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

Well @Jonathan Edwards is my understanding of Lupus correct in that

1. You can't really cure it, you can only manage symptoms? It seems like there is memory in Lupus, aka you get rid of the problematic cells and once you stop they come back.
2. Rituximab works for Lupus so the antibodies are produced by the SLPCs?
3. What about long lived plasma cells in Lupus?
4. There is organ damage in Lupus but it is less known whether there is true organ damage in CFS (at least F/M dont think there is?)
 
Well @Jonathan Edwards is my understanding of Lupus correct in that

So far lupus has not been cured to my knowledge but the recent CAR-T cell therapy cases have long remissions and may be cured. Lupus quite often becomes quiescent after ten or more years though. Also some features of lupus appear to go in to permanent remission (we are now talking 20 years since our first cases were treated). Patients can lose particular organ involvement - thrombocytopenia or renal disease for instance. In isolated immune thrombocytopenia a good proportion of cases remit long term after rituximab.

But rituximab does not necessarily work very well for some things like fatigue in lupus. And some lupus antibodies are hardly touched (at least in our experience). So some of the autoantibodies are made by longer lived plasma cells and the features that would go with them tend to be less responsive. In scleroderma response is dubious and again that may relate to long lived plasma cell production.

In general anti-DNA antibody levels drop markedly with rituximab but not the antibodies to nuclear protein antigens so much.

Organ damage in lupus is easy to document either just by clinical exam or pathology - deformed hands, scarred skin, lung fibrosis etc. Nothing equivalent occurs in ME/CFS, we can be sure of that in almost all cases. There might be very local damage in hind brain, as there is in narcolepsy. There might be damage to sensory neurons that form dorsal root ganglia, but major damage is not reported.
 
Cure

In terms of cure, so my understanding is that compared to CFS you can't really get rid of it permanently. So the autoantibody generation process is basically stuck on in Lupus patients forever, but with treatment, it can be managed so patients can have a decent QoL. Is that correct?
So far lupus has not been cured to my knowledge but the recent CAR-T cell therapy cases have long remissions and may be cured. Lupus quite often becomes quiescent after ten or more years though. Also some features of lupus appear to go in to permanent remission (we are now talking 20 years since our first cases were treated). Patients can lose particular organ involvement - thrombocytopenia or renal disease for instance. In isolated immune thrombocytopenia a good proportion of cases remit long term after rituximab.

This aligns with what I read on the Lupus reddit, patients being on long term immunosuppressant treatment forever (aka you stop and it comes back). Are there cases like you said in CAR-T cell for Lupus, the patients do several treatments and they are pretty much cured from Lupus forever.

I find the issue of 'memory' in Lupus vs ME quite interesting. It's like a Markov chain (a concept in probability), where in CFS there is patients can reach an absorbing state (cured forever) but in Lupus there is none.

Plasma Cells

Is there definitive evidence that it is long lived plasma cells in the protected sites that are generating Lupus AABs? As my understanding is that AAB production can come from plasmablast/SLPC/LLPC, so different sources. Has the specific sources been identified and tested?

Because in ME, at least you have a failed Ritux trial and a 'successful' Dara trial which lets us infer it is LLPC rather than SLPC being the problem in ME.

Comparison to CFS

I'm asking because in comparison to ME, we have some complete remissions on Ritux/Cyclo/Dara without needing continual treatment. So in these cases, the AAB generation process was permanently halted (assuming it is AAB of course) after treatment was stopped.

So my theory would be that in Lupus vs ME:

1. Both are AAB mediated but Lupus AABs are diff from CFS AABs (former causes permanent organ damage, is identifiable by tests. Latter causes no permanent damage and we do not have tests that can identify them yet).
2. Both have diff sources of AAB production within lymphocytes: Lupus is caused by SLPC continuous renewal while ME is caused by one time LLPC living for decades. This is why Ritux 'works' in Lupus but not in ME.
3. Because of the source different, this explains why there is memory in Lupus but not in ME. SLPCs are continuously renewed after stopping treatment in Lupus while once you knock out the LLPCs in ME you are good to go.
 
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If there is, would that be irreversible? I'm wondering whether we could ever in principle fully recover and if not, what that kind of damage in the hind brain would mean.

I think the fact that some people do report recovery, or improvement so that they are not significantly disabled and can work and travel (thinking of Charles Shepherd perhaps) is very encouraging. We have no evidence for any damage and if there is it must be local and at least in some cases open to compensatory mechanisms at least.
 
