ME/CFS as a biological information processing problem

Jo C, Jackie Cliff and I are trying to make sense of this question and I hope we will put out what we currently can argue very shortly.

The effector mechanism in ME/CFS for producing symptoms is very puzzling. ME/CFS is an acquired condition and can come on suddenly. The evidence for linkage to MHC (here HLA-C) is wobbly but the best way to explain the onset is a shift in adaptive immune cell populations. In other words an expansion of some B cell clones or expansion of a T cell population - which might be clones with a specific T cell receptor but could be a whole compartment like NK or MAIT (Jackie's interest). These do not have antigen-specific clones in quite the same way but there may be populations with specific epigenetic changes.

Antibody mediated effector mechanisms as in classical autoimmunity tend to be symmetrical or diffuse - since the pathology is mediated at a molecular level. T cell mediated processes like psoriasis tend to be more patchy, being mediated by clusters of T cells. In ME/CFS the mechanism looks to be diffuse but it is not obviously a tissue specific pattern (type 2 hypersensitivity) or an immune complex pattern (type 3). Moreover, symptoms can change over hours and autoantibody mediated mechanism are very unlikely to change over hours.

The suggestion we are going to make is that antibody is involved but indirectly. And the B cell clones making the antibody may not be in themselves unusual or pathological, but may be more prominent in females. These antibodies engage with an interaction between some expanded T cell population and macrophages, which will involve cell clustering but which produces diffuse symptoms because it is mediated by cytokine-nerve interactions.

I personally doubt that NK cells are the culprits. Although low NK numbers have been reported in ME/CFS you do not have symptoms in ME/CFS similar to NK cell deficiencies. And whatever cells are the problem we would expect more of them. I suspect the NK cells are low because of a feedback negative signal from TGF beta and GDF15 downstream of some other signal.

Our current suggestion is very likely wrong but the point of writing was to discuss the case for and against these options. I suspect that over the coming year we will be able to gather information that will point much more clearly to one option or another. And now that we are pretty sure that there is an error of adaptive immunity and the nerve cells are involved there is hope of funding of new sorts of projects that will clarify things further.

 

Thanks Jonathan. That’s really interesting and given me more to think about and probably read up on.

Some other notes I made earlier thinking more about the permutations and variety involved …
Does this all happen when a particular receptor antigen from a particular gene or genes is produced or triggered?
Or any immune response of a particular intensity?

I’m assuming the former but maybe a bit of both. I wonder about something at the clonal expansion phase too, a little tweak that causes something interesting, perhaps linked to translation/transcription.

So here is one chain of thought or story…
The body creates apl these b cells with this huge variety of receptors

Something comes along and triggers one of them, maybe one which was partly formed with a specific gene or couple of genes

That then gets duplicated many times, clonal expansion

Maybe there’s also another gene at play, one that is used in the transcription/translation steps, so something is copied in a slightly different way, maybe not even for all of them, but some of them

You now have a combination of multiple genes (the receptor and transcription ones), and in systems it’s often when multiple things are at play weird things happen

But let’s take things another step, now say there is a receptor, perhaps in nerve cells, that is also a bit different in some of us

Now maybe these antigens, partly formed by a specific gene, then altered a little while being copied by another specific gene, now interact with this other receptor formed by another different gene, we have a number of things, each of which may be absolutely fine on their own but which now do something a bit special or unexpected in certain locations

None of them were ‘wrong’ or troublesome alone, nothing was caught by the system as a ‘self’ thing so destroyed, but now you have a bit of a system behaving a bit oddly

I’m not saying this is what is happening but it’s the sort of mechanism I can see happening from what I’ve learnt so far, which is I know only a very small part of all that is out there. So maybe something similar is happening elsewhere. Does any of this make any sense to anyone? I accept its all very wooly and conceptual

 

Time scales are interesting. And it sounds like perhaps there are different systems which work at different rates or timescales at play? Perhaps one with cells or proteins which have a life of hours or days and others at weeks or months. Perhaps these give rise to some of the variations directly. Or perhaps sometimes work in opposition or cooperation, a sort of wave interference or coherence if imagined plotted on a chart against time? Maybe problems only occur or occur more when both these different factors appear at the same time and place?

 

This is very interesting I know next to nothing about this kind of thing or the methods they use.

