Long-lived plasma cell (LLPC) theory - Similarities between CFS and Lupus?

forestglip said:
And doesn't antibody provide a good explanation for the 'memory' in ME/CFS?
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Autoantibodies provide explanations for memory in other diseases but if you just kill plasma cells there should be new plasma cells created quite quickly from surviving B cells, so the dara result doesn't fit very well with what we know of other autoimmune diseases. But autoantibody mediated chronic diseases do not follow infections as a rule (I am not convinced they ever do). So there are lots of things that don't fit very well.
forestglip said:
The improvement from dara also lasted for months after the intervention, which lines up with antibody depletion therapies in other diseases.
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Except that at least a good proportion of patients with antibody depletion for autoimmune disease relapse as soon as the blocking effect on antibody production stops.
 
ryanc97 said:
How much probability could it be that the antibodies that are causing harm are not detectable with current technology? Sounds crazy but you know.
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It is certainly possible that there are pathological autoantibodies in ME/CFS that we have not found a way to detect. Autoantibodies continued to be discovered into the 1990s at least. But that is now quite a long time ago and with the development of more sophisticated tissue staining techniques and in particular Western blotting, the chances of not find an autoantibody are probably quite small.

But antibodies might cause harm through more subtle mechanisms - that was the point of our Qeios article. And those mechanisms might easily be outside our current technology to demonstrate. I don't have any great faith that what we suggested on Qeios is the right answer but something like that could be.
 
Jonathan Edwards said:
Autoantibodies provide explanations for memory in other diseases but if you just kill plasma cells there should be new plasma cells created quite quickly from surviving B cells, so the dara result doesn't fit very well with what we know of other autoimmune diseases. But autoantibody mediated chronic diseases do not follow infections as a rule (I am not convinced they ever do). So there are lots of things that don't fit very well.


Except that at least a good proportion of patients with antibody depletion for autoimmune disease relapse as soon as the blocking effect on antibody production stops.
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My take on this whole memory thing which is crazy:

* Lupus AABs (or other auto-immune diseases) are produced by SLPC only which is continuously renewed and hence has memory even if you deplete it. The defect in the assembly line is very deep rooted and currently no drug has targetted it yet.
* ME AABs are produced by LLPC only which is a one time thing and hence has no memory even if you deplete it or somehow LLPCs do not return in force. The defect in the assembly line is accessible with LLPC depleters.

(Assumes that the LLPC event was a one time thing caused by a discrete event trigger - aka the faulty LLPCs were made on ground zero of when ME started in that person as a one time event, and remain today).

But of course its just an uninformed theory. Just putting it out there. I know JE has explained why it is unlikely anyway
 
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Jonathan Edwards said:
We can discount ritux because none of the studies were actually positive for it. Even phase 2 failed strictly speaking - i.e. on the primary outcome measure.
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I'll need to re-look at that. I might have misremembered the improvement being more impressive.

Jonathan Edwards said:
Cyclo and dara will both knock all lymphoid cells and other white cells too - pretty much any immune cell you like in fact, so there is nothing to suggest any specificity here.
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Okay, if they're both just killing everything, that makes B cell specificity less convincing.

EndME said:
Also note that the sample size for the Rituximab study was almost 3x the sample size of the planned Daratumumab study (and there's additional data from the other failed studies making the total sample size even larger), so a straightforward power argument can anyways not work (one will have to invoke much higher efficacy, patient selection, outcome measures, different mechanism or something else).
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Yes, I was going with the idea that higher efficacy is probably the explanation for the difference due to LLPCs persistently making antibodies so would seem to make more sense for an illness that can last for decades, and thus deleting SLPCs shouldn't do very much.

Jonathan Edwards said:
Autoantibodies provide explanations for memory in other diseases but if you just kill plasma cells there should be new plasma cells created quite quickly from surviving B cells, so the dara result doesn't fit very well with what we know of other autoimmune diseases.
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Is it correct that dara doesn't wipe out memory cells, and that's why you say LLPCs would be remade even if all of them got killed? Is there a way that only plasma cells and no memory cells might be made in the original disease onset?
 
Jonathan Edwards said:
if you just kill plasma cells there should be new plasma cells created quite quickly from surviving B cells
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Doesn't this replacement with new B cells require re-exposure to an antigen? I was thinking that the LLPCs are created originally for some reason, but that the antigen is long gone if it ever existed, since there aren't signs this is a typical autoimmune disease, so there'd be no reason for the memory cells to make more LLPCs if the plasma cells get destroyed.
 
forestglip said:
Can someone say why what seems to be simplest way to look at the results we see is not the most likely: that the mechanism of action of dara is due to reducing antibody.
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In general I agree with JE’s responses to this point, but I’ll add that I don’t actually think this is the simplest explanation, it’s just the one that’s been repeated because the Dara trial is being viewed in the context of the justification of the rituximab trial. But in reality, CD38 has its fingers in many pies.

