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

[ryanc97]

I think that might be possible for certain types of dendritic cell - maybe plasmacytoid, that make lots of interferons.

you mean…. CD38 dendritic cell gets hit and stops the interferon production?

But tbh I am more skeptical about Davis stuff now because it is theory first and not evidence first, whereas Fluge started with a random observation then tried a theory

 

[Jonathan Edwards]

you mean…. CD38 dendritic cell gets hit and stops the interferon production?

But tbh I am more skeptical about Davis stuff now because it is theory first and not evidence first, whereas Fluge started with a random observation then tried a theory

I don't think interferons are specifically Davis stuff. People have suggested interferons might be the source of symptoms in ME/CFS for years. Hence the Pariente study. And it was obvious to me, quite independently, that interferons (thinking mostly of gamma) would be good candidates since the evidence did not seem to fit well with TNF or IL-6. And @jnmaciuch is keen on interferon for other reasons.

As I understand it plasmacytoid dendritic cells are interferon megafactories. And they circulate round picking up antigens and presenting peptides and innate signals to T cells.

Antibody might come in to that too. A potential problem with a classic autoantibody story for ME/CFS is that we don't have any very satisfactory candidate antigens that would explain the symptom profile. Vascular regulatory proteins like GPCR or muscarinic ACh receptors might just about do but it is not obvious how they would explain various features, including PEM.

I think it is worth thinking about.

 

[jnmaciuch]

Yes pDCs are the professional interferon factories—though interestingly even in lupus, there’s good evidence that they aren’t driving the interferon signature after the earliest stage of disease. Neutrophils seem to be the culprit (sources cited in this review). So an antibody-pDC story would not be a practical narrative here unless it can be explained how pDC activation could be sustained long term in a way it isn’t in other antibody-mediated diseases

 

[rapidboson]

Neutrophils seem to be the culprit (sources cited in this review).

There was a full presentation on neutrophils and their abnormal activity in the Ron Davis webinar. I was too brainfoggy to remember much though. Maybe somebody else made some screenshots.

 

[Jonathan Edwards]

Neutrophils seem to be the culprit (sources cited in this review).

I wouldn't put too much credence in reviews like that in Nature Reviews Rheumatology, which is where rheumatologists put stuff they cannot get into a decent journal. Ed Vittal is well known to me. He tried to make something of plasmablasts in the use of rituximab in RA but seemed to miss the whole point. (The Leeds people tried to take over the rituximab story because I had cut ties to Roche because they failed to inform me of a death in the phase 3 trial for which I was first author and originator.)

I doubt neutrophils have much to do with interferons driving antibody production in lupus. What cells do in petri dishes or genetically modified mice isn't necessarily of great relevance to clinical disease! The reality is that we don't know why any of these diseases work quite the way we do and since antibody can bind to absolutely anything I don't think one can exclude a role for antibody altogether.

 

[jnmaciuch]

I wouldn't put too much credence in reviews like that in Nature Reviews Rheumatology, which is where rheumatologists put stuff they cannot get into a decent journal. Ed Vittal is well known to me. He tried to make something of plasmablasts in the use of rituximab in RA but seemed to miss the whole point. (The Leeds people tried to take over the rituximab story because I had cut ties to Roche because they failed to inform me of a death in the phase 3 trial for which I was first author and originator.)

I doubt neutrophils have much to do with interferons driving antibody production in lupus. What cells do in petri dishes or genetically modified mice isn't necessarily of great relevance to clinical disease! The reality is that we don't know why any of these diseases work quite the way we do and since antibody can bind to absolutely anything I don't think one can exclude a role for antibody altogether.

I’ve never trusted reviews at face value and never cite a claim from one unless I’ve reviewed the supporting sources, which I’ve done in this case. I cited the review to avoid having to copy and paste a dozen sources.

That particular conclusion was supported in several studies, nearly all in humans. In particular, tissue biopsies from lupus patients show a high interferon stimulated gene signature but no pDC infiltration, and further studies have pretty much confirmed that the interferon signature comes from largely neutrophils or non-hematopoietic cells depending on the tissue studied.

