Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al

Jonathan Edwards said:
That is perhaps the argument from first base but I think there are problems with it. The fluctuation of symptoms typified by PEM doesn't seem to fit with a direct antibody effect - since antibody levels are likely to be constant over many days at least. It seems that there is some other signalling event that can be switched on and go off.
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Maybe we're looking for something that causes little problems while in a well rested state, but interferes with the body's ability to recover from exertion. Maybe something that's important for tissue repair/maintenance is blocked by these antibodies. While there is only a little bit of wear to repair, the repair capacity of cells, while limited, would be sufficient to avoid alarms going off. With exertion, the wear would begin to accumulate quickly, eventually surpassing the thresholds of various alarm signals. The brain, sensing these alarm signals, would enter PEM as a sort of emergency response to stop further unnecessary activity. After a day or several, things would normalize and the patient would feel a lot better and maybe look healthy, deceptively so.

Something similar could be proposed for other things. Instead of repair capacity being affected, maybe it would be the ability to prevent tissue damage from accumulating, so that even a little bit of activity would be similar to an extreme amount.

If we could study PEM more in detail to find out which activities contribute the most to it and which the least then it might help narrow down what is going wrong.
 
Hoopoe said:
Maybe we're looking for something that causes little problems while in a well rested state, but interferes with the body's ability to recover from exertion. Maybe something that's important for tissue repair/maintenance is blocked by these antibodies. While there is only a little bit of wear to repair, the repair capacity of cells, while limited, would be sufficient to avoid alarms going off. With exertion, the wear would begin to accumulate quickly, eventually surpassing the thresholds of various alarm signals. The brain, sensing these alarm signals, would enter PEM as a sort of emergency response to stop further unnecessary activity. After a day or several, things would normalize and the patient would feel a lot better and maybe look healthy, deceptively so.
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If that was the case, wouldn’t e.g. extreme rest improve your baseline through giving the repair system ample time to do its thing?

And how would we explain vastly different thresholds for exertion/stimuli within that model?
 
Utsikt said:
If that was the case, wouldn’t e.g. extreme rest improve your baseline through giving the repair system ample time to do its thing?

And how would we explain vastly different thresholds for exertion/stimuli within that model?
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The repair problem would only manifest as delayed problems occurring after activity if the person was mildly affected. To explain symptoms at rest and inability to recover completely despite sufficient, rest we would need something else. Maybe it could be that when this problem is bad enough, the repair capacity is so limited that the body always fails to fully repair the wear caused merely by basic bodily functions. Disturbed sleep would make this worse and factors that affect sleep quality could be risk factors for ME/CFS. There was a genetic study that reported an association between a circadian rythm gene and ME/CFS. Also there were at least 2 studies showing a blunted response to activity in ME/CFS at cellular level in the recovery period, which seems consistent with this model.

As for vastly different thresholds for exertion/stimuli. I don't know, but maybe when things are bad, the body begins reacting in extreme ways to try and protect itself.

This model also seems like it might fit the "intolerant of everything" phenomenon.
 
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Reading up a bit on IgG4 and came across these

Repeated COVID-19 Vaccination as a Poor Prognostic Factor in Pancreatic Cancer: A Retrospective, Single-Center Cohort Study - PMC

Repeated COVID-19 vaccination is known to increase spike-specific immunoglobulin G4 (IgG4), and there are concerns regarding its impact on cancer immunity. This study aimed to investigate the relationship between repeated COVID-19 vaccination and ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov

Class switch towards spike protein-specific IgG4 antibodies after SARS-CoV-2 mRNA vaccination depends on prior infection history - PMC

Vaccinations against SARS-CoV-2 reduce the risk of developing serious COVID-19 disease. Monitoring spike-specific IgG subclass levels after vaccinations may provide additional information on SARS-CoV-2 specific humoral immune response. Here, we ...
pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
If IgG4 is involved in ME/CFS somehow I wonder if there could be a similar thing happening with people having negative reactions to certain vaccinations they’ve had?
 
Jonathan Edwards said:
That is perhaps the argument from first base but I think there are problems with it. The fluctuation of symptoms typified by PEM doesn't seem to fit with a direct antibody effect - since antibody levels are likely to be constant over many days at least. It seems that there is some other signalling event that can be switched on and go off. Maybe an antibody blocking something might prime cells to signal but I am not sure what it would be. Moreover, people have looked quite hard for autoantibodies (including just screening people for differential diagnosis) and not found anything that would fit.

I agree that antibodies to pathogens aren't usually associated with symptoms in the textbooks. But in fact antibody responses to foreign antigens may be responsible for all sorts of things like rashes, synovitis in rheumatic fever, nephritis after streptococci, maybe the fatal hypersensitivity syndrome of second strain Dengue exposure?

