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

Jonathan Edwards said:
Yes, but I envisage the T cell macrophage interaction as occurring within a highly controlled microenvironment within lymph node or spleen, where bacterial products are not expected to be present at levels that would generate inflammation.
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Jonathan Edwards said:
The advantage of gamma interferon is that T cells can traffic around and secrete it all over the place.
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Apologies, but this kept bothering me. If this model explains ME/CFS symptoms via T cells trafficking around and spewing interferon gamma all over the place, then my original critique still stands:

jnmaciuch said:
The primary issue I see is in the lack of specificity of an interferon gamma-mediated mechanism. Purely theoretically, IFN-g could “prime” a macrophage to be more reactive to FcgRI binding, but the level of interferon gamma stimulation required for this priming would almost certainly also make them more reactive to LPS and PAMPs (bacterial crud, for anyone unfamiliar), oxidized cell free DNA…pretty much anything that activates a TLR or a cytosolic sensor. IFN-g is well known as a pretty broad spectrum sensitizer in that regard.
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Interferon gamma would potentiate any circulating myeloid if it had to get in the circulation to cause symptoms.
 
jnmaciuch said:
The potentiation doesn’t occur through direct interaction with a T cell, just stimulation of the IFNGR
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But the receptor isn't going to be stimulated by a T cell going past like Schumacher in a sea of plasma and red cells. I don't know the details of concentrations but my guess is that gamma interferon signalling in a tissue microenvironment is going to be several orders of magnitude more efficient than puffing some out in the breeze and hoping another cell gets a whiff. And any two white cells in blood probably do not get even enough for a whiff for more than fractions of a second.
 
Jonathan Edwards said:
But the receptor isn't going to be stimulated by a T cell going past like Schumacher in a sea of plasma and red cells. I don't know the details of concentrations but my guess is that gamma interferon signalling in a tissue microenvironment is going to be several orders of magnitude more efficient than puffing some out in the breeze and hoping another cell gets a whiff. And any two white cells in blood probably do not get even enough for a whiff for more than fractions of a second.
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Except that other examples of hypothalmic signaling require a sufficient circulatory concentration. You can induce fever by exogenous IL-1. That indicates that the hypothalmus detects a critical concentration of the cytokine, not specific cells. Similarly, I recall a study posted by someone on another thread showing that injection of a cocktail of cytokines induces myalgia. [Edit: viral infection features detectable levels of type I interferon in the blood]

I've seen some very tentative evidence that e.g. circulatory myeloids make it to the hypothalamus and secrete cytokines locally to induce responses. But when that occurs, it would've been at a sufficient concentration to also observe in the circulation. The idea that a small concentration of IFN-g spewing T-cells would be enough to zip to the hypothalamus and trigger the intensity of symptoms in ME/CFS seems at odds with every other similar example in the literature.
 
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jnmaciuch said:
Except that other examples of hypothalmic signaling require a sufficient circulatory concentration. You can induce fever by exogenous IL-1. That indicates that the hypothalmus detects a critical concentration of the cytokine, not specific cells. Similarly, I recall a study posted by someone on another thread showing that injection of a cocktail of cytokines induces myalgia. [Edit: viral infection features detectable levels of type I interferon in the blood]

I've seen some very tentative evidence that e.g. circulatory myeloids make it to the hypothalamus and secrete cytokines locally to induce responses. But when that occurs, it would've been at a sufficient concentration to also observe in the circulation. The idea that a small concentration of IFN-g spewing T-cells would be enough to zip to the hypothalamus and trigger the intensity of symptoms in ME/CFS seems at odds with every other similar example in the literature.
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But I don't think that is the whole story that we know. Hypothalamic signalling can just be neural - feeling nausea on seeing blood for instance. PEM and other ME/CFS symptoms do not include fever as far as we know so IL-1 signalling is probably not relevant. Yes, you can signal to the hypothalamus with soluble IL-1 or alpha interferon but that doesn't by any means mean it is the only way to signal to it - how about satiety from vagal afferents and indeed fatigue from muscle afferents, as Snow Leopard emphasises. And I don't think we actually know what is needed for signalling malaise during flu.