In terms of cure, so my understanding is that compared to CFS you can't really get rid of it permanently. So the autoantibody generation process is basically stuck on in Lupus patients forever, but with treatment, it can be managed so patients can have a decent QoL. Is that correct?

I would not be so sure. Although it is uncommon, maybe as much as 5-10% of people with rheumatoid arthritis go into comlete clinical and autoantibody remission spontaneously. A good number of older lupus patients we usd to follow up remain well for years with low levels of antinuclear antibodies consistent with normal health. We have not yet found a way of abolishing lupus long term with therapy but it seems we have for immune thrombocytopenia. My feeling is that the main reason why we have not achieved long term remission is that researchers have not fully understood what they are trying to do and have not set up a sensible protocol. Anna Traynor and Alan Tyndall both tried to cure RA and or lupus with high dose chemotherapy and stem cell rescue, which at the time was the most aggressive approach available. But it did not hit plasma cells that hard, so nobody has done the 'wipe the B cell and antibody slate clean' experiment. It might also be necessary to shift T cell populations but the CAR-T approach may get close to the first experiment.

Is there definitive evidence that it is long lived plasma cells in the protected sites that are generating Lupus AABs? As my understanding is that AAB production can come from plasmablast/SLPC/LLPC, so different sources. Has the specific sources been identified and tested?

Plasmablasts are a brief transition phase that people got stuck on because you can find them in blood. I don't think they make significant antibody long term. They would have to be 'long lived plasmablasts' which as far as I know don't exist. But no, we don't have direct evidence for where the antibody populations are coming from - it is just inferred from the dynamics. In simple terms the difference between short and long lived may be whether they are settling in spleen or bone marrow. It is technically almost impossible to get representative data on the main site.

I'm asking because in comparison to ME, we have some complete remissions on Ritux/Cyclo/Dara without needing continual treatment. So in these cases, the AAB generation process was permanently halted (assuming it is AAB of course) after treatment was stopped.

Yes but you are forgetting that we also have remissions with placebo or the Lightning Process - i.e. the illness getting better for other reasons. Both lupus and RA get better for other reasons we do not understand, so I am not sure we can reliably make a distinction.

Nevertheless, I think it is possible that at least for Daratumumab, where we do not have negative phase 3 data, that long term remission can be achieved. We then have to consider whether that has to be because of reducing antibody. Looking at the antibody reductions with dara I am a bit sceptical because we have seen similar or greater antibody reductions with rituximab without long term benefit in RA and lupus. One particular patient I tried to get antibody levels as low as I could with cyclo and ritux and she still relapsed early. I think there is a significant possibility that daratumumab is working through a different mechanism.
 
Alright, so it seems in Lupus it is still unknown whether it can be cured permanently or not, we don't know the specific source of AABs in Lupus but we can identify/test for their type.

From my experience I do think anyone with remission from placebo or CBT either didn't have ME in the first place or more likely are grifters selling the program. Any online comment that says they got cured from a CBT style treatment is probably a grifter trying to sell to earn more revenue.

I would love to see some evidence in trials research papers of placebo remissions. I have not seen any yet.

This grifting also occurs on r/CFS reddit, where now and then a post will pop up saying they got cured/got huge improvement from a supplement. They will link the exact brand they used. They often have a short post history and the company likely bought out the account and repurposed it to grift. It's just marketing. Then after a period of time after the post stops getting traction they delete the account or delete the post.
 
From my experience I do think anyone with remission from placebo or CBT either didn't have ME in the first place or more likely are grifters selling the program. Any online comment that says they got cured from a CBT style treatment is probably a grifter trying to sell to earn more revenue.

I find it hard to regard people improving on placebo in the Norwegians' trials as grifters. Having seen the pharmacodynamics of the follow on open label phase 2 study it is clear that this is not the only explanation. One cannot discount evidence just because it does not fit one's theory. My experience has been that the way forward in science is always to look for where you might have been wrong and rejoice in learning that the answer was not what you expected!
 
Nevertheless, I think it is possible that at least for Daratumumab, where we do not have negative phase 3 data, that long term remission can be achieved. We then have to consider whether that has to be because of reducing antibody. Looking at the antibody reductions with dara I am a bit sceptical because we have seen similar or greater antibody reductions with rituximab without long term benefit in RA and lupus. One particular patient I tried to get antibody levels as low as I could with cyclo and ritux and she still relapsed early. I think there is a significant possibility that daratumumab is working through a different mechanism.

