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

[wigglethemouse]

I think this quote is key.

On the other hand in the context of FcRI they may pass bits of the junk to T cells and mediate a T cell immune response.

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?

 

[Hutan]

Female Predominance
Despite problems with diagnostic ascertainment, the prevalence of ME/CFS is consistently reported as between twice and four times greater in females than in males[12] ...

... Female predominance is consistently seen for antibody-mediated processes in a way not often seen outside diseases of female organ systems such as the uterus or breast. Such ratios are not seen in T cell-mediated diseases like psoriasis or ankylosing spondylitis (where the ratio is reversed)[21].

I have been looking at some ankylosing spondylitis papers and it appears that there has been some movement in the idea of male dominance in it and related illnesses lately. Issues such as the illnesses presenting differently in women, prejudices about women and possibly cultural differences in how pain tends to be described by men and women might all be playing a part.

Attributing 'maleness' or 'femaleness' to T cell-mediated diseases and antibody-mediated diseases appears to be complicated. I haven't checked the ME/CFS hypothesis paper for how definitively the distinctions are made. It might be worth checking the literature to be sure that recent thinking doesn't affect the claims though.

Perhaps there are some clues in how women and men tend to present with these diseases for what might be happening in ME/CFS. Reading these papers, I am reminded that there are probably a lot of people who should have been diagnosed with some of these recognised conditions, or who at least would benefit from the same sort of treatments, but who, because of their sex, and/or the prejudice or disinterest or lack of knowledge of their doctors, have instead ended up with a label of psychsomaticism.

Understanding differences between men and women with axial spondyloarthritis, 2020

Although women tend to report poorer PROs, including fatigue, these results should be interpreted with caution because women similarly experience poorer PROs than men in rheumatoid arthritis [41]; furthermore, the presence of comorbid fibromyalgia may skew PROs in women with axSpA (discussed later). However, it is possible that women are perceiving greater disease burden because they may indeed be experiencing worse disease activity.

Anxiety and depression may be more common in women than men with AS, contributing to the overall burden of disease. In a real-world study of 235 patients with a self-reported AS diagnosis, women were significantly more likely than men to receive diagnoses of psychosomatic disorders (40.8% vs 23.0%; P < 0.05) prior to diagnosis with AS [42].

Biases may exist in the clinical evaluation of disease in women that lead to a delayed or incorrect diagnosis, and a key unmet need is health care provider awareness of the general sex-specific manifestations of axSpA. Currently, misunderstanding of axSpA manifestations in women may contribute to a delay in diagnosis. Women may have additional potential diversions in the journey to diagnosis with axSpA, and awareness of these could be improved. Abdominal symptoms in women may be diagnosed as irritable bowel syndrome rather than inflammatory bowel disease, and pain may be diagnosed as fibromyalgia rather than symptoms related to axSpA. While awareness of diagnostic delay is an unmet need for all patients, the need is greater for women.

Because AS is a more advanced form of disease than nr-axSpA and has been historically viewed as a disease predominantly occurring in men, a number of implicit biases exist in the diagnosis and treatment of axSpA that can lead to poorer outcomes in women if not recognized early. The burden of nr-axSpA and AS on patients is similar despite differences in sacroiliac or spinal radiographic progression, and women may have a greater disease burden than men regardless of classification. The underlying pathophysiological differences in spinal and sacroiliac joint radiographic progression across sexes are being investigated, and appropriate understanding of these differences should lead to earlier diagnosis and better outcomes in women.

 

[Jonathan Edwards]

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?

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.

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.

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.

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?

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.

 

[Jonathan Edwards]

I have been looking at some ankylosing spondylitis papers and it appears that there has been some movement in the idea of male dominance in it and related illnesses lately. Issues such as the illnesses presenting differently in women, prejudices about women and possibly cultural differences in how pain tends to be described by men and women might all be playing a part.

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.

 

[Simon M]

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

I wonder how relevant neural hypervigilance is.

(If I’ve understood right, that’s the basic idea of the interception hypothesis, which a few years ago seemed to be the most popular way to add the bio to biopsychosocial. Just checking I have that right – it’s not an objection in itself.)

But it seems to be saying that the pain and fatigue we feel, which can be overwhelming, are false or exaggerated signals (edited from sensations). If that is the case, then it should be possible to push through without any real consequence. Sure, the fatigue and pain are likely to get worse in the short term, but beyond that?

My experience of pushing through is that I have a relapse - a dramatic loss of function. The pain and fatigue worsen initially, but they return to normal levels before too long. The loss of function remains.

How does that square with neural hypervigilance?

 

[hotblack]

The idea is that whether or not you appear to have antibodies to something knocking around depends on what context the antibody is binding in

What appears to be a single integrated immune response orchestrated by macrophages, T cells and B cells is in fact contrived by all sorts of swap-over moves that only work well because everything is aligned right. The system is shimmed up pretty much so that any particular error sufficient to produce major disability only occurs in about 0.5% of people and lethal errors in not more than 0.1%. That is pretty good but isn't perfect.

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.

 

[Jonathan Edwards]

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

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.

 

[Jonathan Edwards]

I wonder if there is a way of emphasising this in the paper?

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.

 

[hotblack]

I think it would get too philosophical.

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.

 

[hotblack]

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.

 

[hotblack]

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!

 

[Utsikt]

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.

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.

 

[Utsikt]

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!

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.

 

[Sasha]

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.

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

 

[Sasha]

I’ll deduct some of the potential treatments based on the paper

Main Targets for Treatment: Persistent low-affinity IgG antibody populations, FcγRI expression on macrophages, local gamma interferon release, and T cell activation or clonal expansion.

Treatment Options Immune supression :

• anti-CD38 (e.g. Daratumumab, Isatuximab) with small molecule agents like mycophenolate or bortezomib to reduce IgG levels.
• Intensive chemotherapy (e.g cyclophosphamide) reduced IgG populations and contributed to ME/CFS improvement - NOT recommended but as a reference
• FcRn blockers (e.g. efgartigimod, rozanolixizumab, etc) reduce total IgG levels by blocking the neonatal Fc receptor, indirectly lowering IgG at FcγRI.
• Intravenous immunoglobulin therapy IVIG may help but is cumbersome and expensive.
• Empalumab (anti-IFN-γ monoclonal antibody) can block gamma interferon production or interaction from T cells.

Targeting T cell populations:

• cyclosporine - Suppress T cell activation; memory cells may persist but become less responsive
• mTOR inhibitors = Rapamycin, evosirolimus
• Alemtuzumab, anti-CD3 T cells = Lemtrada, Campath - Long-term T cell depletion with anti-CD52 proved to be associated with relatively little morbidity in trials for rheumatoid disease
• more subtle approach T cell signalling JAK/STAT pathway = JAK-STAT inhibitors

Maybe in the future heavy duty Teclistamab and CAR-T when more researched and advanced ?

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).

 

[V.R.T.]

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.

 

[Jonathan Edwards]

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

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!

 

[Utsikt]

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.

 

[MeSci]

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?

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!

 

[Kitty]

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

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.