerve cells supplying muscle etc.

Not being able to find anything actually doing any signalling in ME/CFS is a major puzzle but something must be doing it that was not doing it before you were ill. TNF and IL-1 seem even less likely. If it is not cytokines maybe it is all nerve signals, but then what is making the nerves signal for no reason?