While I am thinking it is LLPC, if it is a different mechanism, one interesting way to infer it would be to overlay the CD20 vs CD38 expression on various types of immune cells like you posted in an earlier chart. That would let you infer something about mechanism. Or even better have a third overlay that shows the impact of cyclo.

I can't find any charts that show the exact amounts.

Obviously, the biggest CD20-CD38 expression delta is greatest on plasma cells, hence I infer LLPC. But if there is another cell (say dendritic cell) that has a huge delta, that could a possibility as well.

Another unrelated point is that I'm assuming Rituximab also uses NK cells to kill targets and because F/M did not measure NK cell count in their P2/P3 papers for Ritux that is another confounder.
 

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While I am thinking it is LLPC, if it is a different mechanism, one interesting way to infer it would be to overlay the CD20 vs CD38 expression on various types of immune cells like you posted in an earlier chart. That would let you infer something.

I don't think it helps much to be honest. CD20 is pretty much restricted to B cells. And you cannot predict what will happen even if you know markers because cells are protected in different environments in different ways.
 
Do you have any ideas on what that mechanism could be? Also would that mechanism not need to align with the improvements on cyclophosphamide. I see that CD20 is expressed on 3-5% on T cells but CD38 is "As a NAD consuming enzyme, CD38 is closely related to the number and function of T cells"

I mean the way I see it is mechanisms must be inferred from evidence. There must be some data that lets you draw a conclusion, given that the biology of ME is still unknown.

"Looking at the antibody reductions with dara I am a bit sceptical because we have seen similar or greater antibody reductions with rituximab without long term benefit in RA and lupus."

I believe the type of antibody and the source matters here. In Rituximab you would be depleting SLPC antibodies and their precusor B cells but in Daratumumab you would be depleting SLPC and LLPC antibodies. So if the source of faulty antibodies is not hit, you could get an IGG drop but no improvement.
 
From my experience I do think anyone with remission from placebo or CBT either didn't have ME in the first place or more likely are grifters selling the program. Any online comment that says they got cured from a CBT style treatment is probably a grifter trying to sell to earn more revenue.
I find it hard to regard people improving on placebo in the Norwegians' trials as grifters. Having seen the pharmacodynamics of the follow on open label phase 2 study it is clear that this is not the only explanation. One cannot discount evidence just because it does not fit one's theory. My experience has been that the way forward in science is always to look for where you might have been wrong and rejoice in learning that the answer was not what you expected!
I wonder if the issue here is that 'remission' can mean both a complete absence of symptoms and a lessening of symptoms. We've discussed before that placebo effects don't represent any direct biological effects on the body of a person's expectations, but rather their willingness to ignore or downplay symptoms. But I still find it impossible to believe that a PwME at any level of severity can manage for any length of time to behave as though they're well when they're not. It would be tantamount to 'pushing through'. I could do that without crashing for thirty minutes, tops. And as far as we know, spontaneous full remission in people with ME/CFS of several years is very rare. So I find a placebo-driven full remission that just happens to pop up among several PwME out of a few dozen in a trial literally incredible. I'd find a placebo-driven claim for a bit less fatigue more credible, but not one that's showing up over a long period as measured by actimeters.

I wonder if I just have a false idea of the immovability of severity in short time periods, based on my own experience, and based on the lack of data on ME/CFS's natural course. I wonder if there should be a long-term study with actimeters that's simply observational (though I'd rather see the money go to other things).
 
Do you have any ideas on what that mechanism could be? Also would that mechanism not need to align with the improvements on cyclophosphamide.

Sure, blocking CD38 itself - which is involved in activation of all sorts of immune cells. And cyclo modulates activation of lots of immune cells. It is much easier than invoking antibodies.

I believe the type of antibody and the source matters here. In Rituximab you would be depleting SLPC antibodies but in Daratumumab you would be depleting SLPC and LLPC antibodies. So if the source of faulty antibodies is not hit, you could get an IGG drop but no improvement.

