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

[MelbME]

But that’s different from PVFS, no?

If it’s post-viral, we’re presumably past the acute stage, which is when you suggested there was inflammation that might later lead into ME/CFS if I understood correctly.

And are we talking about the JE kind of inflammation or just the presence or some cytokines or immune activity in general?

Well from the early long COVID literature, especially when they were including patients at 1-3 months post-acute, they all seemed to show elevated cytokine profiles.

This is what my mind was thinking of when I said inflammation in PVFS.

The idea is that this ongoing inflammation may be part of the trigger that sets up the maintaining factor (LLPCs) to be self sustaining without inflammation in ME/CFS.

 

[MelbME]

I agree with Jonathan there, cross-species Ig transfer is pretty messy. If there was a very very clear phenotypic difference that strongly resembled ME/CFS (as much as you could get from an animal model, anyways) then maybe it would warrant a further look, but I’d still be pretty skeptical.

Wasn't it the pain profiles that were most clearly transferred in to the mice? Just from memory.

 

[jnmaciuch]

Wasn't it the pain profiles that were most clearly transferred in to the mice? Just from memory.

In LC? Yes, pain and balance issues from Akiko's study

 

[MelbME]

If plasmapheresis never really works for antibody mediated diseases what out of the box thinking is needed?

I also think the fact that bigger response in those with higher baseline NK cells suggests getting to the pathogenic plasma cells and destroying them is the difference, rather than clearing antibody alone.

Do we know that plasmapheresis didn't provide immediate relief that was unsustained?

 

[MelbME]

In LC? Yes, pain and balance issues from Akiko's study

Also the original work on Fibro where I think they got the idea.

Do we know if pain was a major improver in the Dara trial?

 

[Jonathan Edwards]

Well from the early long COVID literature, especially when they were including patients at 1-3 months post-acute, they all seemed to show elevated cytokine profiles.

The point Utsikt is referring to is that cytokines are known to be able to cause inflammation but they do not always do so and can be present in the absence of inflammation. And if we are looking for a stimulus to change in B cell behaviour we need a biochemical signal. Cytokines could likely do that, but there is no need to invoke inflammation.

 

[MelbME]

1) CD38 induction in this paper was not a subtle shift visible only if you knew where in the body to look.

2) could you point me to the evidence that VH4-34 is globally induced in B cells by the disease state in lupus other than through the expansion of autoreactive clones? Otherwise it’s not a comparable example.

Being the explanatory black box they are, antibodies are always going to be a viable explanation for any currently unexplained disease because any combination of clinical features can be explained away as “antibodies do weird things and we don’t fully understand them.”

But it does stretch believability to claim that an antibody problem is simultaneously so subtle and isolated that we don’t see what tissue it’s affecting or signs of the cytokines it’s producing to cause an enduring disease state, and also so global that it will result in a clear difference in the response of randomly sampled B cells ex vivo. Unless you want to claim that it’s two separate enduring abnormalities.

These might be useful:

Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus - PubMed

9G4(+) IgG Abs expand in systemic lupus erythematosus (SLE) in a disease-specific fashion and react with different lupus Ags including B cell Ags and apoptotic cells. Their shared use of VH4-34 represents a unique system to understand the molecular basis of lupus autoreactivity. In this study, a...

pubmed.ncbi.nlm.nih.gov

Understanding B-cell activation and autoantibody repertoire selection in systemic lupus erythematosus: A B-cell immunomics approach - PubMed

Understanding antibody repertoires and in particular, the properties and fates of B cells expressing potentially pathogenic antibodies is critical to define the mechanisms underlying multiple immunological diseases including autoimmune and allergic conditions as well as transplant rejection...

pubmed.ncbi.nlm.nih.gov

 

[Jonathan Edwards]

I am not sure that an apparent particular effect on pain in mice tells us much. Mouse models of pain are easy - you put them on hot plates and things and the behavioural responses can be measured easily. Effeects on other symptoms tend to be much more difficult to interpret.

Testing mice for an effect on pain is a bit like putting the Marvel in the coffee in a pharma lab.

 

[forestglip]

In case it's helpful, a recent review talking about immunoadsorption studies:

Autoantibody targeting therapies in post COVID syndrome and myalgic encephalomyelitis/chronic fatigue syndrome, 2025, Wohlrab et al

Immunoadsorption (IA) has proven to be a highly effective treatment in a wide range of AAb mediated diseases. The principle of IA involves efficient removal of immunoglobulins by filtering the plasma with a column selectively removing antibodies or immune complexes. Different adsorbers range from broad removal of total immunoglobulins to highly selective depleting specific antibody subsets.

