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

I think this quote is key.

1. I'd like to understand how you settled on macrophages with FcγRI passing on bits of junk to T cells and not monocytes, dendritic cells, or neutrophils that also express FcRI? What is special about macrophages?

2. I understand you propose macrophages set of a chain reaction with T cells that might be key but what are the side effects of "junk" also attaching to FcγRI of other cells that express that receptor? e.g. monocytes, dendritic cells, or neutrophils.

3. Apparently mast cells also express FcγRI, and its expression can be significantly increased by IFN-γ. Eosinophils also express FcγRI. If the "junk" can attach to FcγRI, could we see an uptick of allergy type reactions? Does the "junk" only attach to FcγRI on macrophages?

 

Monocytes are in blood so don't have time to stop to talk to T cells.
The argument for dendritic cells would be the same as for macrophages. But up regulation of FcRI on macrophages is a well established phenomenon. Dendritic cells fall into various subgroups and it is all a bit murkier.
Neutrophils are not professional antigen presenting cells so are of less relevance.

The junk does not need to activate the receptor - or at least that is not part of the hypothesis. It gets internalised and because the macrophage, or dendritic cell, is adapted to talking to T cells and presenting peptides on MHC II the T cells can get activated.

I don't think mast cells or eosinophils present antigen to T cells much and, again, I am not suggesting that the cell bearing the FcRI need itself be activated.

 

This was actually raised back in the 1980s when I was training. Women may have almost as high a prevalence of low grade sacroiliac changes as men but there is no doubt that the full clinical picture, with rigid ankylosis, is more common in men. There are unlikely to be cultural differences when it comes to a minimum occiput-to-wall distance.

 

@Jonathan Edwards, did you see this? I’ll be interested in your response (apologies if you responded and I missed it)

 

I wonder if there is a way of emphasising this in the paper? I’m not sure how clear this subtlety will be to people who haven’t had the benefit of talking to you about these ideas for weeks/months as we have. Lay and perhaps scientific readers may (and I think I have already seen this) get hung up on one specific aspect rather than the bigger picture?

It could fit with the t cell clonal expansion and population comments made earlier.

 

Sorry, @Simon M, I missed responding to that.

I think that in a sense we can argue that in all the 'immune over-responsive' diseases we have a problem with 'false or exaggerated signals' In RA, lupus, familial Mediterranean fever and ank spond signals that are supposed to flag up microbial or physical injury are just firing off on their own.

In RA the signals also cause damage and that damage leads to more signals later but in lupus most of the arthralgia is non-damaging. There may not even be much swelling, so not very different from MECFS.

The false argument is that false or exaggerated signals can be overcome by pushing through. You cannot do that for lupus or RA. It might seem you should be able to for ME/CFS but if there is a loop that amplifies the immune signal further every time you push then you cannot.

The false argument depends on this naive distinction between mind and body (Cartesian dualism) that the biopsychosocial people make, with the mind being some 'other' causal unit. My work on brain biophysics tells me that this is nonsense. The 'psyche' of psychology is a bogus concept. It is entirely unreasonable to suggest that there is a 'me' that can override the casual pathways in my body. In fact the situation does not even arise if the signals are at an earlier level that does not even figure in conscious perception or thought.

If neural hypervigilance consists of dorsal root ganglion cells being sensitised by gamma interferon and setting up local reflex loops that perpetuate that sensitisation the pushing through makes no sense. The psychologists seem to forget things like reflex sympathetic dystrophy, where spinal and autonomic neuron loops as far as we can see have the power to alter bone density, skin temperature and colour, and tissue growth and generate agonising pain.

I fully understand the concerns people have about giving the BPS people grist to their mill but I think once the real sceince starts to unfold that will be irrelevant anyway. To some extent I do wonder whether the mistake the BPS people made was not to assume ME/CFS is psychological when it is physical, but to miss the fact that it probably involves important neural and indeed neuropsychiatric (brain fog) events that they have completely failed to analyse intelligently. It got passed to the 'psychodynamic' brigade when it should have been studied by people who had some understanding of organic brain disease.

