ME/CFS as a biological information processing problem

Creekside said:
I was under the impression that circulating cytokines trigger glial cells, which in turn cause "flu-like symptoms".
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I have not looked at the latest information on this but the picture I have had is that yes circulating cytokines signal directly to CNS cell but those are probably very specialised cells I hypothalamus, where the blood brain barrier is a bit more open to protein diffusion or cells are interdigitating with endothelium.

My guess is that glial cells everywhere else in the brain are not directly affected by these cytokines - it is not their job to pick up these signals and they have other things to do that would be interfered with by cytokine signals.
 
Jonathan Edwards said:
You have to remember that single dots on fluorescence nearly always include a proportion of artifactual signals (binding to dust or aggregates in the reagent). In the two pictures I have on file I don't see any significant signal in muscle cells. In the image without a vessel there are no dots within muscle cells. All the signals are between muscle cells. They are mostly dots but about 10% are short linear segments. That indicates they are almost certainly all sections of linear structures (taking into account the likely section thickness to be ~3micron). In the other picture there are about three dots the look to be inside muscle cells but (a) they look to me a slightly different hue, suggesting maybe artefact and (b) muscle cells can have peripheral invaginations that may not be apparent in terms of the background staining that shows us 'edge' here.

To me the muscle cells are pristine clean of stain.
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Thanks for the further info. I am happy to say that the signal is more likely some oligomer attached to nerves, though like @chillier, I just don't see what the story would be with that signal increasing at 24 hours post-exercise. Hence why I was interested in mtDNA, as that would be much more in line with other pieces of the puzzle, assuming that mtDNA fragments would stick around long enough to be detected at that timepoint (which they may not be).

I initially reached out to Rob asking if there was any indication of more puncta in the cytosol from the other images that weren't in the paper, but I wasn't able to get a a clear answer. I think that particular data is too confounded to use as evidence for anything on its own, but I would like to see it make sense in the grand scheme of things.
 
Creekside said:
I was under the impression that circulating cytokines trigger glial cells, which in turn cause "flu-like symptoms".
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With my new found knowledge of what a glial cell is (okay only roughly, at least I know different types exist) I have a question…
Which type of glial cell are you thinking of here or more generally with the glial activation idea?
 
hotblack said:
Which type of glial cell are you thinking of here or more generally with the glial activation idea?
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At first I thought it would be microglia, just because my symptoms got worse with tryptophan, and IIRC, microglia process that while astrocytes don't. That was ~20 years ago, while I was just beginning to learn about brain cells. Astrocytes have some properties that would fit as well. There are other types of glia that I haven't looked much into, and there are also very specialized ones that only reside in specific parts of the brain, which could be involved in ME but which probably haven't been studied in an ME context. I don't have enough base knowledge to make a comprehensive theory for glia in ME. To me, it just fits well, with glia responding to immune signals, responding quickly, and having the potential to explain most ME symptoms (some symptoms could be far downstream of the initial effects).

Jonathan Edwards said:
I have not looked at the latest information on this but the picture I have had is that yes circulating cytokines signal directly to CNS cell but those are probably very specialised cells I hypothalamus,
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Could those specialized cells not then signal other glia? A specialized mediator doesn't mean that it can't trigger a wide range of flu-like symptoms. Has anyone figured out how a viral infection does cause that constellation of symptoms?
 
Creekside said:
Could those specialized cells not then signal other glia?
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I don't see that as likely. How would they do it? There are no diffusion pathways from hypothalamus to the rest of the brain to transport soluble factors. Glia do not send action potentials. We are talking about cells maybe 50 microns across signalling to tissue fifteen centimetres away.

The main way the hypothalamus works is to convert biochemical signals into neural action potential signals that allow instantaneous and highly specific signalling right across the brain - and even down to your colon through autonomic outflow.

I personally do not see glial activation as likely to explain anything much in any of these diseases - it is usually just a sign of attempts to repair damage neural tissue. In the absence of damage and of any good evidence for glial activation I doubt it is going to contribute to the ME/CFS story
 
Jonathan Edwards said:
I personally do not see glial activation as likely to explain anything much in any of these diseases - it is usually just a sign of attempts to repair damage neural tissue. In the absence of damage and of any good evidence for glial activation I doubt it is going to contribute to the ME/CFS story
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"Glial activation" is probably too vague as a concept, but glia play critical roles in neurovascular coupling and sensing metabolic state:

https://pubmed.ncbi.nlm.nih.gov/35201268/
https://www.sciencedirect.com/science/article/pii/S0306452215003139
https://www.frontiersin.org/articles/10.3389/fcell.2021.732820/full
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01024/full
 
Apologies if my random thought is completely inappropriate - and if so, please ignore me!
Does ME need to be an acquired condition?
I’m wondering from my position of having an inherited condition, but having been basically symptom-free (as far as I knew) for my childhood and the first 15 years of my adult life. And then things started to go wrong in lots of ways…
The disease had been there all along, but my ability to make muscle had hidden it until I got to a tipping point.

