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

[Jonathan Edwards]

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

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

Why would it not be good for the NK cell levels to indicate subtypes?

Problems would not come back if by temporarily blocking CD38 daratumumab allowed a vicious cycle of unwanted cell activation to collapse. If, for instance, the cycle was fed by subpopulations of T cells misinterpreting each others' signals in tissue compartments that had been expanded to a critical level then calming everything down might drop things below that level. In psoriasis we see T cells arguing with other cells in skin and other tissues for months or years but then quietening down. In Reiter's they argue for a few months and then usually give up long term. If you abolish inflammation in a knee joint with a high local dose of steroid you can induce resolution of the local inflammation for good. So we know that T cell based interactions can sometimes be switched off with a one off intervention.

(When I say T cells here I am really meaning any non-B lymphocyte subset you like, including NK, MAIT etc.)

 

[Jonathan Edwards]

We have been discussing how disease persistence may be carried over by 'loops' or re-iterated signalling pathways. That requires some sort of reset of some cell group to signal too much. In autoimmune disease we can attribute that to the known positive feedback loop in antibody production, based on acquired mutations in B cell Ig genes. For T cell diseases expansion of clones with somatic mutations of T cell receptors would do, but there might also be expansion of innate T populations that maintain their bad actions through aggregation at certain sites such that above a certain number faulty signalling keeps itself going. Jnmaciuch has suggested that the persistence might be an epigenetic shift in resident tissue cells.

All of these potential mechanisms are likely to be dependent on local concentrations of cells in an active signalling state. That is certainly true for B cells where the key events occur in follicular clusters with interdigitating dendritic cells. A period of signal blocking that encourages cells to wander off and ignore each other may have the potential to break the cycle. And it does seem as if we need to invoke some sort of cycle, since both somatic mutation and epigenetic explanations seem unlikely to persist lifelong without some sort of reinforcement. It is also difficult to explain fluctuating disease with long remissions and relapse with just one permanent change in cell programming.

 

[Utsikt]

I think it is fair to take the line you do in scientific discussions- after not from - but to expect patients and advocates to do so outside of a scientific context is asking too much. People should be able to name the evil that has been committed against them.

People are obviously free to express their interpretations of their experiences. I’m arguing in the context of a forum focused specifically at science.

The vultures will descend to pick apart what we say no matter if we're perfect or not. Look at what they've said about DecodeME. Facts don't matter to them.

I think you can see the contradiction here. They are not picking apart what we are saying when we apply the highest standards. They are ignoring the facts, and ignoring the flaws of their own arguments. I.e. ignoring the standards.

I do sort of resent this idea that we as pwME have to be perfect like this. I understand why, but outside of the scientific advocacy we do on here I think it is too much of an ask.

Personally I don’t mind the standards at all, but that might be because of my own preferences and world view. Although I don’t think we can expect anyone else to follow them if we do not do so ourselves.

There is something extraordinarily cruel about the way pwME/CFS have been treated, and we can be certain that great harm has been caused. It’s grossly unfair that those causing harm are getting away with thing we could never get away with ourselves. We live in a world of hypocrisy, at the expense of those who don’t have.

 

[ryanc97]

I'd like to understand the link between the CD38 theory and the NK cell baseline count argument. For LLPC it comes from the same results in MM where NK cell count also predicts response.

 

[EndME]

I'd like to understand the link between the CD38 theory and the NK cell baseline count argument. For LLPC it comes from the same results in MM where NK cell count also predicts response.

As far as I recall the NK measurements in the MM study are not the same as in the Fluge and Mella study and might have nothing to do with each other?

 

[Jonathan Edwards]

I'd like to understand the link between the CD38 theory and the NK cell baseline count argument.

I don't think anyone has any definite explanation other than that if CD38 is the functional target, and whatever intereaction it mediates involves NK cells then NK cell numbers might correlate.

 

[jnmaciuch]

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

How does high NK cell here predict a good response?

