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

[Jonathan Edwards]

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!!

 

[Jonathan Edwards]

so it would easily explain why people with very severe ME\CFS have such acute sesitivity to touch ?

Certainly.

 

[JemPD]

Certainly.

what about sound/light?

 

[Braganca]

I had Botox for migraine treatment three months ago. It is about 40 shots of Botox down the neck into shoulder region, up and over the entire scalp and on forehead, nose etc. The treatment helped reduce frequency and occurrence of headaches hugely, unexpectedly eliminated my neuropathy on both arms, also seems to have turned down the tinnitus and buzzing in head and overall my feeling of PEM seems reduced. I’ve been able to increase my step count by about 25% which I haven’t been able to do in years and may be related or not.

The theory of mechanism is that Botox is taken up by the nerves and interferes with neurotransmitters. It’s also thought to travel down the nerves to the brainstem itself. Any thoughts on this as related to the discussion @Jonathan Edwards? I’m wondering if further treatments will further dial back my symptoms even more..

 

[Jonathan Edwards]

what about sound/light?

Light is interesting because the optic nerve is part of the brain and does not have the equivalent of dorsal root ganglia and things. On the other hand sensitivity to light may be mediated through innervation of the iris (that is what makes you photophobic with inflammatory eye disease) and that works more like other nerves.

The auditory nerve is again different, and so for that matter the olfactory nerves.

But I think they could all be sensitised in much the same way one way or another. Something sensitises them when you have bad flu in my experience.

 

[Kitty]

But I think they could all be sensitised in much the same way one way or another. Something sensitises them when you have bad flu in my experience.

It's almost like some types of migraine and the alcohol hangovers friends and ex-partners have described.

I've never had either, but I could see how acutely sensitive they were—I think it was worse than anything I've experienced. It was interesting how it began to fade after a number of hours too, and the enormous difference it made to them when it did.

 

[arnoble]

Since we all have dodgy discs at the vertebra prominens (the worst is usually c5-6 just above) and in the lumber region we can expect to get pain or other unpleasant feelings in those places when we have an infection or an immune disease.

The penny has finally dropped, I think: immune "molecules" can activate or amplify signals in sensitized nerves near (for example) degenerated discs.

 

[Utsikt]

The penny has finally dropped, I think: immune "molecules" can activate or amplify signals in sensitized nerves near (for example) degenerated discs.

Wait, does it amplify an already existing signal from other nerves, or does it make the nerve create a signal from less input from its surroundings than what it would normally take to get it to create a signal?

 

[Simon M]

Thanks for bearing with me, @Jonathan Edwards.

My brain is in slightly bit of shape this evening, so I’ll try one more post.

my brain is doing better this evening, so I’ll try again in response to your points.

First of all, it would be wonderful if everything amounts to signalling issues – presumably, Things are easier to fix if there has been underlying damage (I don’t have any strong feelings about what’s happening in my body, but I would like to know what ).

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’m familiar with the idea of complete block, but that’s not what’s happening to me. (I should also say that these relapses happen if I try to push through, but they happen anyway due to relatively minor activity.)

The pattern of this is very different from the pain and fatigue – perhaps that this is still consistent with your model.

Pain and fatigue are pretty variable for me anyway, as I think they are for many people. I don’t have a steady level of fatigue All day every day from day-to-day, that only changes by a small amount.

In contrast the profile of the loss if function is very different. First of all, it can easily take me six months to recover (or at least as far as I recover before the next relapse). So a completely different time scale. Secondly, any changes are very, very slow. I will either make very small progress in a day or not at all (obviously, bad days happen and it’s hard to know what’s going on then. It’s a bit like playing snakes and ladders, but without any ladders. And I only ever throw in a one or two on the die. Which sounds to me different from a complete block that can be overcome with an electrical signal.

But would this still fit with your model?

I this really is my last post, I don’t want to bore you or everyone else anyy with my personal musings

 

[Jonathan Edwards]

Wait, does it amplify an already existing signal from other nerves, or does it make the nerve create a signal from less input from its surroundings than what it would normally take to get it to create a signal?

You'd better read up on it. I rely on everyone to provide the actual facts!