Yes but we have taken that into account. Some of our RA patients developed much lower total antibody levels than these on dara, so their LLPC compartments must have been depleted. One or two had to be rescued with IV immunoglobulin. Dara will hit both short and long lived cells and probably does not kill more than half. Our experience would suggest that that is unlikely to be good enough to break a loop, although for ITP it seems that the loop is fairly easily broken.
 
I'm not that up to scratch on biology of CD38 sadly, if I was healthy I would be consuming an immunology textbook but sadly my brain is not.

Would CD38 blocking correlate with baseline NK cell count at all? Since that is one of the stronger findings in the Dara study.

"Some of our RA patients developed much lower total antibody levels than these on dara, so their LLPC compartments must have been depleted."

But isn't CD20 not on LLPC so Ritux cannot deplete it? Or it can... Mella thinks Ritux did deplete CD20+ LLPCs in the Ritux trials, he said in the video. On the other hand you have the failed P3.
 
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I'm not that up to scratch on biology of CD38 sadly, if I was healthy I would be consuming an immunology textbook but sadly my brain is not.

CD38 is increased on immune cells with various forms of 'activation'. It is expressed on NK cells about as much as plasma cells. The more I think about it, the treatment strategy that makes most sense to me is blocking some sort of molecule on the surface of immune cells expressed as part of an active state. So CD38 is at least superficially an interesting candidate. It has enzyme activity and binds various things but I am not sure that its precise roles are well defined yet.

So a correlation of effectiveness with NK cell number makes a lot of sense.
 
But isn't CD20 not on LLPC so Ritux cannot deplete it? Or it can... Mella thinks Ritux did deplete CD20+ LLPCs in the Ritux trials, he said in the video. On the other hand you have the failed P3.

There are lots of ifs and buts. I don't think rituximab kills any plasma cells much. Total Ig levels after rituximab do not fall significantly in the first 3 months in most cases, which they should do if a decent proportion of LLPC were killed. Rituximab starves the plasma cell pool of new recruits so plasma cell numbers should die off with regular rituximab shots. They do but the fall in Ig levels varies a lot between people.

I think we can probably say that short lived plasma cells are mostly in spleen and last 3-6 months, and long lived plasma cells are mostly in bone marrow and last maybe 1-10 years. Some people's LLPC seem only to last about a year and so their Ig levels drop over that time. Others can be B cell depleted for 5 years and not get much drop.

The reason for mentioning the RA case is that our experience with all the autoimmune diseases we treated was that we did not seem to be able to break a cycle even if Ig levels fell to below 50% - sometimes down to 25%. Mechanistically it makes sense that if you leave plasma cells behind that can keep the disease going by re-igniting a loop when B cells come back you probably do not need more than 10% or even 1% of the bad antibodies around. So that made sense.

It is worth noting that for us it is necessary to assume that plasma cells carry on the 'disease memory' by making antibodies that can pass on bad educational practices to new B cell and plasma cell clones over decades. If LLPC in autoimmune diseases were to keep the disease going simply because they were a bad set of antibody producers then the disease should fade away over ten years or so. Mostly we have no evidence for that. And when B cells return after rituximab we know that very often autoantibody levels come back up again smartish, indicating that new cells are being educated into bad ways.
 
I can see the idea of memory being in Lupus as the evidence is patients need to be on long term treatment if not it comes back.

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.

Many of us patients like me were perfectly healthy after infection and then a single bout of exercise triggered CFS. If I ever recover I will not be doing any exercise and probably swear off it for life, because of the experience I had.

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 course it could be too soon to tell, but the fact that patients exercised (one of the ladies did bodypump) and not relapsed is quite telling.

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

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.
 
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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.
Many of us patients like me were perfectly healthy after infection and then a single bout of exercise triggered CFS. If I ever recover I will not be doing any exercise beyond brisk walking because of this phobia.
I don’t think you can use those anecdotes to infer that exercise «triggered» ME/CFS. And if you no longer have whatever ME/CFS turns out to be, exercise would be no issue.
 
I don’t think you can use those anecdotes to infer that exercise «triggered» ME/CFS. And if you no longer have whatever ME/CFS turns out to be, exercise would be no issue.
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)

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.
 
There is also a small anecdote in the paper where FM mention two patients who improved transiently on Bortezomib.

Bort depleted plasma cells but does not work through CD38. Granted there is a paper saying LLPCs resist Bort.

I am quite curious on your claim that LLPC lives up to 10 years. There is papers online saying decades or even worse, for lifespan.
 
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