ME/CFS as a biological information processing problem

Note that although we have treated RA on the basis that we think autoantibodies are causing inflammation by forming complexes and ligating FcRIIIa we have never actually measured that in patients. You cannot find complexes triggering TNF release inside a joint. You have to set up in vitro model systems. Animal studies are by and large useless for studying disease, although animal studies are useful for understanding normal mechanisms.

Much of our understanding of pathophysiology comes from inference.

 

Reductionism is a word philosophers use almost exclusively for theories they personally find distasteful and not in line with their own preferences!!!

 

Nobody was comparing to the whole body. If I spend hours trying to repair some stitching in a chair the demand on any given muscle is minimal but the procedure is seriously tiring. I am fairly sure that our S4ME fact sheet says that PEM can be induced by levels of activity well below what would be expected to cause a problem. That is seen as a defining feature.

Aren't you being a bit reductionistic here, assuming that it is all metabolism!!!

 

To be honest, my thought here is that nothing really fits - nobody's theory adds up. We need to understand some form of interaction between nerves and T cells that so far we haven't really got a handle on. But to identify that we need to be completely open minded about where the critical events are. I think they may not be in muscle at all. But signalling from muscle afferents certainly seems to follow.

 

How can e.g. objectively very low levels of stimuli like light or sound cause PEM in the very severe, then? Are those taxing enough locally, metabolically speaking?

 

One thing that I think is worth keeping in mind is reflex algodystrophy. This is a gross tissue pathology that appears to be dependent, at least in some cases, purely on adverse neural signalling.

A hand or foot or even knee can develop severe contracture, severe dystrophy of nails, marked colour change to a cold dusky purple, gross osteoporosis to the extent that the bones actually disappear on x-ray beyond a pencil outline and pain that drives the person mad.

The problem can be precipitated by a fracture or a stroke but in some cases it appears to come on entirely spontaneously. It is generally assumed that the affected domain is based on sympathetic nerve distribution but we don't really know.

Maybe we are looking for a similarly obscure mechanism that may involve some local cytokine or prostanoid or metabolic signals but invokes nerve behaviour that so far we know nothing about.

 

Just to put it out there, we know from interferon therapies that you really do get the whole shebang of fatigue-fever-chills-pain-etc. from a single circulating interferon. What’s happening in actual viral infection is undoubtedly more complex. But the effect of a single interferon does quite closely align with what is described in PEM.

for what it’s worth, I agree with you on the local metabolic environment being the initial trigger. It just needs to turn over somehow from a local signal to a global signal, and that’s where I look to the immune system.

 

I am not too sure about the role of sleep wake cycle specifically, but it has already been shown that there seem to be “phases” of immune response to various stimuli, some of which occur at earlier phases and some of which only peak at ~24-48 hours.

some discussion of that is here:
https://www.s4me.info/threads/two-stage-metabolic-remodelling-in-macrophages-in-response-to-lipopolysaccharide-and-interferon-γ-stimulation-2020-seim-et-al.43874/

This paper only looked at a few possible candidates from one type of stimulation, but I think it is very plausible for the same principe to hold otherwise explaining the time differential of PEM very neatly. Especially if the earlier (perhaps IL-6 and TNFa) stages are dependent on some metabolic state in immune cells that is abrogated somehow by the trigger for PEM, causing only the later response to be strong enough to notice.

Also, to your point, I think it is a fairly common phenomenon for people to “wake up feeling like crap” when they are actually sick with the flu, so I wouldn’t be surprised if sleep-wake cycles had something to do with it. I think the easiest culprit is diurnal cortisol which would suppress an initial response until it dips overnight. But there may be other stronger candidates.

 

Were these model systems completely divorced from RA patients? Or was antibody taken from the patients to apply to the model system? That would still be measuring a parameter directly linked to the disease which possibly we wouldn't be able to do with ME.

 

I wonder how Rob Wuest is doing with his muscle staining. There was the question of whether he was inadvertently staining acetylcholinergic neurons. There's the nerve gas acetylcholinesterase connection with GWS. There's sets of genes from precisionLife and heal2 pertaining to synaptic function, neuron and glia. Is there a chance the leucocyte infiltration you appear to get in muscle following exercise interacts with neuromuscular junctions or sensory afferents in some way. Wuest's study reported CD3 cells in long covid patient muscle at baseline, which were absent from controls.

 

I recently reached out to Rob, and he said they had some further evidence that it was not nerves, but exact confirmation would be forthcoming.

