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

[Jonathan Edwards]

It's hard to draw everything together without ending up with a huge post. I think the arguments are there in the thread - and in the Qeios paper, which has a thread.

It might be antibody related, but I think other possibilities deserve serious thought.

 

[Kitty]

?

Possibly Cover Your Ass, though it could have a much more sciency-related meaning!

 

[ryanc97]

Might be off topic but I have managed to get my NK cells from 49/μL (2nd Aug) to 92/μl (2nd Sep) with a protocol of blueberries, zinc, vit D/C/E, high dose melatonin. I hope it keeps going up.

Next test on 17th Sep Wed. Results take 2W.

 

[Jaybee00]

blueberries

Like how much blueberries?
500g/day? I could probably eat that much no problem.

 

[ryanc97]

https://pubmed.ncbi.nlm.nih.gov/22111516/ is the reference study. I think it was 300 to 600 in healthy athletes over a few months of 250g blueberry equivalent (in powder)

I'm doing 125g a day because they arent cheap in Singapore, it would be $3 USD for a 125g tiny box.

 

[DHagen]

Might be off topic but I have managed to get my NK cells from 49/μL (2nd Aug) to 92/μl (2nd Sep) with a protocol of blueberries, zinc, vit D/C/E, high dose melatonin. I hope it keeps going up.

Next test on 17th Sep Wed. Results take 2W.

May I ask the reasoning behind this? I assume that this is related to dara (please correct me if I am wrong) - is your thinking that the difference between responders and non-responders lies in the NK cells themselves, rather than in some upstream process, so you want to get your NK cells as high as possible? Or is there some other reason for wanting high NK cells?

I had never paid much attention to my own NK cells until recently; looked at last test results and noted that I am at 283/μL Ab NK (CD56/16) and 21.8% NK cells (interestingly, t-cells are apparently slightly low?).

 

[ryanc97]

May I ask the reasoning behind this? I assume that this is related to dara (please correct me if I am wrong) - is your thinking that the difference between responders and non-responders lies in the NK cells themselves, rather than in some upstream process, so you want to get your NK cells as high as possible? Or is there some other reason for wanting high NK cells?

I had never paid much attention to my own NK cells until recently; looked at last test results and noted that I am at 283/μL Ab NK (CD56/16) and 21.8% NK cells (interestingly, t-cells are apparently slightly low?).

Well yes if NK cells are the predictor of response because of ADCC mediated CD38 cell killing then my logic is to boost NK cells as high as possible, then take Dara.

283 is pretty good.

From limited anecdotes it seems severity is not correlated to NK cell count (we saw this in the study already), I am an example, mine is 50 (super low) but I would classify as mild.

Also wondering if it really is low NK cells being a non responder subset... if you can boost them up.... are you still in the subset or not?

 

[ryanc97]

@Jonathan Edwards could you think of a reason why for CD38 binding, the response would take 2 months?

Would a feedback loop be pretty quick?

The scores for SF36 all started going up in tandem around the 6W mark (3rd dose) in responders. So if it was AABs, then it could be like the supply was cut off, but the remaining AABs in the blood still circulate. Given a 3W half life at 6W they would be 75% consumed/finished.

I think it is interesting to note the SF36 scores were not linear in time, they were flat until the 6W mark.

So to me, it would be like gas/fuel in a pipe feeding a power plant. The supply is cutoff and the remaining fuel is pumped into the power plant. At the 6W mark, almost all the fuel is consumed and the plant shuts down.

 

[Jonathan Edwards]

@Jonathan Edwards could you think of a reason why for CD38 binding, the response would take 2 months?

It's a very interesting question.

I have no idea how long it would take to quieten down T cells by blocking CD38. My guess would be a week or two but I think it could be longer. There might be artefactual aspects to when people say they are better. If they are pacing it might take them a week or two to be sure they are really able to do more with impunity. There might be expectations that more than one dose was needed to produce an effect.

But antibody attrition does present a possible explanation. It is a bit quick for that but maybe these are antibodies with short life spans.

 

[ryanc97]

Definitely something that the response was not linear in time but piece-wise after 6 weeks.

If the patients were not in communication with one another (e.g all together in a whatsapp group updating each other) then it would be quite a coincidence indeed.

 

[EndME]

If the patients were not in communication with one another (e.g all together in a whatsapp group updating each other) then it would be quite a coincidence indeed.

I think this is quite a worry with many of trials currently happening in this sphere because it is often that case that a majority of participants are indeed communicating with each other. That cannot be neglected (some of the decentralised trials have essentially even been recruiting patients from specific social media channels where they communicate with each other). Unfortunately, we've even seen researchers sharing results of unblinded trials on social media whilst they are still ongoing.