If cells get to hypothalamus and signal I see no need for that to be reflected in circulation. In a tissue microenvironment tiny amounts will produce useful concentrations - almost like neurotransmitters. If there are bits of hypothalamus that harbour T cells, as it seems there are, then presumably they are there to signal locally so I don't see anything 'at odds' here. Maybe it isn't in the literature but whatever we are looking for isn't in the literature yet!

I don't have any very strong feelings about what is the most likely site for T cells signalling their annoyance but there seem to me to be several options open.
 
Jonathan Edwards said:
I don't know whether they assessed time delay to onset of fatigue. My information on this comes partly from asking individuals but mostly from the poll I did here. You do not need a very big poll to see that time delays before fatigue onset are common and very variable - some people say six months.
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Can anyone provide me with a link to this poll, please? I wasn't able to find it on a search.
 
Jonathan Edwards

Thread 'Was there a gap between trigger and onset of your ME/CFS?'

We may have done this before but if so I forgot. The question is, if you attribute your ME/CFS onset to a trigger such as an infection or a vaccination, was there a gap when you seemed OK in between?

What I am interested in is slightly complicated because it is the time delay between onset of the trigger and onset of ME/CFS. If the trigger infection lasted three weeks and you had a gap and then had ME/CFS symptoms at three and a half weeks then the answer is 'more than two weeks' even though the well gap was half a week.

If there was no well gap at all then the answer is no even...
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@Sasha
 
Huge thanks again, @Jonathan Edwards, to you and your co-authors for this paper. I've just been reading the 'Synthesis' section of the new version, where no bun dares to go, and have a few minor editing suggestions:

p. 12, para 2: 'However, for antigens to which high-affinity antibody is present...' - should that 'to which' be 'for which'?

p.15, para 3: 'Different interactions may suit early warning, cell lysis, antigen eradication, systemic behavioural shifts (myalgia), and repair.' - should that be 'via myalgia', because myalgia is not a behavioural shift?

p. 15, para 4: 'ME/CFS may have wrong-footed us because it does not follow the textbook account of inflammatory disease. Signalling mechanisms operate invisibly in unknown compartments. In the past, that led people to abandon interest in immune mechanisms in ME/CFS, but we now know enough to see that it may not be so surprising.' - what is the 'it' that may not be so surprising?

p. 16, para 1: 'The proposed mechanism for ME/CFS raises several possible options for treatment. All present potential risks in terms of blocking important immune signalling mechanisms but probably no more than many immunomodulatory treatments currently in use. ' - I read 'present' as an adjective at first, as though you were saying, 'All current potential risks...'. Maybe better to steer people with, 'All of these options present...'?
 
Qeios paper said:
Targeting T cell populations, particularly those expected to provide protection from viral infection, has been met with little enthusiasm in the context of other T cell-mediated conditions. Long-term T cell depletion with anti-CD52 proved to be associated with relatively little morbidity in trials for rheumatoid disease, but a more subtle approach targeting T cell signalling probably remains a more attractive option, perhaps through the JAK/STAT pathway.

Arfmeister said:
  • more subtle approach T cell signalling JAK/STAT pathway = JAK-STAT inhibitors
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Can anyone speak to the horribility or otherwise of JAK-STAT inhibitors?

As a side-question, why do these drugs all seem to need to be infused/injected? Google isn't very helpful on this. Presumably they'd all get wrecked by stomach acid but what is it about them, as opposed to, say, aspirin, that makes them wreckable?
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Can anyone speak to the horribility or otherwise of JAK-STAT inhibitors?
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The theoretical skin cancer risk would be a worry for me, as close relatives have had malignant melanoma. Maybe no worse than other immune modifiers for most, though?

If it were a single, time-limited course of treatment, it might not even be an issue for a melanoma kindred though. It's really hard to assess risk out of context.
 
