Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al

forestglip said:
I'm not totally sure what this means and I have to take a break for now. Just a scatter plot of mean SF-36 over the whole study to the baseline NK? What would this show?
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No worries
Jonathan Edwards said:
To be honest none of the measures of NK cells we have may tell us much. Numbers in blood do not tell us how many can get to a target. Numbers are probably of some relevance but we do not know how much. Numbers need not correlate with function at all.

I think the separation of responders on NK numbers is impressive, but what it means I don't know.
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could numbers be a proxy for how healthy the persons NK cell generating process is?
 
If ME/CFS worked like MuSK Myasthenia Gravis wherein IgG4 blocks a protein (without T-cell involvement and skewing male as in IgG4 related diseases) would that fit the data? It looks like IgG4 downregulates NK cells, so maybe that fits? Also, it looks like in IgG4 diseases sometimes Rituximab works, but not always. When Rituximab doesn't it work, Dara has been tried with success according to case reports like this one: https://pubmed.ncbi.nlm.nih.gov/39180414/
 
Jaybee00 said:
Can we have a plain English translation of this for us lower IQ folks? Thanks.
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Yes, the paper has a thread here somewhere. My memory is that Jo said that the increase in CD38 on B cells was seen when they were stimulated using a bacterial product (the chemical motif CPG DNA) that binds to the innate Toll-like receptors (and other things). I said Toll-like receptor 4, which we talked about, but I think TLR-9 may be as important. We didn't discuss the details further.

Basically the B cells were much more easily activated by an innate signal. (Not a specific antigen but a generic foreign motif.)
 
Jonathan Edwards said:
Yes, the paper has a thread here somewhere. My memory is that Jo said that the increase in CD38 on B cells was seen when they were stimulated using a bacterial product (the chemical motif CPG DNA) that binds to the innate Toll-like receptors (and other things). I said Toll-like receptor 4, which we talked about, but I think TLR-9 may be as important. We didn't discuss the details further.

Basically the B cells were much more easily activated by an innate signal. (Not a specific antigen but a generic foreign motif.)
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Does that mean that Dara would target those B cells to a larger degree in pwME/CFS compared to healthy people?

And was this shift clear in everyone, or just a subgroup? Is this where e.g. genetic vulnerabilities could come into play, and Dara working better for the people with an increase in CD38?
 
Stuart79 said:
Perhaps IgG4 downregulates NK cells below the threshold needed to clear IgG4 LLPCs, so you have a bit of a feedback loop than need to be broken for some.
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Can you explain further? I don’t get it.

If IGG4 down regulates NK cells the responders with higher IGG4 should have lower not higher NK cells no?
 
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Utsikt said:
Does that mean that Dara would target those B cells to a larger degree in pwME/CFS compared to healthy people?
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That feels like one of those wires-crossed thought moments to me. You don't give Dara to healthy people! Why do you ask?

The paper has a thread here somewhere. It has figures with individual data points. Best to look at that. There was a lot of overlap with controls but the differences were quite clear.
 
Is it this thread? It's about one paper but also contains a link to another.

E

Thread 'In vitro B cell experiments explore the role of CD24, CD38 and energy metabolism in ME/CFS, 2023, Armstrong et al'

In vitro B cell experiments explore the role of CD24, CD38 and energy metabolism in ME/CFS


Disturbances of energy metabolism contribute to clinical manifestations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Previously we found that B cells from ME/CFS patients have increased expression of CD24, a modulator of many cellular functions including those of cell stress. The relative ability of B cells from ME/CFS patients and healthy controls (HC) to respond to rapid changes in energy demand were compared. CD24, the ectonucleotidases CD39, CD73, the...
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Jonathan Edwards said:
That feels like one of those wires-crossed thought moments to me. You don't give Dara to healthy people! Why do you ask?

The paper has a thread here somewhere. It has figures with individual data points. Best to look at that. There was a lot of overlap with controls but the differences were quite clear.
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You know what, that’s a very good question. I can’t even remember why I wondered about this.
 
Jonathan Edwards said:
yes, for cd38 in response to TLR4 ligation.
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If this is the case are we looking at Immature or Transitional B Cells?

human studies have, by and large, described a rather homogeneous population of transitional B cells (T1/T2) defined by the expression of high levels of CD24, CD38 and CD10.
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https://en.m.wikipedia.org/wiki/Transitional_B_cell

I also read that CD38 can influence intracellular calcium levels. In the linked thread on the paper there was discussion of energy production, but what about implications for electrical changes? Or can thee and metabolism be seen as sort of the same thing?

I wonder if it could be something which links both changes in localised energy usage/production and changes in potentials around synapses, so tie up the two muscle/neuron cell pieces?

Also interesting that long term depression shows up as a link to CD38 in gene ontology, I do wonder how much that correlation we keep seeing is related to problems at the synapse in both depression and ME/CFS
https://en.m.wikipedia.org/wiki/CD38
 
hotblack said:
I wonder if it could be something which links both changes in localised energy usage/production and changes in potentials around synapses, so tie up the two muscle/neuron cell pieces?
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It would be amazing if this did all tie together, but it takes me a log time to absorb each fact and make a connection. This is why an open discussion forum is so useful.
 
hotblack said:
I wonder if it could be something which links both changes in localised energy usage/production and changes in potentials around synapses, so tie up the two muscle/neuron cell pieces?
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That’s exactly the speculation I was tossing around earlier in the thread :) there’s definitely a point of relevant overlap—in another thread I posted a link connected neuron firing to intracellular calcium signaling and mtDNA regulation via CAMKII. Plus this same signaling cascade happens during contraction in muscles. Long story short, the mitochondria are extremely sensitive to calcium as a regulator, and also are able to affect intracellular calcium levels.

Immune cell “activation” nearly always requires a rewiring of that cell’s metabolic functioning, and calcium signaling is one way that this could be mediated. These metabolic changes usually include changes in glycolytic or OxPhos pathways, but one potentially relevant related phenomenon is mtDNA release which triggers interferon production. The Paulenda et al. paper showed that this drives TLR responses in macrophages, and it’s also one of the main theories for how Cyclosporin works for T cells (by blocking the mPTP—a calcium-sensitive pore in the mitochondrial membrane that mtDNA exits through).

Basically, it seems like multiple immune cells have evolved to respond in slightly different ways to external stimuli by a chain of events that causes their own mtDNA to be released and trigger a reaction as if the cell was detecting DNA from a foreign pathogen. Kind of like hearing an alarm far outside and mobilizing everyone who is asleep in your house by holding up a flame to the closest fire alarm. it’s a somewhat bizarre system but it’s how our immune system evolved.

I haven’t seen specific documentation of it in B cells but the wiring would be similar with what goes on in macrophages, so it’s not hard to imagine that something in this calcium signaling pathway get globally primed (involving CD38) and that explains the enhanced reactivity to TLR.
 
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