I'm not a fan of NDA clauses but I think social media has changed that in the context of ongoing trials. Even for double blinded randomised placebo-controlled trials there are non-negligible risks (I've seen patients that are sharing extremely detailed accounts whilst the trial is ongoing often including specific side effects, results of objective measurements, how they made it into the trial etc). I think this is something that has to thought about.

We've seen some people faking medical information to be part of trials or abort them as soon as they don't get the same reaction as their friends in the trial. If the sample sizes are large enough and there's a placebo that offers a perfect control the risks seem fairly low but quite often that is not the case.

I do have the feeling that things with Fluge/Mella are generally better, especially since they are not "influencer scientists", but then again I'm also not part of any Norwegian communities.

 

[Utsikt]

I do have the feeling that things with Fluge/Mella are generally better, especially since they are not "influencer scientists", but then again I'm also not part of any Norwegian communities.

I’m part of some of the larger groups, and I’ve not seen anything from the patients before the results were made public. But I might have missed some.

 

[ryanc97]

I think this is quite a worry with many of trials currently happening in this sphere because it is often that case that a majority of participants are indeed communicating with each other. That cannot be neglected (some of the decentralised trials have essentially even been recruiting patients from specific social media channels where they communicate with each other). Unfortunately, we've even seen researchers sharing results of unblinded trials on social media whilst they are still ongoing.

I'm not a fan of NDA clauses but I think social media has changed that in the context of ongoing trials. Even for double blinded randomised placebo-controlled trials there are non-negligible risks (I've seen patients that are sharing extremely detailed accounts whilst the trial is ongoing often including specific side effects, results of objective measurements, how they made it into the trial etc). I think this is something that has to thought about.

We've seen some people faking medical information to be part of trials or abort them as soon as they don't get the same reaction as their friends in the trial. If the sample sizes are large enough and there's a placebo that offers a perfect control the risks seem fairly low but quite often that is not the case.

I do have the feeling that things with Fluge/Mella are generally better, especially since they are not "influencer scientists", but then again I'm also not part of any Norwegian communities.

Well im quite sure they didnt communicate with each other because the woman in the IG video has no idea who the other participants are.

 

[EndME]

Well im quite sure they didnt communicate with each other because the woman in the IG video has no idea who the other participants are.

Yes, I think it's plausible that its a non-issue for the Fluge and Mella trial (even if one person not knowing other participants doesn't rule out other communications between participants), my comments were supposed to be more general than that but probably not quite fitting to this thread.

 

[ryanc97]

I'd like to summarize my thoughts on the study. So it seems we have two mechanisms of it working and one not.

1. CD38 being the problem
2. Faulty LLPCs being the problem
3. Improvement was due to chance, drug doesn't work.

For 2, the main arguments for:

* NK cell correlation was high with response = more ADCC. Very strong correlation.
* Same NK cell function is seen in recovery rates in MM patients using Dara.

Against:

* IGG drop was quite similar across responders/non-responders despite NK cell differences.
* Somehow, healthy antibodies from vaccination remained suggesting the healthy LLPC were less affected. So it's either the faulty LLPC were killed off or hardly any LLPC were touched at all and the improvement came from blocking CD38.

Unknown:

* Vaccinated antibodies from LLPCs remained in all patients. If LLPC theory was true, this means that somehow, Dara selectively targets faulty LLPCs and leaves the normal healthy ones alone. This implies somehow maybe more CD38 on faulty LLPCs or they are more prone to dying out. This means Dara is even more of a silver bullet.

What evidence would we need to narrow in on the correct theory? The P2 will tell us the probability of 3 being true but not the probabilities of 1 and 2.

* Any LLPC depleters that don't use CD38 working e.g Teclistamab in Habets patients will strongly support or refute the LLPC theory. We have to wait and see.
* Non responders being re-administered Dara as they had higher NK cells in responder range post study.
* The supposed trial by Scheibenbogen and Sanofi using Isatuximab. Again it will tell us more on 3 being true or not but not 1 or 2.

@Jonathan Edwards

 

[forestglip]

I'd like to summarize my thoughts on the study. So it seems we have two mechanisms of it working and one not.

1. CD38 being the problem
2. Faulty LLPCs being the problem
3. Improvement was due to chance, drug doesn't work.

I think also:

1. Faulty T cells being the problem
2. Faulty NK cells being the problem
3. Some other cell that expresses CD38 being the problem.

* Somehow, healthy antibodies from vaccination remained suggesting the healthy LLPC were less affected. So it's either the faulty LLPC were killed off or hardly any LLPC were touched at all and the improvement came from blocking CD38.

I don't think they say anything about exact levels of protective antibodies, just that they're still at protective levels at 12 months, so maybe, say, ~25% of the protective antibodies were killed as well as ~25% of the LLPCs that cause disease, and a 25% decrease was enough to see substantial improvement.