Could ME be like that too?
 
hotblack said:
etc. So inhibitory and excitatory can often go hand in hand.
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This from another thread but… I was listening to descriptions of neurotransmitters and receptors and this was said

Neurons are often referred to as excitatory or inhibitory, but more accurately it's the synapse that's excitatory or inhibitory, and even more specifically, it's the combination of the neurotransmitter that's released at the synapse and the receptor that it binds to on the post synaptic membrane. Because many neurotransmitters can bind to multiple types of receptors so that the neurotransmitter can sometimes be excitatory and it can sometimes be inhibitory to the target cell.
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Which seemed relevant here, with different people having different effects of drugs, varying symptoms etc. With a neuron having both excitatory and inhibitory receptors, perhaps ideas of variations in receptor availability, either through shape, density or being blocked or interacted with by other molecules resulting in change in how they’re triggered.

In other words some variation in receptors at the synapse, with ionotropic or perhaps more interestingly metabotropic receptors could influence graded or resting potentials so modify if not the threshold how easy or hard it is to reach the threshold for the action potential and have longer lasting impact on both that and other cell behaviour.

At least that’s what the synapses firing this morning are thinking.
 
Daisybell said:
Does ME need to be an acquired condition?
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I’ve wondered that. There seems to be at least a genetic predisposition. Could there be a natural development towards it to? Perhaps with people pushed over an edge by an illness if not that illness being a trigger as has often been seen? I suppose some comes down to how you define these things and lots of conditions are ‘a bit of both’. And if we add on that there may be different types of ME/CFS.
 
I think it almost certain that we will find that ME/CFS is a bit like lupus in that there are some people who are more or less genetically programmed to develop it (e.g. homozygous C1q deficiency for lupus) and others who are only slightly more at risk than average but get clobbered by some combination of infections and random immune software bugs.
 
arnoble said:
Are Jarred Younger (eg his YouTube #15, #14) thoughts about microglia unlikely?
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I don't see any particular reason to think microglia are doing anything relevant in ME/CFS. I find talk of neuroinflammation unhelpful when we have no evidence for it and it seems as much as anything to be a hangover from the historic clinical 'encephalitis' concept that has nothing to do with ME/CFS as now understood.

I am not sure what Younger's thoughts are specifically but that is my general position. T cells don't go into brains as a rule so I doubt that the 'synaptic' side of ME/CFS is to do with immune cells doing things in brain per se.
 
Jonathan Edwards said:
I am not sure what Younger's thoughts are specifically but that is my general position. T cells don't go into brains as a rule so I doubt that the 'synaptic' side of ME/CFS is to do with immune cells doing things in brain per se.
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What are the reasonable tissues to look at?
if we're thinking neurons generally then we've got muscle NMJ and sensory neurons, para/sympathetic ganglia, dorsal root ganglia, CNS, lymphoid tissue, some other tissue like adipose tissue?

If we're thinking thinking peripheral synapses then the only choice is para/sympathetic ganglia right? Synaptic proteins like those found in zhang: homer, dlgap, syngap aren't expressed in NMJs or sensory nerve endings are they?
 
chillier said:
If we're thinking thinking peripheral synapses then the only choice is para/sympathetic ganglia right? Synaptic proteins like those found in zhang: homer, dlgap, syngap aren't expressed in NMJs or sensory nerve endings are they?
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Though i suppose it could be synapses behaving poorly in the brain that directly affects the events at peripheral neuron tissue junctions which is where the substance of the pathology is happening.
 
chillier said:
If we're thinking thinking peripheral synapses then the only choice is para/sympathetic ganglia right? Synaptic proteins like those found in zhang: homer, dlgap, syngap aren't expressed in NMJs or sensory nerve endings are they?
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I don't think we are necessarily thinking peripheral nerves to explain the Zhang synapse connection. There may be a neural side to the story that is separate from the lymphocyte side but with both engaged in a complex non-linear 'bistable' system dynamic as Robert Phair would put it.

This is where I think we are being led into new territory in terms of modelling - we have two different arms to handle. But that would be no surprise from previous experience of modelling chronic disease.

chillier said:
What compartments can you definitively rule out? Blood... others?
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I think we can rule out blood as a venue for relevant interactions but the cells in blood might carry functional tendencies that are relevant that could be identified with short-term co-culture perhaps.
 
chillier said:
Though i suppose it could be synapses behaving poorly in the brain that directly affects the events at peripheral neuron tissue junctions which is where the substance of the pathology is happening.
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The thing that I tend to think of in this context is the way the hypothalamus integrates over all the signals it gets about what you are eating over a period of at least a day and more likely a week and then sends out signals to ensure you address any imbalances. If you eat no green veg for four days the hypothalamus cries out for some lettuce or beans. If you eat no meat it wants a T bone steak now. I have a suspicion that in ME/CFS some brain stem centre is totting up all the gamma interferon this week and getting the sums wrong. That will very much depend on synapses. But it goes beyond anything we have really thought about in terms of immunology up until now.
 
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