Do we think fatigue during illness eg flu works in a similar kind of way? I understand cytokines like IL-6 IL-1beta act on the CNS to invoke fever, is a similar mechanism involved in illness fatigue too? Do these cytokines act long range through the blood or via acting peripherally on nerve endings such as in lymphoid tissue / site of infection?

Is it possible the initiating infection that kicks off ME is actually infecting CNS tissue, or creating an environment that allows latent virus resident in the brain to activate - leaving in some way long term dysfunction (possibly epigenetic memory as has been suggested) long after the offending virus is gone. In this way stimulation of nerve endings in peripheral tissues (maybe by immune cells) that might occur during a subsequent infection would retrigger these CNS neuron phenotype (manifesting as brain fog, visual disturbance, fatigue, temperature dysregulation etc - PEM).

Also, is it relevant that the type of lengths in delay from activity to PEM commonly reported (eg 24hr, 48hr), would involve at least one wake-sleep cycle. Given 'unrefreshing sleep' is a core symptom, and the likely relevance of the circadian rhythm master regulator CLOCK: is the maintenance of CNS neurons that is presumably supposed to happen during sleep compromised?

 

I'm still impressed by how my general ME symptoms could abruptly rise--in minutes if not less--48 hrs +/- a few minutes, after stimuli (food ingestion), and my general ME symptoms could abruptly vanish (seemingly 100% ME remission) over the space of minutes. I think that rules out a bunch of possible theories.

My cognitively-induced PEM had delays under an hour, so no sleep cycle involved. My guess for the longer delays is immune system processes, and someone else will have to answer whether sleep cycles are important for those.

 

Another one of my pet questions.

It's based on experience of doing more activity than I have capacity for, and ending up so wired-but-tired that I can't sleep at all. There's no PEM the next day, and I feel pretty okay by ME/CFS standards. I usually sleep on the second night and wake on day 3 with hard-hitting PEM.

If I did manage to sleep the first night, the PEM would start on day 2.

It's been consistent for half a century, and I've never heard a plausible explanation for why PEM caused by physical activity doesn't begin until I've slept. Not even if I've pushed myself so far over my limit that I don't sleep for four consecutive nights (that happened more than once when I was working ).

 

All this new talk on S4ME about nerves and glial type cells that might be involved in ME/CFS got me thinking again about dysregulation of sphingomyelins/sphingolipids found in several large ME/CFS research studies e.g. Hanson et al, Lipkin.

Peripheral nerves rely on sphingomyelins for regeneration and repair. Schwann cells are a variety of glial cell that keep peripheral nerve fibres (both myelinated and unmyelinated) alive and help them regenerate.

Studies have shown that up to 50% of people with ME could have small fiber neuropathy.

And I'm reminded of a recent Stanford study by Jensen et al. Is it worth revisiting that paper given @Jonathan Edwards new thoughts on possible non-typical T and/or B cell involvement with nerve function.
Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2023, Jensen, Davis et al

Have their been any studies in ME/CFS looking at the biological make up of the peripheral nervous system in detail (not electrical testing)?

 

In a word, no.
We don't really feel the effect of cytokines at all.

There is no "long range" effect of cytokines. The whole point of cytokines is that they have a local effect.
They don't do much in the blood, they basically end up their (or they lymph) after they spill out of tissues.

For almost all diseases, blood cytokine testing is a red herring and reveals little that is useful that wouldn't be better revealed with other tests or clinical judgement. The exception is the https://en.wikipedia.org/wiki/Cytokine_release_syndrome which is caused by specific feedback loops that cause very high cytokine levels in specific tissue which spills over into the blood.

Metabosensitive muscle afferents (in the tissues surrounding the muscle fibres) are specifically tuned to sense a specific set of metabolic effects - a coupling of P2x receptors that sense leakage of ATP outside of cells, of ASICs (acid sensing ion channels), TRPV1 (transient receptor potential cation channel subfamily V member 1) which in combination activate over a specific PH range. That is the minimum set. Some other receptors can also lead to heightened sensation, such as the effect of beta-adrenergic receptors, α7-nicotinic acetylcholine receptors and presence of bradykinin and or Arachidonic acid can also lead to sensitisation of these nerve endings.

I'm not going to speculate on the rest, but I do not believe ME/CFS is due to a persistent or latent infection in the CNS.

 

I agree with most of what you say @Snow Leopard but there are rabbits loose in the ME/CFS argument chain.