I’m not saying neutrophils are driving antibody production in lupus, I’m saying they are the predominant source of actual interferon signatures in lupus tissue rather than pDCs. In all likelihood the neutrophil response probably does has something to do with antibodies, directly or indirectly. My point is that pDCs specifically have not demonstrated capability to produce a long-term abnormal interferon response in other contexts where antibodies drive disease.

 

[Jonathan Edwards]

I am afraid I don't take studies like that very seriously. People have no clue when it comes to placing molecular signals in appropriate tissue environments. Biopsying lesions and finding no dendritic cells tells us nothing. A lot of lupus pathology has nothing to do with neutrophils.

All this sort of stuff is driven by fashion and always has been. That is why working out a new way to treat rheumatoid despite not actually being an immunologist at the time was like shooting fish in a barrel.

 

[jnmaciuch]

Do you have specific methodological critiques for all those studies, or actual evidence that it must be pDCs driving the interferon signature in lupus despite this evidence to the contrary?

 

[ryanc97]

Well there are JAK STAT inhibitor trials ongoing:

Three clinical trials for Long COVID are testing JAK inhibitors to treat immune dysregulation - The Sick Times

Three separate trials are testing the immunomodulator drugs abrocitinib (Cibinqo), baricitinib (Olumiant), and upadacitinib (Rinvoq). All are JAK inhibitors, which target specific inflammation pathways.

thesicktimes.org

But to be honest I find the Davis theory, while I'm sure the shunting is definitely a valid process, just saying it happens because of a stuck on Interferon-Alpha loop is a very weak argument.

And also I don't understand the story of how they came up with the theory. Did they empirically measure higher levels of IFN by alot in CFS patients compared to healthy controls then made the theory? Because I don't think there is a difference:

The LLPC theory makes more sense to me.

 

[Jonathan Edwards]

Do you have specific methodological critiques for all those studies, or actual evidence that it must be pDCs driving the interferon signature in lupus despite this evidence to the contrary?

I think you have missed my point. I don't think I ever said that dendritic cells were making the interferon in lupus. All I was saying was:

The things you are li'ble,
To read in the Bible
Ain't necessarily so.

From my perch, people understand less about lupus now than Gerry Weissman and Henry Kunkel did in the 1970s. The Holy Scrolls now seem to be written by the blind.

 

[Jonathan Edwards]

just saying it happens because of a stuck on Interferon-Alpha loop is a very weak argument.

I tend to agree and Robert has said that so far the evidence from looking for interferon doesn't seem to support the theory. I think interferons are of interest for other reasons and could well be involved in loops, but so far we don't have evidence.

 

[Stuart79]

Antibody might come in to that too. A potential problem with a classic autoantibody story for ME/CFS is that we don't have any very satisfactory candidate antigens that would explain the symptom profile.

If it does turn out to involve antibodies, is it possible that an IgG4 antibody could be to blame? Perhaps something like inhibiting a signal necessary for resolution or inducing an incomplete immune tolerance wherein it’s a little like having one foot on the brake and one foot on the gas?

 

[jnmaciuch]

The things you are li'ble,
To read in the Bible
Ain't necessarily so.

Yes, as you so often say. Which is why I don’t base my information on hearsay, but on examining evidence. If you have strong reason to completely dismiss all those findings, I’ll hear it. If not, I will go with my own examination of actual evidence rather than someone else’s intuition

 

[jnmaciuch]

Well there are JAK STAT inhibitor trials ongoing:

Three clinical trials for Long COVID are testing JAK inhibitors to treat immune dysregulation - The Sick Times

Three separate trials are testing the immunomodulator drugs abrocitinib (Cibinqo), baricitinib (Olumiant), and upadacitinib (Rinvoq). All are JAK inhibitors, which target specific inflammation pathways.

thesicktimes.org

But to be honest I find the Davis theory, while I'm sure the shunting is definitely a valid process, just saying it happens because of a stuck on Interferon-Alpha loop is a very weak argument.

And also I don't understand the story of how they came up with the theory. Did they empirically measure higher levels of IFN by alot in CFS patients compared to healthy controls then made the theory? Because I don't think there is a difference:

The LLPC theory makes more sense to me.

From what I recall in other threads, their idea for interferon alpha came from the fact that interferon itself is an interferon stimulated gene and so had the right “structure” to form a pathological loop.