IA using immunoglobulin G (IgG)-binding columns was already shown to be efficacious in two small non-controlled studies in pre-pandemic ME/CFS patients [6].

In a prospective cohort study, 20 PCS ME/CFS patients with elevated β2-adrenergic receptor autoantibodies (β2-ARA) were treated. Each received five IA sessions. This led to marked reductions in total IgG and β2-ARA levels. Fourteen out of twenty patients showed improvement of several key symptoms and hand grip strength [7].

In another observational IA study 12 patients with PCS and ME/CFS and elevated GPCR-AAbs, including β1/2-ARA were studied. After treatment, neuropsychological function and hand grip strength improved significantly [8].

Despite these promising data, all published trials were observational so far. Results from three sham-controlled studies in PCS and ME/CFS are expected in 2025.

However, the clinical benefits of IA are temporary in most patients and it is a highly specialized and demanding procedure. Plasma exchange can clear inflammatory mediators and also lower immunoglobulins although less effective than IA.

A recent randomized controlled trial (RCT) in PCS was negative [9].

Refs:

• 6. Scheibenbogen C, Loebel M, Freitag H, et al. Immunoadsorption to remove ß2 adrenergic receptor antibodies in chronic fatigue syndrome CFS/ME. PLOS ONE. 2018 Mar 15;13(3):e0193672. doi: https://doi.org/10.1371/journal.pone.0193672 S4ME
• 7. Stein E, Heindrich C, Wittke K, et al. Efficacy of repeated immunoadsorption in patients with post-COVID myalgic encephalomyelitis/chronic fatigue syndrome and elevated β2-adrenergic receptor autoantibodies: a prospective cohort study. Lancet Reg Heal – Eur. 2025;49:49. doi: https://doi.org/10.1016/j.lanepe.2024.101161 S4ME
• 8. Anft M, Wiemers L, Rosiewicz KS, et al. Effect of immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS. Mol Ther. 2025 Jan 9;S1525–0016(25):00011–5. doi: https://doi.org/10.1016/j.ymthe.2025.01.007 S4ME
• 9. España-Cueto S, Loste C, Lladós G, et al. Plasma exchange therapy for the post COVID-19 condition: a phase II, double-blind, placebo-controlled, randomized trial. Nat Commun. 2025;16:1929. doi: https://doi.org/10.1038/s41467-025-57198-7 S4ME

 

[MelbME]

The point Utsikt is referring to is that cytokines are known to be able to cause inflammation but they do not always do so and can be present in the absence of inflammation. And if we are looking for a stimulus to change in B cell behaviour we need a biochemical signal. Cytokines could likely do that, but there is no need to invoke inflammation.

Oh right. Sorry @Utsikt, thought you were asking what I originally meant by inflammation. My initial thoughts were on pro-inflammatory cytokines are what we see elevated in the 1-3 month post-acute COVID patients.

But you're both right, no signs of inflammation needed. The cytokines themselves are what is important.

Could cytokines without inflammation develop niches for LLPCs?

 

[forestglip]

I am not sure that an apparent particular effect on pain in mice tells us much. Mouse models of pain are easy - you put them on hot plates and things and the behavioural responses can be measured easily. Effeects on other symptoms tend to be much more difficult to interpret.

Testing mice for an effect on pain is a bit like putting the Marvel in the coffee in a pharma lab.

What's interesting to me is there being any effect at all. If they gave the mice the IgG and they grew longer hair, or if they put the IgG on a petunia and it turned more yellow, it'd still indicate something is different about the IgG. Maybe then you could isolate the specific antibodies.

And I guess you would see if IgG from any populations with similar lifestyles but known to not have an antibody-mediated disease also have a similar effect.

 

[Utsikt]

Refs:

Thanks for the S4 links! The link for 7 is a dupe of 8.

If those are it, there isn’t much proof of efficacy.

 

[Utsikt]

Oh right. Sorry @Utsikt, thought you were asking what I originally meant by inflammation. My initial thoughts were on pro-inflammatory cytokines are what we see elevated in the 1-3 month post-acute COVID patients.

But you're both right, no signs of inflammation needed. The cytokines themselves are what is important.

No worries, I could have been clearer.

I’m a novice at this, but can’t cytokines have completely different functions in different context? From the little I’ve gathered here it seems like pro-inflammatory or anti-inflammatory are generalisations that might go a bit too far.

But what you’re saying is that there are elevated levels of some cytokines 1-3 months after infection, and that for some that, in combination with other factors, might eventually end up in a chronic state that’s ME/CFS?