I think the NK cell counts would simply be an indication that this person’s disease is driven by a specific mechanism that overlaps with the enzymatic activity of Dara. If the person has low NK counts, it might indicate a different disease subtype driven by a different signaling pathway and doesn’t have the same effect on NK cells.

1. NK cell count at baseline being linear and predictive in response which is also seen in cross section in MM studies implying same mechanism

A mechanism which encouraged NK cell proliferation independent of Dara’s effect on ME/CFS symptoms could present with the same trend.

Like I said, it’s just an alternative story—I don’t have specific evidence for why it must be true over an antibody-NK cell targeting theory other than the fact that the alternative theory fits well with other theoretical mechanisms that might explain why activity leads to PEM (which I’ll be biased towards since it’s my idea).

I mostly bring it up to encourage not overinterpreting the NK cell dependency because more than one explanation would lead to the same trend, and there are other reasons to think that a theory involving a specific antibody is inconsistent with disease presentation, as others have pointed out.

 

[OrganicChilli]

Can't the NK cell count fluctuate over time? We have no data for pwME, but might have data for healthy people/other illnesses? Or do we assume if the NK cell count is low today someone will always be a non-responder because their specific ME/CFS subtype suppresses NK cells?

 

[forestglip]

As far as I recall the NK measurements in the MM study are not the same as in the Fluge and Mella study and might have nothing to do with each other?

The Fluge paper looked at "CD16/56 positive NK cells" and found higher baseline levels correlate with recovery.

From multiple myeloma paper:

We show reduced proportion of CD16+ cytotoxic NK cells in a subset of patients at diagnosis, which correlated with decreased cytokine production and NK-cell degranulation against MM cells in the presence of the anti-CD38 antibody daratumumab. In line with these findings, a low proportion of CD16+ bone marrow NK cells at diagnosis was associated with a reduced likelihood of achieving measurable (or minimal) residual disease (MRD) negativity

So they seem similar. I don't know the implication of the difference in the ME/CFS study also including CD56 though.

 

[jnmaciuch]

And it does seem as if we need to invoke some sort of cycle, since both somatic mutation and epigenetic explanations seem unlikely to persist lifelong without some sort of reinforcement

I agree—it’s one of the reasons an epigenetic theory of interferon regulation appeals to me. If I’m right about synaptic firing being able to cause mtDNA release (and subsequent sterile anti-viral response) in neurons via a calcium-dependent mechanism, the floodgates could be continually kept open just by regular brain activity. Or muscle use.

It could potentially explain long term remission from Dara as well, if it is causal—if CD38’s enzymatic activity in calcium signaling is blocked, it might work to suppress the aberrant release of mtDNA in response to calcium flux. With substantially less sterile anti-viral response, chromatin remodeling would occur stochastically and stay closed until the next infection. At which point all the pieces might be in place to allow for proper resolution of the infectious response this time around.

 

[ryanc97]

Can't the NK cell count fluctuate over time? We have no data for pwME, but might have data for healthy people/other illnesses? Or do we assume if the NK cell count is low today someone will always be a non-responder because their specific ME/CFS subtype suppresses NK cells?

Yeah this is the million dollar question, perhaps the responders happened to have high NK cells, because of certain supplements they took (e.g vitamin D).

So the question is, are NK cell counts sticky or mean reverting/stationary/whatever statistical term you want to use.

One way would be to do a longitudinal study sampling NK cells of diff patients over time and see how much variance there is in the time series.

Anecdotally I know a few people in my group that I'm in that have NK cells declined quite significantly over time as they took tests

 

[ryanc97]

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.

If they don't, then the alternative theory has more weight.

Sadly only Leo Habets and some self-experimenters are doing that right now....

 

[EndME]

So they seem similar. I don't know the implication of the difference in the ME/CFS study also including CD56 though.