There is evidence that cells and tissues can sustain interferon-stimulated genes signatures for months or years without continued stimulation—not as pathologically high as in active infection or interferonopathies, but certainly higher than “expected” constitutive levels. My PI and his former lab have several studies showing that there is quite a lot of variability among the population and that baseline ISG levels are predictive for efficacy of vaccination, for example.

The issue is that even the high end of this normal range doesn't usually present with debilitating symptoms—but it does show that a self-sustaining interferon signature is possible and that there is quite a suite of fine-tuning mechanisms that could potentially go wrong.

I am not sure how much [edit: of those details factored into the theory], I am not aware of what immunology background they might have. When I was discussing the itaconate shunt idea with Rob in another thread, I brought up the fact that itaconate itself is unlikely to be upregulated constitutively without a sustained NFkB response and even then it would only be in a handful of cell types—the negative mRNA data he spoke about seems to support that.

 

[ryanc97]

From what I recall in other threads, their idea for interferon alpha came from the fact that interferon itself is an interferon stimulated gene and so had the right “structure” to form a pathological loop.

I see, but still, this wasn’t based off some observation or evidence. Some evidence would be finding CFS patients have super high levels of IFN.

 

[Stuart79]

I see, but still, this wasn’t based off some observation or evidence. Some evidence would be finding CFS patients have super high levels of IFN.

I believe Phair has said the shunt would only need to be stuck on in a relatively small number of cells. So, high interferon levels would be local rather than systemic, and thus not so easy to locate or measure.

 

[ryanc97]

I believe Phair has said the shunt would only need to be stuck on in a relatively small number of cells. So, high interferon levels would be local rather than systemic, and thus not so easy to locate or measure.

This is true, but unless they found some measurement of high IFN in a local place, their theory is not evidence first. If they did then it would be.

 

[V.R.T.]

This is true, but unless they found some measurement of high IFN in a local place, their theory is not evidence first. If they did then it would be.

But if the evidence is not detectable with avaliable technologies as ME/CFS currently isn't, then unless you hit on something by happenstance like Fluge and Mella did then you need to go hypothesis first.

 

[jnmaciuch]

I see, but still, this wasn’t based off some observation or evidence.

Sure, though most science operates on a hypothesis first, evidence second basis because specific hypotheses require specific experimental setups to confirm. Existing screening studies may pick up on a weak signal somewhere far downstream of the issue, but usually those findings are non-specific and could be explained by multiple different theories.

For what it’s worth, itaconate shunt does align with some metabolic findings, inconsistent though they might be—but like I said it wouldn’t be the only viable explanation for those findings.

I don’t know of any examples of a theory that is both logically consistent with the features and dynamics of the disease and already has strong preliminary evidence before the theory is formed—I can see that you are strongly in support of an antibody-driven theory but I think it would have issues on both counts, as others have already brought up.

Some evidence would be finding CFS patients have super high levels of IFN.

A small technical point—we wouldn’t expect to see super high levels of interferon anyways since that would likely lead to tissue calcification a la interferonopathies. It would more likely be an issue in regulation of downstream signaling rather than out-of-control interferon production—so what we’d be looking for is an interferon-stimulated gene signature higher than controls, which may or may not present with slightly higher levels of interferon itself.
The sustained ISG signatures I referenced above do not present with substantially higher interferon.

Your point about needing positive evidence is still valid, I just wanted to clarify to avoid anyone getting the wrong impression for what would actually support or discount an interferon-based theory.

 

[ryanc97]

Your point about needing positive evidence is still valid, I just wanted to clarify to avoid anyone getting the wrong impression for what would actually support or discount an interferon-based theory.

That's fair. I mean when I first got sick in Jan this year I jumped onto the Davis hype train immediately as I found that out of all researchers he is the most credentialed, I mean he worked under James Watson for his PhD.

I then trialed Rinvoq for a month with absolutely no changes to anything.

I just feel like now there is no basis for the theory since it came purely from conjecture and we have other theories that are observation first.

Also another point on their theory is they mentioned ammonia is a product of the re-wired TCA cycle in shunting cells, and ammonia is toxic to brain. If that was the case surely CFS would cause permanent brain damage but we have seen in recovery cases that is not the case.