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

[Utsikt]

No but my point is that exercise is one of the worse things to do with ME (don’t think you need an anecdote for this)

Sure, but that wasn’t what you said which is why I commented on it.

and the fact that patients that recovered exercised during the trial and not relapsed gives a very good signal that ME is memoryless unlike say Lupus.

I don’t think that’s completely right. If I understood JE correctly, Lupus patients can have temporary improvements that eventually disappear due to the memory being used to produce new faulty cells.

If ME/CFS follows the same pattern, we could in theory see temporary remissions in some, that eventually result in relapses.

I also think JE mentioned highly variable time profiles, so for all we know, the Dara patients, if the effects are actual effects, might have been the ones with a longer window before relapses. The follow up is too short, but F&M have a habit of long followup and few losses to dropouts, so we’ll probably see more data eventually.

 

[Jonathan Edwards]

But in CFS at least in the small Dara trials, the disease has not came back after 4-7 shots of Dara, and some of the patients even went back to exercise, which would be a clear trigger to reignite CFS but it didn’t.

Yes, which makes it very atypical for standard autoimmune disease. It is also atypical in that it follows infection - which is why in our Qeios piece we suggested that antibody was not acting as typical autoantibody but as some other 'permissive component. If we take the dara result at face value I think we have a choice between this sort of atypical role for some antibodies, maybe that got produced as a one off after an infection or we say dara is working by blocking CD38.

So it looks to me like purely based off the pilot study evidence ME is “memoryless”, if you flip the switch off it stays off. Of

But the fact that it seems to go on for ever without treatment must surely mean there is a memory - just that this memory is easier to break than the autoimmune type. If the memory is just continued production of bad antibody by LLPC that were set up by an infection then that would fit nicely with our Qeios model. But LLPC are thought to die off over decades, which makes it a bit puzzling.

Also on the LLPC lifespan, could it be possible the bad LLPC educate new LLPC and keep the cycle going in ME?

LLPC cannot educate LLPC. LLPC have closed their learning files and gone out to work. They have shut off their Ig gene mutation facility (where the learning occurs). LLPC can only educate mature B cells that are in the process of being selected for later work. New LLPC can only come from B cells. They do not divide to produce new clones as far as we know. That might not be entireoy true but if we are talking of LLPC dividing, there is no need for educating, the info for making bad antibody will just be carried over.

I am pretty sure that plasma cells do not divide much because if you keep people B cells depleted they do gradually lose their antibody levels and some quite quickly. Without new supply from B cells plasma cells do not appear to be able to re-expand to fill a deficit.

 

[Jonathan Edwards]

And Mella in his talk says they live for decades but you say they live for 10 years tops. So this is two conflicting sources of info.

Olav and I are not disagreeing here. Some LLPC seem to go on for nearly a lifetime but the average life is shorter - which is why most people on repeat rituximab gradually lose Ig levels. Ten years seems a reasonable average from what we can see.

What I think is reasonably clear is that if the dara data are valid any bad antibodies in ME/CFS are not behaving the way we see in autoimmune disease. I think it more or less proven that we are not dealing with anti-G protein coupled receptor autoantibodies for instance.

 

[ryanc97]

I also think JE mentioned highly variable time profiles, so for all we know, the Dara patients, if the effects are actual effects, might have been the ones with a longer window before relapses. The follow up is too short, but F&M have a habit of long followup and few losses to dropouts, so we’ll probably see more data eventually.

I’d be quite surprised if the exercise didn’t trigger relapse since exercise is one of the strongest worsening triggers for ME but over more time a relapse came on but we’ll see.

 

[ryanc97]

There is a tiny anecdote in the paper that says two patients improved on Bortezomib, which does not use CD38 at all.

 

[Kitty]

and the fact that patients that recovered exercised during the trial and not relapsed gives a very good signal that ME is memoryless unlike say Lupus.

I see your point but don't think it's that simple.

It is possible to have almost normal function, including exercise, and still have ME/CFS. I had two long remissions (remission seems uncommon but I'm not the only person to have experienced it), where if I'd known what was wrong with me*, I'd have considered myself recovered.

I wasn't, though. I still had mild illness, I had to pace a bit, and I still got mild PEM. it's just that the pattern wasn't recognisable without the benefit of hindsight and knowledge. I looked very like someone who didn't have the stamina of my peers, but whom you wouldn't describe as ill or disabled. I worked, I taught contemporary dance, I hiked, I was fit and strong. First time round I had about five years of that, second time it was four and a half.