Jonathan Edwards said:
If cells get to hypothalamus and signal I see no need for that to be reflected in circulation.
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The main concern is still the same, though. Why would we expect this gamma-interferon spewing T cells to only have salient effect at the hypothalamus, or at certain peripheral nerves (and potentially interacting with macrophages in muscle as mentioned in the text), but not anywhere else we would expect circulating T cells to interact with and sensitize other cells? This wouldn’t only be in the circulation, but also gut and skin as previously mentioned and probably other locations I’m not thinking of.

The theory relies on both the ability of T cells to travel and for their effect to really only be seen at one venue (brain/nerves, and not any of the numerous nerves in the gut at that).

Sure there might be some completely unknown mechanism that explains all those dynamics, but to me that seems like a profound Deus ex Machina and parsimony issue.
 
Sasha said:
a few minor editing suggestions:
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Thanks Sasha, but by and large there is method in my madness.

We talk of 'an antibody to an antigen'. That is an antibody (or a population of antibody molecules in a fluid) that binds to the antigen. We do not talk of an antibody for an antigen. That may be convention but it is good practice because the antibody is not 'for' anything. In my model it may well be that the troublesome antibodies actually bind much more strongly to another antigen that is not there most of the time. They may be produced by plasma cells derived from B cell clones expanded during a viral infection and they may be 'antibodies to the virus' as well as antibodies to the usual junk that the model invokes.

I agree that the construction seems wrong and only works in a rather obscure abstract sense, but I think 'for' cannot work here either so I will stick to 'to'.

Myalgia is nota behavioural shift but an aspect of a functional interaction. I agree 'via' could go in but I think it is clear enough.

The 'it' is the fact that "Signalling mechanisms operate invisibly in unknown compartments." I suppose I could have put 'that that' but that always seems clumsy.

I can see the possible mis-parsing of 'present' but I try be succinct where I can and prefer not to add more words.
 
jnmaciuch said:
Why would we expect this gamma-interferon spewing T cells to only have salient effect at the hypothalamus, or at certain peripheral nerves (and potentially interacting with macrophages in muscle as mentioned in the text), but not anywhere else we would expect circulating T cells to interact with and sensitize other cells?
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That's easy; because T cells are that clever. Cells, especially white blood cells, are extremely clever at modulating their behaviour in response to highly specific contexts. These might be T cells that only traffic to neural tissue. Nobody has found such a population or set of addressins as far as I know. But there may well be and people may know about them for all I know. The cells that give us psoriasis only give trouble in skin and entheses pretty much. Reiter's T cells produce little brown marks on the middles of the soles of your feet - totally specific to that unique part of your anatomy.
 
Jonathan Edwards said:
I am sorry that you are confused @Simon M. I think at some point there must have been crossed wires.

One thing maybe worth adding is that the neural mechanisms that generate pain can also directly generate weakness, even without pain. There is a complete block to voluntary use of a muscle group but electrical stimulation of the muscle will produce a response.

I think a plausible model for ME/CFS is one where both nerves and immune cells are involved in generating inappropriate signals in the absence of any pathology in muscle itself. What I am less clear about is whether the neural signals actually loop back on to the immune cell function. They may do but I don't yet see a very convincing story for that. But either way all this signalling is a bit like the complex electronics of a Mercedes Benz that you would like to drive up the road. It doesn't go because of some too clever feedback safety programme that is completely invisible to the driver. There is nothing wrong with the engine but the engine sends signals to the software system in the electronic drive control which sends signals back to the engine to stop. CBT for the drive is not going to help!!
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Jonathan Edwards said:
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.
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I am confused in (I think) a similar way to @Simon M here. If I'm understanding correctly, you're saying in your paper that some signalling is going on that's telling a PwME that they're exhausted, even when the mitochrondria are fully charged, etc. etc. I don't understand why we then can't push through without ill effect. Even if there's some sort of feedback loop that makes the symptom of exhaustion worse and worse, why can't we push through the worse exhaustion?

You've argued against this possibility by saying that none of us have a 'me' that can override the causal pathways of the body but I surely have a 'me' that can decide whether to try to raise my arm or not.