Could cytokines without inflammation develop niches for LLPCs?

 

[jnmaciuch]

These might be useful:

Apologies @MelbME, I meant the question somewhat facetiously--I used to be in a rheumatology lab and am pretty familiar with this already. My point was that you can't use VH4-34 as an example of why its plausible for a gene like CD38 to be induced globally in B cells by an antibody-mediated problem. It will be upregulated anyways if you have autoreactive VH4-34-encoding B cells bypassing checkpoints and starting clonal expansion, so you can't claim that it is evidence of some problem downstream of antibody binding leading to a transcriptional change in other B cells. Unless I've missed some pretty foundational paper that showed the opposite

 

[jnmaciuch]

Do we know if pain was a major improver in the Dara trial?

There would have been some general pain-related items in the DSQ-SF and a pain-related subscale on the SF-36 but the trial results only report an overall score from the questionnaires, as far as I'm aware.

 

[MelbME]

Apologies @MelbME, I meant the question somewhat facetiously--I used to be in a rheumatology lab and am pretty familiar with this already. My point was that you can't use VH4-34 as an example of why its plausible for a gene like CD38 to be induced globally in B cells by an antibody-mediated problem. It will be upregulated anyways if you have autoreactive VH4-34-encoding B cells bypass checkpoints and start clonal expansion, so you can't claim that it is evidence of some problem downstream of antibody binding leading to a transcriptional change in other B cells. Unless I've missed some pretty foundational paper that showed the opposite

So rather you'd be looking for epigenetic changes? What if the autoantibodies targeted orexin pathway or CRH neurons? Similarly to African Sleeping Sickness but antibody induced and not the parasite. I think that alteration might set up a system to perpetuate the B cell priming of CD38.

 

[MelbME]

No worries, I could have been clearer.

I’m a novice at this, but can’t cytokines have completely different functions in different context? From the little I’ve gathered here it seems like pro-inflammatory or anti-inflammatory are generalisations that might go a bit too far.

But what you’re saying is that there are elevated levels of some cytokines 1-3 months after infection, and that for some that, in combination with other factors, might eventually end up in a chronic state that’s ME/CFS?

Yes.

1. Cytokines elevate during acute infection and stay elevated for several months. This might resolve itself or number 2 happens.
2. Cytokines prime B cells to more rapidly produce CD38 when activated.
3. Rapid CD38 activation leads to altered BCR and you get skewed pathogenic long live plasmas cells.

The only part that inflammation might add beyond cytokines alone are more niches for the LLPCs to hang out in. The findings from Wust lab suggested macrophages infiltrated muscle more in LC, that mechanism in the body could be producing more niches.

I think the non-PEM state in ME is not an inflammatory one, but I wonder if the PEM state is an inflammatory one that actually sustains this process.

 

[jnmaciuch]

So rather you'd be looking for epigenetic changes? That was my first thought.

That would be my thought as well, or a stably upregulated transcription factor (which would probably be epigenetically upregulated itself). There's a protein complex involved in mediating the interferon response that I've been very interested in--ISGF3 (containing STAT1, STAT2, and IRF9). It's been shown to be upregulated long term in multiple cell lines and primary tissue (link) and has transcriptional activity even without active interferon signaling. Leads to a stronger ISG response upon stimulation.

Currently unknown what exactly causes it to be upregulated in those cases, but the consistent observation in different contexts means that there is probably some accessible "switch" within all cells.
CD38 wasn't specifically assessed in the study I linked, but its a canonical target of STAT1/this complex.

 

[Jaybee00]

Are there any drugs that raise NK cells that could be used prior to Dara? Like a combo treatment.

Yes Anktiva. @ryanc97 is the expert here.

ImmunityBio’s ANKTIVA® Reverses Lymphopenia and Extends Overall Survival in Patients With Advanced Non-Small Cell Lung Cancer Resistant to Checkpoint Therapy - ImmunityBio

immunitybio.com

Also Blueberries.

 

[Snow Leopard]

My point is just that we have no apparent sign whatsoever of any abnormality that can be traced back to antibodies other than the feeling of being sick. [Edit: it would be a magic bullet solution indeed if there was a way that antibodies caused a problem that only lead to the feeling of being sick, by a completely different and unknown mechanism than the ones we already know about that mediate sickness behavior during infection.]

That's not my experience at all, when suffering from acute Guillain Barre Syndrome, I felt severe fatigue/weakness/paralysis and had autonomic symptoms (OI) but I wouldn't say I had that fluey/feeling sick feeling at all. I think "sickness behaviour" is too nonspecific to be a useful construct and doesn't really describe my experience at all.