 

[Jonathan Edwards]

But would this still fit with your model?

I this really is my last post, I don’t want to bore you or everyone else with my personal musings

Please don't feel you are boring anyone @Simon M . Going over these things so that everyone feels they have a measure of them is so important. We may be further ahead by August more because of data than musings but I like to think the musings are just as important because the data need interpretation.

I guess I do the deus ex machina bit here by saying that when things go wrong the normal rules need not apply. The brain is way more complicated even than the software in a Mercedes and when a Mercedes goes wrong none of the normal rules of what the car is supposed to do apply.

And the block can be long lasting even for the normal rules. The state of my knees now is such that I have not been able to get up off the floor other than by rolling over, getting up onto hands and knees and then leveraging myself up with one arm holding on to something in a particular way. I presume my brain has learnt that this is the only way that would not be agonising so it just prevents me from even trying normal ways of getting up This has been going on for about five years now. It is set in. But no doubt if some magic made my knees better I could teach my brain to go back to doing things normally. I don't get much pain doing any of this. It is just that I have no 'strength' in the muscles I would normally use for that manoevre because my hindbrain forbids it.

 

[hotblack]

It's almost like some types of migraine

Absolutely this. I didn’t get migraines until I had ME but do now, and although it may not be entirely linked (my mum developed them around the age they started for me) and I don’t always have visual auras, I do sometimes and there are a lot of similarities between those and the more general ME sensitivity, but the latter can go on for longer than a migraine or post migraine state.

 

[Deanne NZ]

I am enjoying this thread and I am excited about the possibility that this hypothesis may result in advancement in the understanding of and potential treatments for MECFS.
The signal malfunction & likely genetic propensity make sense to my observations of my son’s experience.

He has a range of symptoms that wax & wane over the years and some that are constant (per MECFS diagnostic criteria). Some of the additional crash symptoms would fall into the central nervous system bucket & others the immune system one. I have mentioned before that is his longest & most severe crashes he has had swollen lymph nodes that are visible for around 9 weeks, but blood tests show no sign of infection. However, he has had other long crashes without swollen lymph nodes. Some crashes involve prolonged & severe headaches, others are more GI symptoms.

 

[tuha]

Are there already any reactions from the scientific community (outside this forum) about this paper?

 

[Turtle]

Please don't feel you are boring anyone @Simon M . Going over these things so that everyone feels they have a measure of them is so important. We may be further ahead by August more because of data than musings but I like to think the musings are just as important because the data need interpretation.

I guess I do the deus ex machina bit here by saying that when things go wrong the normal rules need not apply. The brain is way more complicated even than the software in a Mercedes and when a Mercedes goes wrong none of the normal rules of what the car is supposed to do apply.

And the block can be long lasting even for the normal rules. The state of my knees now is such that I have not been able to get up off the floor other than by rolling over, getting up onto hands and knees and then leveraging myself up with one arm holding on to something in a particular way. I presume my brain has learnt that this is the only way that would not be agonising so it just prevents me from even trying normal ways of getting up This has been going on for about five years now. It is set in. But no doubt if some magic made my knees better I could teach my brain to go back to doing things normally. I don't get much pain doing any of this. It is just that I have no 'strength' in the muscles I would normally use for that manoevre because my hindbrain forbids it.

That way of getting off the floor feels familiar, I have to do it on hands and feet.

The "its the nerves doing it" does not stike a chord with me, part of it maybe, not all though.

I only had 1 1/2 half minute of aerobic energy on my CPET. Are nerves eating my pyruvate, or the immune system taking all my oxygen?
There must be more than immune and nerves. Inadequate blood supply, vasoconstriction will hamper muscles to function and lactate will build up too.
When I was still working I had to walk a bare minimum of 40 minutes, 5 days a week. Lactate on top of lactate building up that made my muscles burn and it always did feel like wounds inside, raw flesh.
Worst thing that could happen at the end, almost home, the elevator out of order, I lived on the eight floor.

 

[Snow Leopard]

But it sounds like it’s more likely the Neuro pain and fatigue, false signals, in the sense that they are not related to the pathology.