We are looking for something that does not fit any very obvious rules. And in fact most chronic immunological diseases do not fit any consistent rules in one way or another - probably because they are all aberrations of rules. I agree that the question is open but to me blaming an autoantibody is the stock easy solution.
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For the PEM thing, let's say that the antigen is the SLC24A3 protein. If it's dysfunctional, it can lead to calcium overload in the cell. and calcium overload messes with the mitochondria, and this is how PEM is formed after exercise, for example, when you need more calcium but can't clear it.
 
zar nola said:
For the PEM thing, let's say that the antigen is the SLC24A3 protein. If it's dysfunctional, it can lead to calcium overload in the cell. and calcium overload messes with the mitochondria, and this is how PEM is formed after exercise, for example, when you need more calcium but can't clear it.
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How does calcium in the mitochondria lead to PEM? And how does this explain PEM from otherwise trivial exertion in the more severe?
 
Utsikt said:
How does calcium in the mitochondria lead to PEM? And how does this explain PEM from otherwise trivial exertion in the more severe?
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Mitochondria is the "powerhouse of the cell." Too much calcium leads to an increase in ROS. Too much ROS and calcium is overall weakening the mitochondria and the ability to produce ATP.

When I talk about calcium, don't think about calcium from food, etc. I'm talking about calcium in the cells, and it has nothing to do with dietary calcium.
 
zar nola said:
Mitochondria is the "powerhouse of the cell." Too much calcium leads to an increase in ROS. Too much ROS and calcium is overall weakening the mitochondria and the ability to produce ATP.

When I talk about calcium, don't think about calcium from food, etc. I'm talking about calcium in the cells, and it has nothing to do with dietary calcium.
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Yes, I’m aware. But that doesn’t explain how it would cause a significant increase in symptoms a day after trivial exertion for the more severe.
 
Utsikt said:
Yes, I’m aware. But that doesn’t explain how it would cause a significant increase in symptoms a day after trivial exertion for the more severe.
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1. Maybe the mitochondria got to a point that it’s in such a bad condition that every single thing can cause PEM because the ability to recover is lower than the physical activity impact on it.
2. Maybe there are other subtypes
 
zar nola said:
1. Maybe the mitochondria got to a point that it’s in such a bad condition that every single thing can cause PEM because the ability to recover is lower than the physical activity impact on it.
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That doesn’t explain how calcium in the mitochondria causes PEM, or how anything relating to the mitochondria causes PEM.

You’re saying:
Calcium buildup in mitochondria -> magic -> significant and prolonged increase in symptoms a day later

I’m trying to ask about the magic part. How do we get from A to Z?
 
Utsikt said:
That doesn’t explain how calcium in the mitochondria causes PEM, or how anything relating to the mitochondria causes PEM.

You’re saying:
Calcium buildup in mitochondria -> magic -> significant and prolonged increase in symptoms a day later

I’m trying to ask about the magic part. How do we get from A to Z?
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Mitochondria gets permeable, and instead of making energy, it’s now wasting its energy on trying to close the holes.
It’s the explanation in simple words.
You can fit this in what you call magic
 
zar nola said:
Mitochondria gets permeable, and instead of making energy, it’s now wasting its energy on trying to close the holes.
It’s the explanation in simple words.
You can fit this in what you call magic
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You’re still a far way away from symptoms that only start a day later. But we’re getting off topic for this tread and we’re going in circles.
 
zar nola said:
Who says that the effect should be immediate?
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That’s a deflection and not what I’ve been asking about.

You said that SLC24A3 protein as an antigen could lead to calcium overload in the mitochondria which could explain PEM.

I’ve asked you to elaborate on the proposed causal pathways between calcium overload (or anything with the mitochondria) and PEM - both wrt the symptoms themselves and the characteristic pattern of the delay that is often observed between the exertion/stimuli and onset of symptoms.
 
But PEM isn't about weakness or lack of available ATP. It is about feeling terrible, as I understand it.

From all the physiological studies I am not aware of any evidence for muscles not being able to generate force after a previous bout of exertion. Maybe there is, but it still isn't PEM as I have understood it.
 
The whole muscle/mitochondria angle just doesn’t come close to explaining my symptoms. This is not a muscular, physical tiredness like I used to get after strenuous physical exertion, nothing like it.

I suppose I could envision some mechanism involving calcium channels and changes there. But that seems to be different to what is being described with energy and mitochondria?
 
Jonathan Edwards said:
But PEM isn't about weakness or lack of available ATP. It is about feeling terrible, as I understand it.

From all the physiological studies I am not aware of any evidence for muscles not being able to generate force after a previous bout of exertion. Maybe there is, but it still isn't PEM as I have understood it.
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Autoantibodies to Arginine-rich Sequences Mimicking Epstein-Barr Virus in Post-COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
They are thinking it's not just 1 target, and it's not only muscle.
 
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