Why do people feel generally bodily exhausted after a long spell of mental effort? Similarly why do people with flu feel pain all over when they have not done anything much with most of their muscles?

Cytokines mostly act locally but there must be systemic signals for fever and malaise. Pyrogens do produce fever.

I agree that muscle afferents look like a key site for symptom generation but I am sceptical that the only signal can be metabolic. It is widely understood that in other contexts afferent nerves are sensitised by additional signals such as prostanoids and probably interferons. I think there are good reasons for invoking those if we think there is an immune thread to the process, which I think we are going to find is right.

The question is which signals are acting locally and which sensitising long range. I agree that what we know at the moment does not seem to provide a simple story for ME/CFS but I think the question is legitimate.

I agree that latent infection in CNS does not seem plausible. I do wonder, however, whether sequestration of something like herpesvirus in peripheral nerve might be relevant. I am not a fan of such theories in general but I don't see that we can discount it.

 

From another thread but relevant to throwing idea around I think

After some reading/listening on what happens at synapses during neural activity..

@Kitty are you thinking there is something happening which means once the neuron fires the channels just stay open so neurotransmitters continue to be released?

Once membrane potential depolarises and neurotransmitters are released, rather than then repolarising and the process stopping, it just… continues. Maybe the sodium/potassium ion channels don’t open and close as they should or the membrane potential or threshold is changed somehow making the synapses more or less likely to fire?

Perhaps there’s a ligand gated ion channels involved? (Yes I have just heard about these, so have new things holding all my attention syndrome). Maybe an antibody could bind, then get confused as it’s bound to something and so stimulate signalling molecules like cytokines and so on? Or just start off a loop with other ion channels like voltage gated or other ligand gated ones triggered by neurotransmitters?

There seems lots of potential for little cascades or feedback loops of different types if something is just a little bit off.

Does Pregalbin helping makes sense if we think there is some sort of action stimulating neurons when they shouldn’t? So drugs which tamps down the activity or makes it less likely can help with at least part of the problem?

I’m sure these ideas are not new, if there’s a decades old discussion or any papers, please feel free to point me in their direction.

 

I don't feel bodily-exhausted after a long spell of mental effort (and we have that poll from a while back that suggests it is not a universal experience), so I don't really know what you are suggesting there. I do feel the converse though, mentally exhausted as a PEM symptom from physical activity.

In the cause of flu, all sorts of things are affected from altered circulation to viral debris building up in lymph tissue all over the body. Until someone pins it all down I'm not really going to blame it on cytokines.

I was under the impression those symptoms require multiple factors to work in concert. The cytokine-as-primary-pyrogen hypothesis was popular in the 90s but I thought the view is more nuanced now.

Note I said metabosensitive afferents, rather than other forms of pain sensing or mechanically sensitive afferents - the primary signal is metabolic and they require multiple signals to respond. I was not discounting sensitisation mechanisms but it probably isn't going to be cytokines from the blood. (see below for alternative hypothesis)

We know from cytokine infusion studies that the effects are largely not felt unless the levels are very high and have less direct effects than acting on the receptors of nerves (due to altering the behaviour of immunological cells). But yes it can have metabolic effects on the body at high levels due to by influencing the activity of immune cells in circulation and the resulting metabolic responses to that - TNF alpha infusion can increase cortisol levels as an example.

Yes, I think that is plausible but in the peripheral nervous system as you mentioned where there is some evidence of this occurring in humans.

https://meassociation.org.uk/2011/01/pathology-of-mecfs-pilot-study-of-four-autopsy-reports/ (damage and evidence of infection in dorsal root)

Evidence of persistent immunological responses to latent infections in ganglia:
https://journals.aai.org/jimmunol/a.../Persistent-cytokine-expression-in-trigeminal
https://link.springer.com/article/10.1080/13550280701447059

 

I take your point about the cytokines, but I still wonder how you get fatigue from eg flu. You have an infection in a peripheral tissue and it has to let the brain know somehow. So even if it's not a cytokine, your choices are most likely either some endocrine signal through the blood, still via the blood but through a circulating cell, or via a neuron right?

You may be right about the latent virus thing, but I still wonder what the original inciting virus (since virus seems to kick it off in many cases, EBV / covid etc) was doing wrong. Was it infecting neurons or glia at the time, or is it more about the immune system response it generated.

About the paper you linked before: do you think it would be a good idea to basically do this study or a slightly modified study design with pwME/controls?

