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

[Jonathan Edwards]

I spoke with Jo Cambridge today and she reminded me that apart fromCD24, CD38 was the most interesting marker on ME/CFS B cells in her studies with Chris Armstrong. What that means, I don't know either, but perhaps it is all linked.

 

[ryanc97]

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?

No worries

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.

could numbers be a proxy for how healthy the persons NK cell generating process is?

 

[hotblack]

I spoke with Jo Cambridge today and she reminded me that apart fromCD24, CD38 was the most interesting marker on ME/CFS B cells in her studies with Chris Armstrong. What that means, I don't know either, but perhaps it is all linked.

We’re they both overexpressed?

 

[Jonathan Edwards]

We’re they both overexpressed?

yes, for cd38 in response to TLR4 ligation.

 

[Stuart79]

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/

 

[ryanc97]

If IGG4 downregulates NK cells why did the responders with mean IGG4 0.6 have higher NK cell counts (mean 230)?

 

[Stuart79]

If IGG4 downregulates NK cells why did the responders with mean IGG4 0.6 have higher NK cell counts (mean 230)?

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.

 

[Jaybee00]

yes, for cd38 in response to TLR4 ligation.

Can we have a plain English translation of this for us lower IQ folks? Thanks.

 

[Jonathan Edwards]

Can we have a plain English translation of this for us lower IQ folks? Thanks.

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.)

 

[Utsikt]

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.)

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?

 

[ryanc97]

C

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.

Can you explain further? I don’t get it

 

[Jonathan Edwards]

Does that mean that Dara would target those B cells to a larger degree in pwME/CFS compared to healthy people?

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.