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 might add that poor old Jo Cambridge has been trying to persuade people along these sorts of lines for about five years now and I couldn't work out how to click it into place. I still can't but I have much more of a sense that it could.

B cells used to be very underrated - treated as the private ranks under control of T cell brigadiers. Jo and I did our best to disabuse people. I was surprised to find that they use TLR-4. Jo thinks CD24 and CD38 are keys to what is going on in ME/CFS. They are both linked to switches in metabolic strategies it seems.

 

[OrganicChilli]

Would we need something that inhibits CD24 in addition to CD38?

 

[hotblack]

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

Ohhh, I need to go back through some posts then. Quite likely I read something and it lurked somewhere until it made sense with ither things I’ve been reading!

If you have the capacity to expand on this at all I'd be really interested to hear about it.

Sure, I will try to post some wild speculations at some point. It’s all vey high level and hand wavey stuff, it’s impossible not to see connections all over the place with the nature of the human mind and something as complicated as human biology.

One snappy phrase that came to mind was.. if MS is a disease of action potentials then maybe ME/CFS is a disease of graded potentials?

The difficult bit though is not coming up with connections but finding the significant ones and proving them, something I think there’s only a few on these forums with the capacity and resources to do.

 

[jnmaciuch]

Ohhh, I need to go back through some posts then. Quite likely I read something and it lurked somewhere until it made sense with ither things I’ve been reading!

It was this thread:
Thread 'Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice, Li et al. (2024)'
https://www.s4me.info/threads/boost...s-cognition-in-aged-mice-li-et-al-2024.45820/

This specific paper looks at mtDNA transcriptional regulation, not mtDNA release. But I made the connection because the CAMKII signaling pathway identified in the study interacts with VDAC, which is another calcium pore that mtDNA gets released through.

And, notably, VDAC-mediated mtDNA release has been implicated in an interferon response in pathological muscle conditions (https://www.nature.com/articles/s41419-024-06863-8) and can occur without killing the cell unlike other methods of mtDNA release (https://pmc.ncbi.nlm.nih.gov/articles/PMC8325171/).

It just seemed like quite a neat way of solving the puzzle if the same pathway could be triggered in neural activity, muscle activity, and TLR stimulation of immune cells. Plus the fact that this pathway culminates in an interferon response, which already seemed like a good candidate for explaining PEM symptoms since the side effects of interferon therapy sound pretty much like PEM to me.

 

[Verity]

It just seemed like quite a neat way of solving the puzzle if the same pathway could be triggered in neural activity, muscle activity, and TLR stimulation of immune cells. Plus the fact that this pathway culminates in an interferon response, which already seemed like a good candidate for explaining PEM symptoms since the side effects of interferon therapy sound pretty much like PEM to me.

This might be a silly question (I’m way in over my head here, sorry), but you mentioned Saphnelo to me in another thread. Would it potentially work for ME if the problem you’re describing is the correct one?

 

[ryanc97]

If someone could persuade F/M to run a concurrent Teclistamab trial and see responses that would give good evidence real quick since Teclistamab targets SLPC/LLPC but not via CD38 at all.

 

[jnmaciuch]

This might be a silly question (I’m way in over my head here, sorry), but you mentioned Saphnelo to me in another thread. Would it potentially work for ME if the problem you’re describing is the correct one?

Not a silly question at all! It’s hard to say, saphnelo works specifically by blocking the type I interferon receptor. My theory has been more focused on genes that are downstream of interferon, which can be stimulated for months without any abnormal levels of interferon itself. But it also seems to be true that this downstream signaling is maintained by constant interferon signaling that happens in all healthy tissues—in another thread I described it like a constant game of telephone where someone calls every once in a while just to make sure that the people further down the chain are tapped in for when the actual emergency call happens. So theoretically if you block the receptor you might be able to tamp down the rest of the chain, but it could take a long time.

Long story short, it’s theoretically plausible if there’s any merit to my theory, but the sheer amount of unknowns here makes it a big question mark overall.

[edited since I pressed Post too early]