You said:

Jonathan Edwards said:
One thing maybe worth adding is that the neural mechanisms that generate pain can also directly generate weakness, even without pain. There is a complete block to voluntary use of a muscle group but electrical stimulation of the muscle will produce a response.
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This really surprises me and I think it would surprise a lot of people. It must be the key to why you think I couldn't decide to raise my arm if it felt completely exhausted. Does this blocking of voluntary use of a muscle group happen to people in normal health? What about exhaustion (which is not the same as weakness)? How can you tell that there's a total block to voluntary use?

I'm not up on the philosophy of mind, probably along with 99.9% of the population, and if we need to tell a story about signalling that gets the world off our backs, it will need to be widely understood. I don't understand from the paper why we can't push through these feelings of exhaustion, which I'm sure must be my failing, but I think we're living in a world filled with people likely to have a similar failing, including a load of health professionals, the media and the general public.

Wondering if we can have another crack at this, because I think it's very important. Thank you as ever for patiently plugging away and helping us to understand.
 
From the paper:
Jonathan Edwards said:
On a broader front, it may be legitimate to see all these chronic disease states – autoimmunity, autoinflammatory states, familial fever syndromes, and ME/CFS – as each feeding off built-in risks associated with positive feedback (as in B cell clonal expansion), autocatalytic (as in coagulation and complement cascades), or ‘focussing’ (as in leucocyte chemotaxis) mechanisms that can get out of control but are still ultimately sensitive to some overriding homeostatic controls.
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I don't understand the principle of action of the therapeutics proposed in the paper well enough to tell whether they're targeting mechanisms downstream of these homeostatic controls. Is there potential to get the homeostatic controls to kick in better, rather than trying to directly squelch various immune cells?
 
Jonathan Edwards said:
The cells that give us psoriasis only give trouble in skin and entheses pretty much.
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Ah but there’s a little detail about exacerbated localized type I interferon production [edit: preceding T cell infiltration] that is a good candidate for explaining that location specificity of T cell activation ;)

[edit: meaning that there is actually no evidence of T cells with homing devices drawing them to act only in certain contexts, but plenty of evidence of type I interferon producing that localization]
 
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Sasha said:
Does this blocking of voluntary use of a muscle group happen to people in normal health?
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Yes. If you put a metal spike in a place where it would dig in and produce severe pain with a certain movement, as soon as the nervous system has logged that it is going to do that you will be incapable of causing yourself severe pain by doing that movement. More commonly, if a torn muscle or tendon insertion produces severe pain from an injury it becomes impossible to override that.

There may be exceptional circumstances where this sort of involuntary inhibition is overcome but generally not through wanting to. Hypnotic trances and psychedelic drugs might do it. Adrenaline may overcome it in some situations - and lots of members here report that adrenaline can partly overcome symptoms.

And when you have flu it is completely impossible to undertake anything strenuous like climbing a rope, or maybe even standing on two feet. And there is nothing wrong with the mitochondria there.

And people with ME/CFS by and large do normally on a first go at CPET. We know that the energy is available. Although it has been popular to talk of mitochondria and energy deficits in ME/CFS right from the start of getting involved it has always seemed to me that this would not fit with the symptoms people describe.

Neural signalling loops are mostly just as much part of your 'body' as muscles and mitochondria. I don't think people should shy away from mechanisms that involve nerves just because of popular myths. If we want the right answer we have to follow the signs to the right answer.
 
Sasha said:
You've argued against this possibility by saying that none of us have a 'me' that can override the causal pathways of the body but I surely have a 'me' that can decide whether to try to raise my arm or not.
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There almost certainly isn't a single 'me' that does that. There is a system of cells in the brain that determines whether your arm goes up or not but it cannot override the cells of the reflexes. Moreover, it is almost certainly not the group of cells that 'feels it is doing it'. We have masses of experimental evidence for thinking that 'conscious will' is largely a narrative concocted by other bits of brain for the benefit of bits that run a narrative of 'me'. The popular simple idea that there is a 'me' that can tell the body what to do is about as wrong as it could be

Which is why the BPS people make no sense because they assume that there is a 'mind' that can control the body. What I am saying is directly opposed to the BPS view. The irony is that if you were right about 'me' then the BPS people maybe should be right too!!
 
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