One thing I'm a bit worried about is if the main pathology of this disease is in the CNS, how do we study this? If the core of the disease mechanisms are happening in the brain rather than peripheral tissues, then where do we start? You can't take a biopsy of the brain like with eg muscle, so would be limited to autopsy. Animal models are probably not going to be much use, especially if the immune system is involved. Then there's cell culture models, which could be good for studying genes from the genetic studies - but still wouldn't be seeing the actual pathology in a patient. Maybe neurobiologists and clinical physiologists have ideas (brain scans?).

Even if it's in something like DRG cells you presumably run into the same problems

I'm really hoping that there will be key elements of the pathology measurable in the peripheral tissues.

 

I think the point is that some do, and we need a way to explain that. And why pwME/CFS can get a flu-like feeling without having the flu, and in places you have not used.

 

The result is a disordered ion gradients and the nerve ceases functioning normally when that happens.

In general, it is better to consider biochemical signals as not a single ligand-receptor binding event, but an orchestra of this occurring at regular intervals, in concert with other receptors. If a receptor is stuck in a particular state, the music stops.

Having said that, there is a hypothesis vaguely along those lines:
https://www.sciencedirect.com/science/article/pii/S1568997220300823
https://www.healthrising.org/blog/2...chronic-fatigue-syndrome-wirth-scheibenbogen/

Further reading (sodium/potassium...)
https://link.springer.com/article/10.1186/s12967-022-03616-z
https://inis.iaea.org/records/jrz9k-7fp24
https://onlinelibrary.wiley.com/doi/abs/10.5694/j.1326-5377.1996.tb122076.x
https://amu.hal.science/hal-01769413/
https://www.tandfonline.com/doi/abs/10.1300/J092v11n01_03

(the above does not add up to a consistent pattern)

But I think if there is such pathology, it's limited to specific tissue.

My last blood test had abnormally low sodium and potassium levels so not really what was by suggested Scheibenbogen, but consistent with Burnet

 

Sure, but I don't think cytokines explains that either. I could imagine an autonomic/circulatory effect however.

The problem is that the body is complex and the set of symptoms we associate with the flu are numerous and necessarily have different primary factors, I think the reduction of flu-like malaise (including sore throat etc) to cytokines when there are many hypothetical explanations is premature and reductionistic.

 

I was thinking of the example of the periodic paralyses. Some of my symptoms are consistent with one of them (but it could be a coincidence).

Anyway, they're ion channel irregularities that often happen in response to stimulus. If I eat sugar, for instance, my arms and legs stop working properly for up to 90 minutes.

In people with hypo-PP the potassium shift resulting from a carb load might be measurable in venous blood, but in others it never goes outside normal range. Needless to say, if an undiagnosed person has shifts that aren't easily detectable, doctors will tell them everything's fine.

The effect of the shift on affected muscles is temporary, changeable, can manifest as anything from complete paralysis to heavy fatigue, and an attack often leaves a hangover in the following days. It's possible to avoid some of the triggers, but not all of them.

The symptoms of PP don't match ME/CFS, and I'm not suggesting a link. It's just an example of a puzzling disorder that often doesn't manifest until adulthood, is invisible on tests except at the peak of an attack (sometimes), has significant effects on muscle, and a proportion of people go undiagnosed—either because low genetic penetrance has resulted in a mild presentation that's not recognisable to doctors unfamiliar with it, or because they don't have one of the known genetic changes.

 

That is fascinating (but also sounds pretty unpleasant!) thanks for explaining @Kitty

And thanks for the reading @Snow Leopard much appreciated

 

Well, quite a lot of members are reporting it!

But viral debris is almost certainly completely inert in itself in terms of signalling. Something needs to generate a host signal.

I don't think the story for the response to typhoid vaccination has changed much. Maybe circulating leucocytes that have picked up lipopolysaccharide signal at close range to hypothalamus but I am not quite sure how they would do that without margination.

I can see that. I am just not convinced that a metabolic signal is what we are looking for at all. Exertion and effort are often associated with tasks that do not tax metabolic pathways at all much.

For some cytokines.

 

At the small scale/cellular level it can be quite taxing in both the brain and the muscle. It doesn't have much effect on the body-wide metabolic homeostasis but that is not what we are concerned about. It is a red herring to compare it to the overall energy consumption of the brain or body.