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]

 

[MelbME]

We’re they both overexpressed?

We cultured the ME/CFS patient and healthy control B cells after both t cell dependent and t cell independent stimulation. We measured CD markers at day 0, day 3 and day 6. What we noticed was that the % of B cells with CD38 grew significantly faster in ME/CFS compared to healthy. We also found the intensity or number of CD38 markers increased on each B cell. Figure 2 is the figure.

I'm currently setting up assays to replicate this in Australia with a different cohort and a different technique. Both the CD24 and CD38 findings.

 

[MelbME]

Part of me wonders if Norwegians thought to trial this drug based on our study as I think we showed them this data before 2020. Took a long time to publish the paper as it kept getting rejected and Fane had finished his PhD (he was driving the cell work).

I say that because this may not be two separate pieces of data from two separate groups but more intertwined. So it might be less meaningful.

 

[Kitty]

I'm currently setting up assays to replicate this in Australia with a different cohort and a different technique. Both the CD24 and CD38 findings.

That sounds good!

 

[forestglip]

I say that because this may not be two separate pieces of data from two separate groups but more intertwined. So it might be less meaningful.

You're saying that if dara was trialled based on prior data showing high CD38, it'd be less meaningful? I'm not sure I follow.

 

[jnmaciuch]

We cultured the ME/CFS patient and healthy control B cells after both t cell dependent and t cell independent stimulation. We measured CD markers at day 0, day 3 and day 6. What we noticed was that the % of B cells with CD38 grew significantly faster in ME/CFS compared to healthy. We also found the intensity or number of CD38 markers increased on each B cell. Figure 2 is the figure.

I'm currently setting up assays to replicate this in Australia with a different cohort and a different technique. Both the CD24 and CD38 findings.

By any chance was CD38 measured on any other cell types? I’d be particularly interested in whether this is a B cell specific phenomenon or a more global shift across immune subsets. I think there was another thread posted recently looking at CD38 in CD8s in ME/CFS which suggest the latter might be more likely.

I was trying to get an answer by downloading the single cell data from Maureen Hanson’s group but it might not be as evident without stimulation.

 

[MelbME]

You're saying that if dara was trialled based on prior data showing high CD38, it'd be less meaningful? I'm not sure I follow.

Still meaningful.

But if they come to this idea from different data unpublished suggesting it then we'd have 2 studies rather than 1. That's all I meant.

 

[MelbME]

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

So CD24 was elevated on ME/CFS B cells compared to healthy when we take them straight out of the blood.

CD38 only popped up as significantly different between ME and controls when we stimulated the B cells in vitro.


CD38 elevating suggests the B cells may be more rapidly transitioning to plasma cells. But it could also be a cell survival thing, if metabolic efficiency is compromised then anything that promotes cell survivability would also elevate (CD38 and CD24 play roles in this). It could also be both where a metabolic issue in the immune cells elevates CD38 and CD24 in response to energy stress which in turn promotes poorer quality plasma cells.

This is speculative but if there are more inappropriate plasma cells being produced then I could see how that could form a few relevant problems for ME/CFS patients. And a treatment targeting CD38 might remove those inappropriate cells.

 

[jnmaciuch]

So CD24 was elevated on ME/CFS B cells compared to healthy when we take them straight out of the blood.

CD38 only popped up as significantly different between ME and controls when we stimulated the B cells in vitro.


CD38 elevating suggests the B cells may be more rapidly transitioning to plasma cells. But it could also be a cell survival thing, if metabolic efficiency is compromised then anything that promotes cell survivability would also elevate (CD38 and CD24 play roles in this). It could also be both where a metabolic issue in the immune cells elevates CD38 and CD24 in response to energy stress which in turn promotes faster transition to plasma cells with less time for checkpoints.

I don't know enough about the checkpoints that may exist between a naive B cell and a memory B cell or plasma cell. But i think if a metabolic issue is rushing the cell through these transitions then that could be important.

If there are more inappropriate memory B cells or plasma cells being produced then I could see how that could form a few relevant problems for ME/CFS patients.

I sound like a broken record but this is exactly what you’d expect to see from B cells exposed to type I interferon. Enhanced differentiation and proliferation by TLR9 stimulation for sure, and also with TD if I’m not mistaken.

[Edit: this is the paper I was thinking of. https://pmc.ncbi.nlm.nih.gov/articles/PMC11042664/ mediated by IRF4 and mTOR]

 

[MelbME]

I sound like a broken record but this is exactly what you’d expect to see from B cells exposed to type I interferon. Enhanced differentiation and proliferation by TLR9 stimulation for sure, and also with TD if I’m not mistaken.

[Edit: this is the paper I was thinking of. https://pmc.ncbi.nlm.nih.gov/articles/PMC11042664/ mediated by IRF4 and mTOR]

Yes I think adding IFN-a as a stimulant is worth trying. We were already thinking about it.because of the itaconate shunt theory.

 

[jnmaciuch]

Yes I think adding IFN-a as a stimulant is worth trying. We were already thinking about it.because of the itaconate shunt theory.

I had a chance to chat with Daniel Missailidis recently about exactly this (he mentioned he works with you). I’ve been trying to get a study off the ground to confirm mtDNA release triggering an outsized interferon response in tissues. It would be an alternative explanation for interferon in ME/CFS that addresses the problem in the itaconate shunt theory of joint interferon and NFkB signaling being required to induce ACOD1 and this only being possible in certain immune cells due to epigenetic lineage restriction.

I’d be very interested in the results if you end up exploring interferon in your future work!

 

[Verity]

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]

Thank you very much for the easy-to-understand explanation! Very interesting!

 

[DMissa]

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?

This is something I want to get some $ look at on the side. Our lab has pioneered intracellular calcium flux measurements for like 40 years now or something.

I had a chance to chat with Daniel Missailidis recently about exactly this (he mentioned he works with you). I’ve been trying to get a study off the ground to confirm mtDNA release triggering an outsized interferon response in tissues. It would be an alternative explanation for interferon in ME/CFS that addresses the problem in the itaconate shunt theory of joint interferon and NFkB signaling being required to induce ACOD1 and this only being possible in certain immune cells due to epigenetic lineage restriction.

I’d be very interested in the results if you end up exploring interferon in your future work!

I have just put in a proposal tangential to this idea while combining some clues from DecodeME and also our fibroblast lines. Fingers crossed.

 

[hotblack]

I'm currently setting up assays to replicate this in Australia with a different cohort and a different technique. Both the CD24 and CD38 findings.

Yes I think adding IFN-a as a stimulant is worth trying. We were already thinking about it.because of the itaconate shunt theory.

I have just put in a proposal tangential to this idea while combining some clues from DecodeME and also our fibroblast lines. Fingers crossed.

This all sounds really really interesting. Hope you get the funding and look forward to hearing how the experiments go.

The wait should give me some more time to read up so I can understand what any results mean!