In order to propose an antibody-mediated mechanism, you’d have to do a lot of finagling just to explain why we don’t see the tissue damage and suite of cytokines that nearly always go in tandem [edit: with] autoantibody recognition. And it’s certainly possible to paint a story that tries to explain all the many deviations from the expected clinical course, but from my perspective it really only makes sense to put so much effort into forcing the theory to stick if you are pretty certain that autoantibodies are relevant. Currently, the justification is really just “autoantibodies are capable of driving long term disease”.

So they are a decent option to explore insofar as you’re looking at mechanisms with “memory,” but they’re far from the only viable option, and invoking them doesn’t really explain anything else other than A Long Term Disease State. Plus, invoking them also brings up additional contradictions that are really hard to explain. So overall, an autoantibody theory scores pretty weakly
 
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jnmaciuch said:
In order to propose an antibody-mediated mechanism, you’d have to do a lot of finagling just to explain why we don’t see the tissue damage and suite of cytokines that nearly always go in tandem autoantibody recognition. And it’s certainly possible to paint a story that tries to explain all the many deviations from the expected clinical course, but from my perspective it really only makes sense to put so much effort into forcing the theory to stick if you are pretty certain that autoantibodies are relevant. Currently, the justification is really just “autoantibodies are capable of driving long term disease”.
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Couldn't it be some unknown types of antibody that doesn't work the way any current one does and hence medical knowledge hasn't discovered how it works yet? Given that ME is still unknown, there is a gap in medicine that exists.

One of those 'the Earth is round' moments back then when people believed the earth was flat. etc.

For example, the antibodies could be classified into

1. POTS - HR/BP control
2. Sensory problems
3. Fatigue/muscle weakness - To do with oxygen delivery/hypoxia
4. Pain
 
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ryanc97 said:
Well to me there's only one way to find out, put someone on Teclistamab or Bortezomib and see if they get better. If they do, then you conclude CD38 has less to do with it and its just a target sign painted on the plasma cell to kill it, since Tecs and Bort kill plasma cell by other ways not using CD38.
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Well we do have anecdotal evidence for non-CD 38 LLPC depletion being effective.

Disulfiram is actually a proteosome inhibitor.

Threads about disulfiram (improvements) here:

Dechi

Thread 'Treatment with Disulfiram (Antabuse) seems to help'

I’ve recently started a treatment with Disulfiram. My doctor thinks there is a possibility that I have Lyme and put me on antibiotics. After reading a lot about it, I’ve decided I didn’t want to go that route. Meanwhile, I learned about a new Lyme treatment with Disulfiram that was supposedly giving good results for some people and that needed to be taken a few months only, and never again. So I decided that’s what I wanted.

I’m not convinced I have Lyme at all, but I think Disulfiram could help me, no matter what I have.

I don’t want to jinx it, but I seem to be having results, even...
  • Like

forestglip

Trial Report Thread 'A pilot study of disulfiram for individuals with persistent symptoms despite prior antibiotic treatment for Lyme disease, 2025, Kuvaldina et al'

A pilot study of disulfiram for individuals with persistent symptoms despite prior antibiotic treatment for Lyme disease

Mara Kuvaldina, Jessica Preston, Denise McClellan, Martina Pavlicova, Thomas H. Brannagan, Brian A. Fallon

[Line breaks added]

Introduction
In vitro studies report that disulfiram is effective in killing Borrelia burgdorferi. Case series suggest disulfiram may help to reduce the symptoms of patients with persistent symptoms despite prior antibiotic treatment for Lyme disease. This pilot study assessed safety, tolerability, and signs of clinical...
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forestglip said:
I'll need to re-look at that. I might have misremembered the improvement being more impressive.
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The phase 2 study had a negative result at the primary endpoint of 3 months. However, in their publication in PlosOne they noted that at 6 months the ritux patients seemed to have done better. They did not claim a positive result but thought the six month data might be worth noting. A BPS guy wrote an ignorant comment saying that six months was irrelevant because in autoimmunity the response woud be seen at 3 months. I was asked to comment and pointed out that Fluge and Mella were absolutely right and I think I made the comment that six months was the usual time point for assessing response in autoimmunity - at least in my own hands - because that was when you saw the clearest difference. I discussed things with the Norwegians and they were encouraged by my comments. They sent me the detailed pharmacodynamics, which did not show a lot of consistency in 'response' times for different measures but I made it clear that I thought the six month time point was of interest and that I would support a phase 3 trial. In fact I set up a protocol for a trial at UCL, although we never followed that through largely because the Norwegians had their phase 3 funded.

My only concern with the phase 3 is that when you get to big trials recruitment of cases can get sloppy and less than ideal cases may be included, but with a flat negative result I think we can be fairly sure that the vast majority of people with ME/CFS are not going to benefit from ritux.
forestglip said:
Is it correct that dara doesn't wipe out memory cells, and that's why you say LLPCs would be remade even if all of them got killed? Is there a way that only plasma cells and no memory cells might be made in the original disease onset?
Click to expand...

Dara would not kill memory B cells. Accepted immunology does not have a way for LLPCs to be made without making memory B cells. When you get vaccinated for tetanus you produce LLPC that keep going for years. Your antibody levels may fade but if you have a booster they come up quickly because you have B and T cell memory reader to generate more plasma cells.
 