Also, as I brought up before, I wonder if the NK cell correlation being in the blood might suggest that the problem cells that need to be killed are easily accessible from the blood compartment (i.e. not LLPCs in the bone marrow). If the vaccine antibody secreting cells are mostly in the bone marrow, but the dara dose wasn't high enough to really kill them, but it was high enough to kill the problem cells somewhere else, that might explain it.

I don't know a lot about the types of LLPCs, but I think maybe the spleen, lymph nodes and other secondary lymphoid organs sometimes house more "innate-like" plasma cells like the marginal zone B cells in the spleen, and maybe that's what the dara needs to kill.

Edit: I'm not sure what I said is right for MZ B cells. I don't know if the plasma cells they turn into are less likely to go to bone marrow, or if they become long lived plasma cells at all.

 

[ryanc97]

I think also:

1. Faulty T cells being the problem
2. Faulty NK cells being the problem
3. Some other cell that expresses CD38 being the problem.


I don't think they say anything about exact levels of protective antibodies, just that they're still at protective levels at 12 months, so maybe, say, ~25% of the protective antibodies were killed as well as ~25% of the LLPCs that cause disease, and a 25% decrease was enough to see substantial improvement.

Also, as I brought up before, I wonder if the NK cell correlation being in the blood might suggest that the problem cells that need to be killed are easily accessible from the blood compartment (i.e. not LLPCs in the bone marrow). If the vaccine antibody secreting cells are mostly in the bone marrow, but the dara dose wasn't high enough to really kill them, but it was high enough to kill the problem cells somewhere else, that might explain it.

I don't know a lot about the types of LLPCs, but I think maybe the spleen, lymph nodes and other secondary lymphoid organs sometimes house more "innate-like" plasma cells like the marginal zone B cells in the spleen, and maybe that's what the dara needs to kill.

Or it could be that the blood NK cells are a proxy of NK cells in the bone marrow.

Regarding the antibodies, could that really be the case?

I would expect if it is LLPC related even any faulty LLPC that is not cleared out could result in not being permanently cured. So it me it’s like the faulty LLPC must be wiped out

 

[forestglip]

Or it could be that the blood NK cells are a proxy of NK cells in the bone marrow.

Maybe, but if blood count was a good proxy for bone marrow count, I'd expect studies showing that blood NK count in multiple myeloma correlates with improvement from dara, but I haven't seen such a study.

Regarding the antibodies, could that really be the case?

I would expect if it is LLPC related even any faulty LLPC that is not cleared out could result in not being permanently cured. So it me it’s like the faulty LLPC must be wiped out

I don't think it's impossible. Maybe the body can deal with the antibodies from, say, 1000 bad LLPCs, but 1200 starts to overwhelm the body's homeostasis mechanisms.

Maybe they're not even necessarily "bad" plasma cells, and it's just too many of a normal type of plasma cell.

 

[forestglip]

I wonder if the NK cell correlation being in the blood might suggest that the problem cells that need to be killed are easily accessible from the blood compartment

I think maybe the spleen, lymph nodes and other secondary lymphoid organs sometimes house more "innate-like" plasma cells like the marginal zone B cells in the spleen, and maybe that's what the dara needs to kill.

It'd would be good to know how correct this is about, for example, spleen plasma cells being mostly non-specific. That's just what I remember from an intro to immunology textbook.

Maybe high IGHV3-30 from the other studies might also point to overly high levels of non-specific innate-like plasma cells.

Probably pretty far into speculative territory though.

I wonder if some genes, over the course of evolution, like 3-23 and 3-30, have proven themselves to be more useful against the kinds of pathogens humans encounter, so are upregulated. And maybe there are signals in the body that can upregulate them further in preparation without the B cells actually seeing the antigen.

Maybe there are studies of B cell repertoires of different innate-like plasma cells that might show a population with high IGHV3-30.

 

[ryanc97]

Maybe, but if blood count was a good proxy for bone marrow count, I'd expect studies showing that blood NK count in multiple myeloma correlates with improvement from dara, but I haven't seen such a study.


I don't think it's impossible. Maybe the body can deal with the antibodies from, say, 1000 bad LLPCs, but 1200 starts to overwhelm the body's homeostasis mechanisms.

Maybe they're not even necessarily "bad" plasma cells, and it's just too many of a normal type of plasma cell.

On a gut feeling I think the thing that separates PWME from healthy people (aka all of us before we got it)

Is we have these special LLPCs that continuously churn out poison. So if you get rid of them, you become healthy again. Of course not scientific.

For the studies, are there studies that showed difference in blood vs bone marrow NK cells? They have to measure both.