So on its own, lack of relapse in response to challenge isn't really a demonstration of anything much, certainly not within two or three years. Obviously it's an incredibly positive development for the individual (and that holds even if they eventually relapse) but I don't think we can rely on it for a theoretical model of ME/CFS.


* Because I became ill in the 1970s when almost no one had heard of ME/CFS—and to be fair to the medical profession, probably also that I have autism and am spectacularly bad at describing symptoms verbally—I wasn't diagnosed for the first 23 years.

 

[Utsikt]

I’d be quite surprised if the exercise didn’t trigger relapse since exercise is one of the strongest worsening triggers for ME but over more time a relapse came on but we’ll see.

Exercise is not established as a «trigger of worsening» of ME/CFS - we have to be very careful about inferring causality. It’s pretty established as a trigger of PEM, even though it isn’t yet established in controlled studies.

You have to distinguish between PEM (worsening of symptoms following exertion/stimuli) and the disease ME/CFS.

 

[V.R.T.]

Exercise is not established as a «trigger of worsening» of ME/CFS - we have to be very careful about inferring causality. It’s pretty established as a trigger of PEM, even though it isn’t yet established in controlled studies.

You have to distinguish between PEM (worsening of symptoms following exertion/stimuli) and the disease ME/CFS.

I know we are playing it uber cautious here, and I get that you are trying to make a point but I do find people taking this line concerning and wrong headed, frankly. We will never be able to do a trial on this. It isn't ethical. There are countless accounts of deterioration from exercise. Yes there isn't evidence from a clinical trial but there never will be. And if we are going to take the position pwME get PEM from exercise but there is no evidence they deteriorate, then our position implies the BPS/BACME model is perfectly safe and valid. And that's a dangerous road to take.

 

[ryanc97]

From the paper:

"Protective antibodies (Diphtheria, Tetanus, SARS-CoV2) were analysed at baseline and after 12 months follow-up. All patients had
SARS-CoV-2 antibodies in line with either a previous infection or vaccination. All patients had protective or probably protective levels
of antibodies to SARS-CoV-2, Diphtheria and Tetanus, both at baseline and after 12 months."

Implies the LLPC depletion in Dara is actually selective, i.e faulty LLPCs more likely to be affected by Dara. Or implies that LLPCs were not affected at all.

 

[Jonathan Edwards]

Implies the LLPC depletion in Dara is actually selective, i.e faulty LLPCs more likely to be affected by Dara. Or implies that LLPCs were not affected at all.

Those statements seem just to imply that there were still protective levels. they might still have dropped by a half.

 

[Utsikt]

I know we are playing it uber cautious here, and I get that you are trying to make a point but I do find people taking this line concerning and wrong headed, frankly.

We can’t lower the standards.

We will never be able to do a trial on this. It isn't ethical. There are countless accounts of deterioration from exercise.

After exercise, not from exercise.

And if we are going to take the position pwME get PEM from exercise but there is no evidence they deteriorate, then our position implies the BPS/BACME model is perfectly safe and valid. And that's a dangerous road to take.

Not at all. There is ample evidence that treatments based on the BPS model does not work. When you combine that with the observed symptom patterns of PEM and the ethical duty to first do no harm, you end up with pacing as a management strategy as the only logical conclusion.

Which means that we do not need to lower our standards to get to the conclusion you want us to get to.

It would be a disservice to ourselves to lower the standards of proofs and evidence. You can see what that leads to with the various biobabble researchers and doctors..

 

[V.R.T.]

We can’t lower the standards.

After exercise, not from exercise.

Not at all. There is ample evidence that treatments based on the BPS model does not work. When you combine that with the observed symptom patterns of PEM and the ethical duty to first do no harm, you end up with pacing as a management strategy as the only logical conclusion.

Which means that we do not need to lower our standards to get to the conclusion you want us to get to.

It would be a disservice to ourselves to lower the standards of proofs and evidence. You can see what that leads to with the various biobabble researchers and doctors..

When you talk like this you disregard the lived experience of everyone whose lives were destroyed by worsening from exercise. Listening to people is not lowering the standards. If no-one had listened to pwME there would not be a single study happening anywhere.

If you can acknowledge PEM from exercise you can acknowledge deterioration from exercise - there is no more 'hard' evidence for the former than the latter.

BACME approach is all based around the fact that they can't make people permanently worse because there's no risk of getting worse from trying to do a bit more and a bit more.

When you take the line you have taken, you validate that approach.

 

[jnmaciuch]

An alternative explanation for the predictive power of baseline NK cell levels (if we choose to take the data at face value) is that the same process both feeds into whatever CD38-related mechanism contributes to disease and also contributes to NK cell proliferation.