The reason I reached out to him was the possibility that the signal was not amyloid or acetylcholinesterase, but actually extra-mitochondrial mtDNA which is rich in G-quadruplexes and binds ThT.

It would fit with the reduced SDH activity that they also noted, since this has been shown to induce mtDNA release. It would also fit with flu-like symptoms, as detection of mtDNA by cGAS-STING triggers a delayed type I interferon response. I’ll note that the Grimson analysis showed upregulated CCL4 response in monocytes, which is specifically a type I associated interferon stimulated gene.

There were some weak puncta in the cytosol in Rob’s 2024 paper that might support it being mtDNA—the only thing I’m unsure about is whether mtDNA would be expected to clump together in the extracellular space like is shown in those figures. It’s known that mtDNA can leave the cell via NLRP3 and triggers TLR9 on nearby macrophages (which might eventually lead to CD3 recruitment), so being in the extracellular space is not a problem.

I just got an email response from a former professor who studies G-quadruplexes and in theory they might be expected to clump together due to their orthogonal structures essentially creating ridges to hold small fragments together. But this is speculation rather than anyone observing this phenomenon in vivo—the people studying G-quadruplexes tend not to be looking for them in muscle cells.

 

There would be a way to indirectly connect mtDNA to synapses via extracellular calcium however, since mtDNA release occurs through VDAC1, which is first and foremost a calcium ion channel and its oligomerization is sensitive to calcium levels controlled by local neurons. I’ll note that many of the Zhang et al. hits were related to calcium signaling, and the synaptic hits noted excitatory neurons most frequently.

Muscle is a highly innervated tissue, so if there was some genetic predisposition leading to increased synaptic density and therefore higher baseline extracellular calcium concentration, that would encourage mtDNA release from much lower exertion levels if coupled with even slight OxPhos impairment. To clarify, I’ve recently read that there is both acute calcium release causing immediate contraction and continued release associated with muscle conditioning. I’ve been idly wondering if this might explain why pwME actually seem less deconditioned than you’d expect from very low activity levels, though it’s only idle speculation that might have other explanations. I’m hardly an expert after reading a few papers, so happy to have someone correct me on any details I may have gotten wrong.

 

It's also plausible that some people with mild/moderate ME/CFS aren't as deconditioned as expected because they have pain and discomfort all the time, and are driven to make a lot of positional adjustments. (Because they can, that is. A severely affected person might have to put up with it because moving to seek a comfortable position is a vicious circle that will lead to them feeling even worse.)

I've had several people comment that I'm a fidget-arse who never stays still for more than 20 seconds. I don't remember doing any of this movement—it's almost a reflex, like moving a strand of hair away from your eye. But when even my GP said I was moving my feet all the time, I started noticing it more. Turns out I'm an appalling fidget-arse.

[Minor edits]

 

Since this has come up a couple of times now. And it’s a very fair counter to my original comment of there being no damage, it is uncertain. However…

Do we know if this damage is common? Do we know if any damage is causative of symptoms? Or the result or byproduct of them? Or even unrelated?

I ask because for me at least, although I feel my body is utterly broken when at my worst, when at my best, even though I’m still very limited, it feels a world away from that. And we have cases of recovery, mainly early on a few later too while we also only have a few cases of confirmed damage. Maybe there is some minor damage (I also have some peripheral damage it seems) but it doesn’t feel like we have any evidence of anything which would stop us getting either entirely better or at least a lot better than we are.

 

Out of interest, is it very common that mild/moderate pwME are in pain to some degree all the time? I guess it's hard to tell because symptoms seem to differ so widely and we don't have any good data.

 

I can’t find the actual reports on the autopsies. Am I missing something?

 

Yes. The most relevant studies were of normal tissue samples and in vitro stimulation studies using monoclonals.

 

I think that staining must be nerve fibres. But it might well not be cholinesterase.

 

I don't know. I get the impression that the people most likely to say they never get pain are men, but it's nothing more than that.

But it doesn't have to be pain. A lot of my fidgeting is driven by discomfort, especially in PEM. Bloated stomach after eating, itchy skin, stiff back, PEM headache, and a kind of 'restless legs' thing that isn't nearly painful enough to describe as RLS, but is enough to make me want to cross my legs or shuffle about in my chair to change the angle.

 

Do you have another possible candidate for the ThT binding? Iirc the acetylcholinesterase binding is driven by a particular structure arising from aromatic residues [edit: in the binding pocket]. I’m not aware of another neuronal protein that would bind to ThT in this way, but I may have just missed it in the literature.