Different arguments about ME/CFS pathology—aabs vs neurons—who is winning?

[Jaybee00]

So a recent preprint from an Italian patient indicated that ME/CFS is a pure brain disease closely related to Alzheimer’s disease and implicated a particular neuron.

Meanwhile other groups such as Iwasaki, Fluge along with Tyler Hulett are suggesting auto-antibodies are potentially involved in ME/CFS pathology.

It’s becoming increasingly difficult for me to follow the various arguments/threads…. They have become super-technical.

So a crude question.

In a nutshell which side is winning in your opinion?

 

[forestglip]

I think they could both potentially be true, i.e. "neuroimmune". Maybe there is a susceptibility in the neurons that only becomes a problem, at least in some people, when some weird antibodies get made.

 

[Jonathan Edwards]

In a nutshell which side is winning in your opinion?

I do not see these aspects as in competition. I see them as orthogonal - the rightness of one has no particular bearing on the rightness of the other.

We need to understand the neurological pathways involved. I don't see any doubt in neurological pathways being involved. Whether people are homing in on the 'right' neurons seems to me unimportant. You have to home in to test ideas. Paolo is the first to say that the point of an idea is to punish it with data. I think everyone involved recognises Chris P's caveats. Differential gene expression need not point in the right place at all. But we might be lucky .

We also need to understand how immune stimuli like infection trigger the illness, as it seems they often do. Here the question is different - around whether antibodies are important, and if so whether they need to be autoantibodies, or whether the immune shift is in T cells, T-like cells such as NK, MAIT, or even myeloid/monocyte lineage cells. There are also questions about latent viruses such as Herpes.

The weight of evidence, including the absence of any DR signal on DecodeME, is against a big role for autoantibodies but the therapeutic studies with Daratumumab remain tantalising.


And we have some suggestions that ME/CFS may arise from a 'two hit' sequence. The first hit may look like post-viral fatigue and the second, the more persistent and sometimes progressive illness with severe features. I was reminded of this by a ceiling light failing at home. Sometimes when a bulb is dodgy it trips the switchboard. Sometimes it just blows. Sometimes both happen at once. I suspect what we are trying to find may be two weak points in the global system, where the normal rules can flip into a counterproductive state - very much as Robert Phair was proposing with the itaconate shunt.

 

[PageofME]

So a recent preprint from an Italian patient indicated that ME/CFS is a pure brain disease closely related to Alzheimer’s disease and implicated a particular neuron.

Meanwhile other groups such as Iwasaki, Fluge along with Tyler Hulett are suggesting auto-antibodies are potentially involved in ME/CFS pathology.

It’s becoming increasingly difficult for me to follow the various arguments/threads…. They have become super-technical.

So a crude question.

In a nutshell which side is winning in your opinion?

Research of the past years found a significant link between HSV and Alzheimer's. Also, MS is closely associated with EBV. I think there are different theories around that and a lot is simply not known yet – not just in ME but also in these better understood illnesses.

Iwasaki researches auto-immunity and herpes, and possibly even more, I don't know.

On this forum I am seeing the discourse shifting over the past weeks to the idea that there might be an autoimmunity subgroup with PEM and a herpes reactivation subgroup with PEM and additionally a flu-like remitting-relapsing picture of symptoms.

Brain disease: I think that the consensus across the leading researchers is that ME starts with an injury to the immune system. With triggers like infections, but also chronic stress and psychological and somatic trauma.

In my opinion the "pure brain disease fraction" from time to time manages to get a lot of attention but no one of them is an established ME and Long Covid researcher. Except you want to think of Avindra Nath as such an exponent. Which I rather wouldn't.

 

[BrightCandle]

I don't think anyone has shown conclusive evidence their version of the disease is right yet. Mostly a lot of hand waving assumptions on the causes of certain odd results that may or may not be relevant to the core of the disease. There is every chance everyone is just looking at downstream impacts and has never measured the core of the disease, I think that is quite likely because when we see it its going to be really wrong because people are extremely ill.

 

[mariovitali]

I wanted to take the opportunity to say that metabolism is being left out for some reason.

Also, we left out several other tests that could be holding the solution such as something called efferocytosis assay.

In other words I believe we may not be closing in as some people suggest with their analyses.

 

[Hoopoe]

And we have some suggestions that ME/CFS may arise from a 'two hit' sequence. The first hit may look like post-viral fatigue and the second, the more persistent and sometimes progressive illness with severe features.

The first would be more immunological and typically self-resolving within months or a few years (post viral fatigue), but in some people it would set off a self-sustaining problem involving primarily the brain?

If this is true then it might be difficult to understand how the second stage comes about without understanding the conditions created by the first stage.