There are some papers saying LLPCs actually resist proteasome inhibitors. But in some cases. You might expect a temporary improvement on Bortezomib. If you can find any anecdotes on that. I guess it damages the LLPC but doesn't kill it
 
Jaybee00 said:
Well we do have anecdotal evidence for non-CD 38 LLPC depletion being effective.

Disulfiram is actually a proteosome inhibitor.

Threads about disulfiram (improvements) here:
Click to expand...
Can you link to something saying disulfiram depletes LLPCs? I can't see anything about that from a scan of those threads or a search.
 
Jaybee00 said:
Well we do have anecdotal evidence for non-CD 38 LLPC depletion being effective.

Disulfiram is actually a proteosome inhibitor.

Threads about disulfiram (improvements) here:

Dechi

Thread 'Treatment with Disulfiram (Antabuse) seems to help'

I’ve recently started a treatment with Disulfiram. My doctor thinks there is a possibility that I have Lyme and put me on antibiotics. After reading a lot about it, I’ve decided I didn’t want to go that route. Meanwhile, I learned about a new Lyme treatment with Disulfiram that was supposedly giving good results for some people and that needed to be taken a few months only, and never again. So I decided that’s what I wanted.

I’m not convinced I have Lyme at all, but I think Disulfiram could help me, no matter what I have.

I don’t want to jinx it, but I seem to be having results, even...
  • Like

forestglip

Trial Report Thread 'A pilot study of disulfiram for individuals with persistent symptoms despite prior antibiotic treatment for Lyme disease, 2025, Kuvaldina et al'

A pilot study of disulfiram for individuals with persistent symptoms despite prior antibiotic treatment for Lyme disease

Mara Kuvaldina, Jessica Preston, Denise McClellan, Martina Pavlicova, Thomas H. Brannagan, Brian A. Fallon

[Line breaks added]

Introduction
In vitro studies report that disulfiram is effective in killing Borrelia burgdorferi. Case series suggest disulfiram may help to reduce the symptoms of patients with persistent symptoms despite prior antibiotic treatment for Lyme disease. This pilot study assessed safety, tolerability, and signs of clinical...
  • Like
Click to expand...
This is a very interesting case study/anecdote. But of course, since it is not double blind it is definitely spontaneous improvement or placebo and should be binned.

On a serious note @Jaybee00 you have any anecdotes of Bortezomib improvement in here?
 
ryanc97 said:
Couldn't it be some unknown types of antibody that doesn't work the way any current one does and hence medical knowledge hasn't discovered how it works yet? Given that ME is still unknown, there is a gap in medicine that exists.

For example, the antibodies could be classified into

1. POTS - HR/BP control
2. Sensory problems
3. Fatigue/muscle weakness - To do with oxygen delivery/hypoxia
4. Pain
Click to expand...
Sure, maybe, but that’s exactly my point. You can pretty much spin the wheel for any part of the body and claim that it’s somehow driving symptoms by a completely unknown mechanism that deviates from everything else we’d expect. We could just as well say it’s the thyroid. Or a specific subtype of tissue resident myeloids that hasn’t been well characterized yet.

As I already stated, the main and really only explanatory benefit of autoantibodies is that we know they can sustain long term disease. But they’re far from the only things that do that, and other explanatory options don’t require you to basically hold out hope for an undiscovered unicorn that magically behaves in exactly the way we want it to, contrary to every other example of that mechanism at play.
 
jnmaciuch said:
I can’t say that either points to T cells moreso than an “immune” process more generally
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But you are not a clinician who has looked after people with all sorts of chronic immune disease!!
Autoantibody diseases mostly get commoner as you get older.
The post-infective diseases we know are all T cell driven as far as I know.
 
forestglip said:
Yes, I was going with the idea that higher efficacy is probably the explanation for the difference due to LLPCs persistently making antibodies so would seem to make more sense for an illness that can last for decades, and thus deleting SLPCs shouldn't do very much.
Click to expand...
I can't claim to understand the comparison. Many autoimmune disease also last for decades if not a full lifetime and you can have efficacy of Rituximab.

The more practical problem will be that if the efficacy is so low that you'd need a study of thousands of patients or even more in an ideal environment, then you can not justify the risks in the first place and you will likely never be able to show efficacy in the first place due to practical problems (the NIH struggled recruiting just 20 patients rigorously, you would probably struggle to recruit that many people in the current ME/CFS world without ending up with a problematic cohort).

It is of note that instead of increasing their sample size Fluge and Mella have decreased their sample size for their upcoming study (but have made some other adaptations instead).
 
Jonathan Edwards said:
Your antibody levels may fade but if you have a booster they come up quickly because you have B and T cell memory reader to generate more plasma cells.
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Right, if you have a booster. But if dara wiped out all LLPCs, would tetanus antibodies quickly be automatically re-made? If some wonky LLPCs got made when a person got a COVID infection and which cause ME/CFS, but without a persistent antigen, I wouldn't expect them to quickly be replaced if they got killed.
 
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