A CD38-TNFa/NFkB loop might fit nicely here--there's some preliminary evidence that NFkB induces CD38, and CD38 induces NFkB (this result is more of a reach, it's showing that a CD38 knockout has suppressed NFkB signaling). TNFa induces NK cell proliferation via its effect on metabolic reprogramming.

I'll note that CD38 also appears to have important roles for calcium and NAD metabolism--both of which would be in substantial flux during muscle contraction and synaptic firing (and therefore could be a link to PEM after both physical and cognitive effort). So one alternative theory is that if Dara is actually effective, it could be through the effect of simply blocking CD38 activity in tissues, rather than NKs eliminating specific CD38+ cells.

 

[Utsikt]

Listening to people is not lowering the standards.

You’re missing the point.

When you take the line you have taken, you validate that approach.

I categorically disagree.

If you read my previous reply I made it very clear that anyone in healthcare has an ethical duty to first do no harm. And because risks by definition involve uncertainties, when it comes to risk of harm we do not need definitive proof. Lived experience and observations is more then enough to say that the risk is simply too high.

Again, there is absolutely no reason or need to lower our standards, and we still get to the same advice that you’d give if you assumed causality.

 

[V.R.T.]

You’re missing the point.

I categorically disagree.

If you read my previous reply I made it very clear that anyone in healthcare has an ethical duty to first do no harm. And because risks by definition involve uncertainties, when it comes to risk of harm we do not need definitive proof. Lived experience and observations is more then enough to say that the risk is simply too high.

Again, there is absolutely no reason or need to lower our standards, and we still get to the same advice that you’d give if you assumed causality.

Ok, maybe. But it's a very fine line to walk.

 

[Utsikt]

Ok, maybe. But it's a very fine line to walk.

Absolutely, but it’s the only line we can walk if we want to make any progress. There are too many pitfalls.

 

[DHagen]

An alternative explanation for the predictive power of baseline NK cell levels (if we choose to take the data at face value) is that the same process both feeds into whatever CD38-related mechanism contributes to disease and also contributes to NK cell proliferation.

A CD38-TNFa/NFkB loop might fit nicely here--there's some preliminary evidence that NFkB induces CD38, and CD38 induces NFkB (this result is more of a reach, it's showing that a CD38 knockout has suppressed NFkB signaling). TNFa induces NK cell proliferation via its effect on metabolic reprogramming.

I'll note that CD38 also appears to have important roles for calcium and NAD metabolism--both of which would be in substantial flux during muscle contraction and synaptic firing (and therefore could be a link to PEM after both physical and cognitive effort). So one alternative theory is that if Dara is actually effective, it could be through the effect of simply blocking CD38 activity in tissues, rather than NKs eliminating specific CD38+ cells.

So, if something like this is indeed what is occurring for the responders, what might be going on with the non-responders?

 

[ryanc97]

An alternative explanation for the predictive power of baseline NK cell levels (if we choose to take the data at face value) is that the same process both feeds into whatever CD38-related mechanism contributes to disease and also contributes to NK cell proliferation.

A CD38-TNFa/NFkB loop might fit nicely here--there's some preliminary evidence that NFkB induces CD38, and CD38 induces NFkB (this result is more of a reach, it's showing that a CD38 knockout has suppressed NFkB signaling). TNFa induces NK cell proliferation via its effect on metabolic reprogramming.

I'll note that CD38 also appears to have important roles for calcium and NAD metabolism--both of which would be in substantial flux during muscle contraction and synaptic firing (and therefore could be a link to PEM after both physical and cognitive effort). So one alternative theory is that if Dara is actually effective, it could be through the effect of simply blocking CD38 activity in tissues, rather than NKs eliminating specific CD38+ cells.

Could you dumb it down for me?

How does high NK cell here predict a good response?

By the way it’s important to remember the NK cell vs max SF36 delta or max step delta is very linear in response

So you’re saying high NK cell is a result of a disease subtype not the drug mechanism? That is not good at all…


Given the cross section with MM improving with more NK cells I’d say the LLPC theory has more supporting evidence

Also if Dara works by blocking CD38 in tissues then once it’s gone surely problems come back …

 

[ryanc97]

You’re missing the point.

I categorically disagree.

If you read my previous reply I made it very clear that anyone in healthcare has an ethical duty to first do no harm. And because risks by definition involve uncertainties, when it comes to risk of harm we do not need definitive proof. Lived experience and observations is more then enough to say that the risk is simply too high.

Again, there is absolutely no reason or need to lower our standards, and we still get to the same advice that you’d give if you assumed causality.

You’re an economist right? Surely any good economist would have realized no willing patient is going volunteer do any controlled trial with exercise lol