In a portion of patients the first stage might be something other than a post-viral fatigue state.

Maybe the brain adapts to a state of constant post-viral fatigue and then is not able to reverse out of it? That's sort of the hypothesis by the CBT/GET proponents, except that they believed that the maladaptation could be reversed by behaving and thinking more and more like a healthy person. Something else seems to be required.

 

[Creekside]

Would it be helpful to have a thread or sub-forum for each popular theory, along with the arguments for and against clearly laid out? Then when people read about a theory--and get all excited--they can read the thread for a reality check. A theory might sound good from the theorist's perspective, but then someone points out that it would have shown up via tests that have already been done, and nothing's been found to support it.

A clearly laid out collection of negative findings and evidence of what isn't involved with ME might be helpful too. For example, the rapid switching of ME is evidence that it doesn't involve permanent degradation or other slow-to-change factors. The lack of evidence of limited ATP seems like evidence against metabolic or mitochondrial theories.

 

[Jonathan Edwards]

Would it be helpful to have a thread or sub-forum for each popular theory, along with the arguments for and against clearly laid out?

I think we have those threads. But this is not about competing 'popular theories' really. It is more like doing a jigsaw. The right theory will be when all the bits are in place. All we can do at present is argue about whether certain pieces fit together well enough to look as if they will be part of the final picture. We have a thread on autoantibodies. We have one on eMSN neurons. We have one on itaconate shunt. We have one on lipids.

 

[Jonathan Edwards]

I wanted to take the opportunity to say that metabolism is being left out for some reason.

Metabolism is not left out @mariovitali. This is what I meant before about this not being a competition.

Theories that focus on neuron involvement bring in neuron metabolism. Theories that focus on autoantibodies bring in B cell metabolism.

Maybe the point here is that disordered metabolism is always going to be kept going by some population of a particular cell type retaining an error. That could be liver cells. But there is a problem with proposing liver cells in that we do not have any recognised explanation for why a group of liver cells should retain an error. We have clearly defined explanations for B cells - somatic Ig mutation and clonal selection. We have clearly defined mechanisms for neurons - changes in synaptic connections. For muscle we have the same problem except that we would really need to say muscle cells everywhere are retaining this error. In the absence of something like a genetic mitochondrial disease that seems hard to explain. (Except maybe with epigenetic shifts in macrophages as jnmaciuch has suggested.)

It is not that people are wanting to leave out metabolism. It is more that people see the solution as needing to be pinned down at the level of which cells retain the regulatory error that shifts metabolism. There are ways to side step that like proposing hidden viruses, or changes in regulatory proteins adsorbed on to matrix (the 'writing on the wall')

 

[Silip]

Hello dear s4me community, I hope it's ok if I as a patient post my amateurish questions on here

After the recent paper by Iwasaki et al., like after almost every paper about autoantibodies, I've seen people and some scientists making confident claims again that a big part of Long Covid and ME/CFS is a primarly autoantibody mediated illness (not on here, mostly on X/Twitter or other plattforms). As a layman I always wondered how this goes together with the lack of patients who respond positive to broad immunosuppression e.g. corticosteroids.

Based on my limited knowledge most "typical" autoantibody mediated autoimmune-disease responds at least partly and for a short time to corticosteroid treatment. In Long Covid and ME/CFS I haven't seen many positive anecdotes or even studies who report benefits from these kind of meds, people even often tend to feel worse on them pretty rapidly, e.g. a recent study with a glucocorticoid in Germany was terminated because there were harsh side effects as well as nobody who profited.

So my question as a layman and patient for the much more knowledged scientists on here would be:
isn't the unresponsiveness to "standard" immunosuppression something you'd had to explain if you want to frame these illnesses as primary autoantibody-mediated?

In every paper and every post arguing for this theory I always search for the part where they discuss this and they hardly ever do.

Or is there something I, as a layperson, haven't considered, or does my reasoning just not make much sense anyway?

 

[Jonathan Edwards]

So my question as a layman and patient for the much more knowledged scientists on here would be:
isn't the unresponsiveness to "standard" immunosuppression something you'd had to explain if you want to frame these illnesses as primary autoantibody-mediated?

It is a fair question. However, autoantibodies do not have to mediate disease through inflammatory pathways, so steroids may not produce any benefit. Steroids are not much use for thyroid autoimmunity for instance. Other sorts of immunosuppression may reduce antibody production and so reduce disease even if not inflammatory but most forms of immunosuppression do not have much impact on long lived plasma cell production of autoantibody.

So the unresponsiveness is not a sure sign that an illness is not autoimmune.

My concerns are more that I don't think this paper provides strong evidence for autoantibodies being involved.