I don't see any reason to think that. Bone marrow NK composition and peripheral blood NK composition are different things (and there's the difference between single-cell transcriptomics and routine clinical flow cytometry NK counts and how the experiments were conducted, things I have no idea about). If the peripheral blood NK composition would already have been predicative in the MM daratumab trial, they probably wouldn't have to gone through the much bigger problem of dealing with bone marrow sampling.

We should not forget that the MM study popped up because somebody google searched "low NK cells+Daratumumab" of course one can almost always find something to supports once view point if this is the approach taken. This is just sampling bias and others have mentioned that NK assays are notoriously difficult to interpret, so the chance of chance findings is probably particularly high.

 

[jnmaciuch]

What mechanism would that be?

One logical possibility is a CD38-TNFa/NFkB loop per one of my previous posts. Given that CD38 is expressed in and on NK cells themselves it could be cell autonomous loop, explaining why we don’t see signs of strong extracellular TNF signaling in the blood or tissue.

The paper that I shared earlier pointed to glycolytic rate as a pretty central mediator of NK cell proliferation (being downstream of TNF signaling in NK cells), so that opens the possibility of any number of mechanisms that can metabolically reprogram NK cells in this way, including immune and non-immune signaling (as much as that distinction is a coherent one).

That’s one of the reasons I’m not inclined to put much weight on NK cell dependency here—the suite of things that could affect their proliferation rate is unfortunately pretty large. The burden of proof would be on the antibody-NK cell targetting theory to eliminate other possible explanations for the correlation

 

[ryanc97]

We should not forget that the MM study popped up because somebody google searched "low NK cells+Daratumumab" of course one can almost always find something to supports once view point if this is the approach taken. This is just sampling bias and others have mentioned that NK assays are notoriously difficult to interpret, so the chance of chance findings is probably particularly high.

These studies exist because people know Daratumumab uses NK cells to do work and obviously the people who administer them want to figure out why it may or may not work in their cancer patients.

If this correlation didnt exist in MM, these papers would not exist and this argument would not either.

 

[EndME]

We should not forget that the MM study popped up because somebody google searched "low NK cells+Daratumumab" of course one can almost always find something to supports once view point if this is the approach taken. This is just sampling bias and others have mentioned that NK assays are notoriously difficult to interpret, so the chance of chance findings is probably particularly high.

To show the problems with this approach I just googled "low NK cells+B-cell depletion+success" and was given an abundance of studies, for example: https://pubmed.ncbi.nlm.nih.gov/37081607/. I think we have to be careful comparing things that might have nothing to do with each other simply because they contain similar terminologies.

 

[EndME]

These studies exist because people know Daratumumab uses NK cells to do work and obviously the people who administer them want to figure out why it may or may not work in their cancer patients.

Yes, but shouldn't the conclusion of that then be peripheral measurements looking at the count have yielded no results, which is why they had to dig deeper to figure out what's going on, not the opposite?

 

[forestglip]

Bone marrow NK composition and peripheral blood NK composition are different things

Oh sorry you're right, I totally skipped over that both the MM studies in that thread are about bone marrow NK cells, not blood.

 

[EndME]

You do realize Rituximab is a MAB right and also recruits NK cells to do work right.... obviously Rituximab being effective is dependent on NK cells beacuse no NK cells = less killing...

Yes, but the point is an entirely different one. There's so many NK cells for B-cell depleting medications studies (for the reasons mentioned) that you can find any result you wish to find if you look for it but there is no indication that for example the MM NK cell finding you are comparing the Fluge and Mella finding to actually have anything in common.

 

[ryanc97]

To show the problems with this approach I just googled "low NK cells+B-cell depletion+success" and was given an abundance of studies, for example: https://pubmed.ncbi.nlm.nih.gov/37081607/. I think we have to be careful comparing things that might have nothing to do with each other simply because they contain similar terminologies.

This argument only works if you found two opposing studies showing low NK cells and high NK cells both correlated with success in Daratumumab treatments and you selectively pick one and ignore the other. That is sampling bias.