The critical point is that the signals are generated peripherally, either at the nerve endings or sensitisation in the DRG. This is not central sensitisation or supraspinal generated signals.

A second (maybe related?) observation is that I generally feel horrible when I wake up but get better as the day progresses and feel the best in the evening. Maybe also related to cortisol levels? Anyone else experience the same?

I am going to say yes to this too. Higher cortisol reduces my symptoms somewhat and my working model of nerve sensitisation explains this in a direct manner (it doesn't require reduced cytokines/interferons or whatever).

 

[wigglethemouse]

I asked Google AI "how do drg neurons signal to immune cells" and yes signalling can happen both ways. It gave examples and some references but I don't know enough to interpret the data.

One reference was an interesting review discussing "Neuroimmune Interactions in Peripheral Organs" and it includes some discussion on DRG neurons. Brains sharper than mine might find something interesting in all this complexity. There seems to be lots of ways signalling can occur in different neurons and immune cell types. Here is the paper.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9436268/

One thing I learned in my reading is that in addition to neurotransmitters, T cells and other immune cells express receptors for neuropeptides for communicating.

 

[Jesse]

@Jonathan Edwards (and others): two things I still want to get a better grasp on from your hypothesis. If you would humor me (again maybe it's a bit too specific, let me know).

Disease severity and worsening:

Would the baseline severity of an individual be a function of the sensitivity of their immune system / nerves? So basically how strong the immune system reacts to the junk and then how strong the nerves signal fatigue / pain?

If so, is there a mechanism that could explain how overdoing it and PEM can lead to a worsening of the baseline of an individual? Would there be any explanation for an upregulation in sensitivity, like a positive feedback loop?

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And secondly, PEM triggers:

So the way I'm understanding it baseline symptoms are triggered by those so called everyday junk’ antigens, as I talked about above. But obviously PEM strongly increases symptoms and is triggered by physical/cognitive/emotional exertion. Would exertion result in an increase of these same 'everyday junk’ antigens thus causing stronger symptoms? And would that fit with all types of exertion (physical/cognitive/emotional)?

So basically I'm wondering if there is a single pathway/trigger (type) that drives both baseline and PEM symptoms (from all types of exertion). In the paper you give the example of muscle microdamage. Does that fit under everyday junk or not? But also obviously that doesn't fully explain cognitive and emotional exertion.

I wonder if cognitive and emotional exertion effects could be from their autonomic effects on the body (i.e. stress). Cortisol/adrenaline increasing metabolism, heart rate/blood pressure/respiration going up, muscle tension, as well as the release of cytokines?

I will say that physical exertion is by far the strongest PEM trigger for me, although I know it's different for some.

 

[Jonathan Edwards]

Here is the paper.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9436268/

Thanks for that.
One paragraph that seemed relevant was:

Recently, a brain-spleen circuit was described that directly impacts on immune defenses by regulating the formation of immunoglobulin-producing plasma cells (Zhang et al. 2020). The stress-responsive central amygdala and paraventricular nucleus of the hypothalamus stimulate splenic T cells via noradrenaline released by the splenic nerve. These T cells in turn secrete ACh, which binds to splenic B cells, driving its differentiation into immunoglobulin-producing plasma cells.

Much of the paper otherwise seemed to cover what I had already gleaned as possible pathways but without any very specific example of what neuroimmune signalling added. The role of nerves in things like triple response we know but I am still unsure that there is a clear story of how nerves would perpetuate or enhance an 'auto-inflammatory' type situation (especially one without inflammation!).

But this is all very helpful. I think I am beginning to see the scope of what is becoming known.

 

[Jonathan Edwards]

Would the baseline severity of an individual be a function of the sensitivity of their immune system / nerves? So basically how strong the immune system reacts to the junk and then how strong the nerves signal fatigue / pain?

Yes, more or less. Severity could be set by the degree of expansion of some T cell subpopulation that together with antibody kept recognising junk too much. I am thinking by analogy with psoriasis where that seems to be the explanation (just T cells maybe). If the nerves are part of the level setting maybe they learn to inhibit muscles and that gets wound up more by an episode of exertion and takes a long time to unwind - although I am much less clear about that idea.