One thing I'm wary of is the search for some hereto known signaling mechanisms. I don't think ME/FS is that novel or complicated. I instead think it's a maladaptive manifestation of existing fatigue/sickness mechanism. Novelty may be exciting for academics and a ground of sensationalism, but they've been searching for novel pathology for decades and have nothing to show for it. And I think it'll be the continuation of that futility if we pursue that line of inquiry.
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ME/CFS as a biological information processing problem
- Thread starter hotblack
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Welcome to the club. A few of us have found something that works for our ME/CFS for whatever reason. I have found pseudoephedrine relieves my head/ear pressure (literally in my case), and some of the symptoms, at least partially. Anything dopaminergic/adrenergic that wakes up my brain seems to help. (Well, ok, nicotine patch didn't work though).
Jonathan Edwards
Senior Member (Voting Rights)
Speculation is something completely differently from concepts based on the wrong use of words and an ignorance of basic biology - which applies to nearly all the 'neuroinflammation' stuff.
I am not in the least bit suggesting it is not cytokines causing PEM. It very likely is, but that is not inflammation.
Jonathan Edwards
Senior Member (Voting Rights)
I think you probably meant 'unknown' and I agree. I suspect we are looking at a very ordinary signalling mechanism that we have not realised could explain things because of hand-waving assumptions about things like 'inflammation' that may not apply to, for instance, isolated interferon production.
Utsikt
Senior Member (Voting Rights)
Would that involve a local increase in cytokines, or could it just be that they ones that are always present don’t work they way they do in healthy people?
How big is the list of known immune system signals? I typically come across mention of cytokines, but I get the impression that it's a lot more complex than that, and there are many more possibilities. Then there's the multitude of receptors, which should respond to specific molecules, but there's also the possibility of them responding to molecules that mimic the critical parts of those molecules. Researchers could be measuring IL-17 at normal levels, but missing that there's a significant level of a mimic resulting from protein folding defects or whatever. There must be plenty of immune system activities that don't qualify as inflammation.
That doesn't helpfully narrow down the theories, but it would be wrong to discount a theory just because classic inflammation isn't observed.
hotblack
Senior Member (Voting Rights)
Good questions @Creekside something I’ve been finding is just how many different cells have receptors and in different densities and how one signal that is talked about as doing one thing, usually does but sometimes does something different on a different cell… and on it goes.
So what would cause certain processes or synapses to be more or less effective for the say the same given inputs? What could be up or down regulated? I suppose I’m thinking along more or less receptors or of the compound that attaches to the receptors or maybe something like how SSRIs work…
Could a particular signalling molecule be more prevalent in a particular area and not globally noticeable or measurable? Or indeed attaching to a receptor we didn’t expect it to?
So what would cause certain processes or synapses to be more or less effective for the say the same given inputs? What could be up or down regulated? I suppose I’m thinking along more or less receptors or of the compound that attaches to the receptors or maybe something like how SSRIs work…
Could a particular signalling molecule be more prevalent in a particular area and not globally noticeable or measurable? Or indeed attaching to a receptor we didn’t expect it to?
hotblack
Senior Member (Voting Rights)
I had similar hopes about covid vaccines for some reason, but very different experiences (with both AZ and Pfizer). What is a vaccine, it’s a way of introducing something to the immune system so it can learn about it and respond. For some of us that response was positive for others negative, others neither. Why? What about this immune process or reaction could have that effect? Why different for different people? And even for the same people but different vaccines? Is it just any new pathogens or ones with a particular shape of antigen or….?
Jonathan Edwards
Senior Member (Voting Rights)
I think there must be some local increase in cytokines. But yes, one has to think of the 'error' being somewhere else along the chain.
Jonathan Edwards
Senior Member (Voting Rights)
Absolutely, I hope nobody is doing that. But as long as they are tying the theory to specific signals.
If you take antibodies as immune signals, which we should, the diversity runs into billions of molecular species. So no shortage!
hotblack
Senior Member (Voting Rights)
It was only after trying to get my head around the Ryback paper and finding VDJ recombination that the scale of it started to dawn on me. I’m sure I don’t get it all now but the elegance of that part of the immune system was a wow moment.
And it seems that with that range of possible permutations it’s more surprising that things don’t ‘go wrong’ more often or perhaps that we think we know how things always behave.
And then adding on transcription and translation and… I start to wish I did biology at school. Never too late I guess.
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jnmaciuch
Senior Member (Voting Rights)
Never too late
Jonathan Edwards
Senior Member (Voting Rights)
I had the privilege of having Rodney Porter as a family friend (father of schoolmates and college friend of my parents). Together with another group Rod showed that a protein species known to be variable in its behaviour had a very specific reason for that, in having a variable sequence region, for which they got a Nobel prize.
Maybe 25 years later `I also had the pleasure of meeting and talking about mechanisms with Michael Neuberger, who worked out how activation induced deaminase is used to create that variation in various ways Sadly, and ironically, Michael died from a plasma cell disease, without I think getting the Nobel he also deserved.
