ME/CFS as a biological information processing problem

[poetinsf]

For some to me still inconceivable reason, low to medium doses of gabapentinoids (say 75-150 mg pregabalin) do wonders to my cognitive dysfunction most of the times. It feels like the "pressure" in my forehead is somehow relieved and I can start thinking straight again.

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]

Sure, we eventually need a real science to back up the speculative theory. But I thought we are speculating at the moment for plausibility. And cytokine/PEM linkage is as plausible as any. We shouldn't shut down theories as a meme long as they make sense without contradicting observed phenomenon, PEM in particular, unless it is already tested and proven false.

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]

One thing I'm wary of is the search for some hereto known signaling mechanisms.

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]

I am not in the least bit suggesting it is not cytokines causing PEM. It very likely is, but that is not inflammation.

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?

 

[Creekside]

A lot of researchers now think you can call a minuscule rise in some obscure cytokine inflammation.

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]

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?

 

[hotblack]

The first AZ Covid vaccine was like the treatment I've been imagining, the one that won't need anyone carefully sanding the edges off the outcome stats because it'll be a profound change. This one only lasted five to six days, but those days were glorious.

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]

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?

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]

That doesn't helpfully narrow down the theories, but it would be wrong to discount a theory just because classic inflammation isn't observed.

Absolutely, I hope nobody is doing that. But as long as they are tying the theory to specific signals.

How big is the list of known immune system signals?

If you take antibodies as immune signals, which we should, the diversity runs into billions of molecular species. So no shortage!

 

[hotblack]

If you take antibodies as immune signals, which we should, the diversity runs into billions of molecular species. So no shortage!

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.

 

[jnmaciuch]

And then adding on transcription and translation and… I start to wish I did biology at school. Never too late I guess.

Never too late

 

[Jonathan Edwards]

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.

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]

Never too late I guess.

Absolutely never too late. I knew very little about lymphocytes until 1990. Necessity is the mother of invention as they say.

 

[Creekside]

So what would cause certain processes or synapses to be more or less effective for the say the same given inputs?

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.

 

[Creekside]

Could a particular signalling molecule be more prevalent in a particular area and not globally noticeable or measurable?

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?

Or indeed attaching to a receptor we didn’t expect it to?

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]

Obviously I’m quite biased towards the first option, since locally elevated extracellular lactate fits quite nicely with other parts of my pet theories. But I’d be curious if you had other thoughts since you have much more experience in this domain

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]

I'm inclined to believe the latter: the cytokine level change is normal, but microglia or brain network is responding abnormally to the slight raise that healthy people don't even notice.

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]

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.

 

[hotblack]

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.

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?

 

[Jonathan Edwards]

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?

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.