The paper deliberately avoids trying to build in any neural loops but I think we need to be comfortable with the idea that they may contribute. But not 'psychological' loops.

 

I think it would get too philosophical. My tactic is to introduce some specific negations of popular myths - that autoimmunity is triggered by infection or that ME/CFS involves inflammation. I think that is enough for this paper. People who do not understand the complexity of the puppetry will never understand I am afraid. They are in the majority in immunology and one just has to carry on without them. The sort of discussion we have here you cannot have in an immunology department. You have to have it in a back office with some bottles of wine. When you do a definitive experiment you do to expect most people to understand what it means but you have still made progress in solving the clinical problem.

 

Fair enough. You know best what your aims are and the ways of working within that world and community. Glad you can discuss things more philosophically here.

I’m obviously positive about the paper because of the relevance to me and my life, but I’ve also just found it really interesting. And I know we’ve all said thanks to you and Jo and Jackie here, but please do pass that on from all of us in person.

 

On reversal of any neural plasticity changes once the feedback loop is stopped. I feel confident this could be possible, just a feeling from my experiences within my illness.

But also, to be honest, even if something described here just got me into a steady state of the best I’ve been since ill that would be significant. So still probably very limited, largely housebound and having to manage activity, but able to be stable and move around and do a few things, and not have massive months or years long crashes of hell from immune system triggers like illness or vaccines, that would be a huge quality of life improvement. Not everything we’d want in terms of full reversal of course. But for many of us that first step, a pause on the immune side of things, would be life changing.

I do think there’s more than that possible. But thought the perspective worth voicing.

 

At the other end of the scale I did have an amusing (well, for me) thought. What if we do find a complete cure? Many/most of us would then actually need and benefit from the sort of rehab that we’ve been offered for years to get our bodies working again! And probably to work with some of the psychological impacts we’ve been through. I’m not sure we’d trust some of those offering it but so many people in need of their services would mean there’s nothing for them to fear about us finding the biological answers. So they should get on board and support these efforts!

 

Whate would be steady, though? To me, PEM is the limiting factor in everything. I’ve got bad OI as well, but that can be somewhat mitigated with adaptations.

If I stopped getting PEM, I would have a drastically higher level of functioning.

 

I don’t think we would have any use for their services at all, because they are clueless about how to do things in general.

 

I think that's an important argument to present, though, but rather than being part of this paper, it should be a standalone?

 

A lot of these are sounding fairly horrible and potentially quite dangerous, given their immune-suppressing properties. I'm wondering whether there's a non-horrible view of our future that doesn't include continuing to have to shield (I've been shielding for five years now).

 

I hope there is. I would love to be able to go to gatherings and play/attend gigs again if there was a really effective treatment. In some ways being functional but still shut out of the world would feel like a much more bearable but still quite rubbish sort of purgatory.

I have also been shielding since winter 20/21 and it is awful and maddening when the world has 'moved on' and memory holed the illness that you're shielding from.

But of course we cannot bargain with what will and won't work. And do all of these drugs leave people totally immune compromised? Or do some of them just increase the risk a little? Its complicated by the fact a lot of people who should shield or mask from covid due to being immune compromised don't because of social pressure and a desire to be around others.

 

I am afraid that it is pretty much the old Jazz saying:
"If you gotta ask you ain't ever going to know."
Some people have basic nous even if they have no technical knowledge. The great majority of people in biomedical science don't seem to have that nous, and explaining it to them doesn't achieve much!

 

I think shielding will be easier if I could just say that I’m on immunosuppressants or chemo, instead of that I just don’t want to get sick.

 

I'm brain-fogged as usual, so just ignore this if it's rubbish.

Could it be that certain things are not acting in the way that they would normally, rather than things acting in a certain way?

I hope that makes some sense!

 

It's a thought I keep having, but I wonder if it ends being a bit circular anyway—is the problem that an unhelpful loop is set in motion, or that it's not being stopped once it has.

I keep trying to pinpoint whether I mean something slightly different to that, but usually end up thinking I should just make some toast.