The work that Jo Cambridge and I did in the 1990s focused on the idea that this almost infinite shape variability in Ig CDR means that antibodies can pretend to be anything else you like, or stop anything else you like working properly. If they interfere with the homeostatic signals of the cells that produce them then you have a perfect storm - called autoimmunity.
Jonathan Edwards
Senior Member (Voting Rights)
Absolutely never too late. I knew very little about lymphocytes until 1990. Necessity is the mother of invention as they say.
It needn't be the same synapse. I expect that some brain cells (or portions of) might respond differently to the same input, depending on where in the brain the cell developed. Maybe an astrocyte in the hypothalamus responds differently to IFN-g than an astrocyte in the parietal lobe. Imagine that the two regions produce effects that balance each other out normally, but ME alters one of them, so it goes out of balance and feeds back on itself, locking into that state. Another possibility: ME changes the response to an input (misfolds a receptor or whatever) so instead of countering a rise in a signal, it boosts it. Maybe astrocytes (or whichever cell) are subtly different when produced from precursors in the 21st week after conception than after the 4th week. Technology keeps allowing discovery of new aspects of cells, so there's still lots unknown about cells.
In my inexpert opinion, I think so. I've heard of some important signalling molecules with really short lifespans. They might not exist long enough to travel a cell's diameter. Could there be molecules that provide a critical function but don't last long enough to be detected? Maybe there's a well-known protein that spends its first few nanoseconds in a different configuration before twisting into the known form, and the first configuration is important. Are the contents of vesicles completely known, or might there be important differences there?
Evolution re-uses tools, so I can imagine a cell in one part of the brain repurposing a receptor or signalling molecule that does something different in a cell in a different part of the brain. I vaguely remember reading some recent articles about some parts of the brain working or communicating differently than previously understood.
Snow Leopard
Senior Member (Voting Rights)
I think both are causes, I don't believe ME/CFS has a single etiology, only commonalities. My health history is that of peripheral neuropathy so one of my key hypotheses is increased sensitisation of nerves post-injury. In principle this could be true with classic ME/CFS etc post-nerve infection by EBV or other pathogens.
Snow Leopard
Senior Member (Voting Rights)
Whatever feedback mechanism we propose, there still needs to be a clear physiological picture. If microglia are responding to aberrrant signals, there still has to be a physiological correlate eg altered local blood flow. In the muscles, (extracellular) purinergic signalling is key to sensing metabolic state and something similar may occur in the brain in terms of sensing fatigue.
https://pubmed.ncbi.nlm.nih.gov/35201268/
hotblack
Senior Member (Voting Rights)
Last night before going to sleep I was thinking more about what could do his at a very basic level. Presumably there would need to be changes in physical, chemical or electrical properties of cells. Of course the question is which and why.
But it seems with such a complex and finely tuned/balanced system, something which even subtly changes neuronal cells in a way which changes the timing or strength of signals or messages in or out of the brain, could cause all sorts of confusion. And nit necessarily with damage. Maybe there is some somewhere, but is it causative of our symptoms or a byproduct or even unrelated? I don’t think we have a definitive understanding of that.
So what are we talking about, something which physically constrains, or interferes with function, a cell or protein or molecule in the wrong place creating (or removing) a physical barrier, enveloping or overwhelming a cell surface? Or something which changes the permeability of a cell, maybe how fast other reactions can take place or what other molecules are around and available for them to take place? Or something which changes concentrations either side of a cell wall, maybe changes electrical potential?
I am blindly throwing stuff around here to be sure. And very much at a layer of abstractions away from the detail and understanding many have. I studied some physics and chemistry so have a bit of grounding but little biology. I didn’t really know what a b or t cell was until 6 months ago. But more than anything am enjoying being able to think about these ideas in a way I haven’t for a few years. And thank everyone for the environment to do so.
But it seems with such a complex and finely tuned/balanced system, something which even subtly changes neuronal cells in a way which changes the timing or strength of signals or messages in or out of the brain, could cause all sorts of confusion. And nit necessarily with damage. Maybe there is some somewhere, but is it causative of our symptoms or a byproduct or even unrelated? I don’t think we have a definitive understanding of that.
So what are we talking about, something which physically constrains, or interferes with function, a cell or protein or molecule in the wrong place creating (or removing) a physical barrier, enveloping or overwhelming a cell surface? Or something which changes the permeability of a cell, maybe how fast other reactions can take place or what other molecules are around and available for them to take place? Or something which changes concentrations either side of a cell wall, maybe changes electrical potential?
I am blindly throwing stuff around here to be sure. And very much at a layer of abstractions away from the detail and understanding many have. I studied some physics and chemistry so have a bit of grounding but little biology. I didn’t really know what a b or t cell was until 6 months ago. But more than anything am enjoying being able to think about these ideas in a way I haven’t for a few years. And thank everyone for the environment to do so.
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hotblack
Senior Member (Voting Rights)
Do you think there is some sort of interesting direct antibody interaction with synapses/nerve cells or instead something more mediated through NK cells or complement or something else?