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

Snow Leopard said:
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
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That supports my point then. I’m saying that if someone wants to hypothesize ME/CFS as an antibody mediated disease, theyre effectively hypothesizing that there’s a magic antibody that only creates malaise/flu-like feelings as in ME/CFS and not any other recognizable phenomena from any other antibody-mediated disease. Which could end up being true, but is not a basket I’d put my eggs in (nor an idea I’m supporting here)
 
jnmaciuch said:
That supports my point then. I’m saying that if someone wants to hypothesize ME/CFS as an antibody mediated disease, theyre effectively hypothesizing that there’s a magic antibody that only creates malaise/flu-like disease and not any other recognizable phenomena from any other antibody-mediated disease. Which could end up being true, but is not a basket I’d put my eggs in
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I think there are different phenomena going on, malaise isn't just fluey symptoms but I maily attribute those fluey symptoms to histamine related symptoms (sore throat, sinusitis etc)
 
Maybe a bit off-topic, but since some people here asked about immunoadsorption, I’d like to share a story.

My best friend also has ME/CFS. We met through a self-help group. He is only mildly affected, but still unable to work. He developed ME/CFS back in 2017, before COVID.

At some point, when CellTrend started offering autoantibody testing, he had the test done and all values came back elevated. After that, he contacted a clinic near Kempten in the Allgäu (Germany), which offered him five immunoadsorption sessions using the Miltenyi filter.

At that time, I was still mildly affected myself and accompanied him to the first appointment, as we weren’t sure whether he would be fit enough to drive afterwards. After the first and second sessions, he didn’t notice much change. However, after the third session, he said that his pain was completely gone — especially that constant muscle soreness — and his head suddenly no longer felt flu-like.

After completing the treatment, he no longer felt ill. One week later, he even went bouldering at an indoor climbing gym, and the next day he had no PEM. He thought he might have recovered. Unfortunately, about a month later, the symptoms slowly started to return.

I also had the CellTrend test done myself, but my results were negative, so I did not try immunoadsorption.

That said, the reliability of these tests is questionable. I’m not an expert — this is just what I’ve heard. Apparently, it may depend on whether the autoantibodies are actually receptor-bound or not.
 
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jnmaciuch said:
I’m saying that if someone wants to hypothesize ME/CFS as an antibody mediated disease, theyre effectively hypothesizing that there’s a magic antibody that only creates malaise/flu-like feelings as in ME/CFS and not any other recognizable phenomena from any other antibody-mediated disease.
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But in a sense this is already well known. People with antibodies to Sm, Ro, RNP with a diagnosis of lupus or probably lupus can spend much of their lives with the malaise/fatigue side of flu-like symptoms but without fever or raised CRP and nothing else in the way of pathology. If you sit in a lupus clinic you spend a good proportion of your time dealing with this sort of situation. These people may have had episodes of more specific antibody-mediated problem like thrombocytopenia or myositis or arthritis in the past but very often they are left with unremitting 'fatigue'. People with cerebral lupus also often feel really terrible with no evidence of activation of TNF or IL-6 and pretty little to show on any other test until their intracranial pressure rises measurably and they go from hiding under the bedclothes to being unconscious.

A lupus clinic is a good place to dispel any illusions that all 'sickness behaviour' is mediated the same way. After all, people feel unwell having ingested a huge range of inadvisable chemicals, including ethanol, each of which probably mediates feeling terrible in a slightly different way. There must be lots of routes to choose from and an antibody could mimic any one of those.
 
well if it were magic antibodies that are beyond science and technology it would explain why it hasn't been solved or even understood yet...
 
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Probably the phase II study and Scheibenbogen and Sanofis Isatuximab trial. And Teclistamab trials. Clearly measuring the antibody won't work so the only option is to hit the source of them and see what happens.

On a side note, how exactly are auto antibodies discovered and identified?
 
jnmaciuch said:
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.
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If it some genetic change then what is the solution? Gene editing?
 
ryanc97 said:
On a side note, how exactly are auto antibodies discovered and identified?
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Mostly by scientists messing about in labs doing crazy things like mixing patients' serum with sheep blood or shaking up blood and looking at it under a microscope. Things started to get systematic around 1960 when people like Deborah Doniach developed standard ways of putting serum on to sections of tissue and using fluorescein tags to show antibody binding. Doniach's PhD student was Ivan Roitt, who was my boss in the 1980s.
 
jnmaciuch said:
Sure, like I said before, you can always say that antibodies behave weirdly and heterogeneously and therefore you can't disprove their involvement. What I'm looking for is evidence for which "antibodies-mediating-disease" is the most plausible explanation. People getting better after plasmapheresis would be one such piece of positive evidence, though it's lack doesn't disprove antibody involvement.

The fact that depleting IgG by half with dara seems to show more convincing evidence of improvement in a small cohort than depleting IgG by a larger fraction via plasmapheresis does require some out of the box thinking to reconcile.

If I had more data points for which antibodies were the most convincing explanation, I could easily get on board the same train as you and come up with a million ways to reconcile seemingly contradictory data points. But I don't have that. Barring that, it would help to at least have some clear way to explain how this problem could be worsened by exertion (besides a hand wave to the idea that lots of things change with exertion), or how it specifically aligns with the symptoms and time frames of PEM or other hallmark clinical features of the illness, or how it could be triggered by an infection. Which is also lacking. So we're back to the same point of discussion we've come to before, where the reasons for thinking B cells are because they mediate some other diseases and that you've studied them a lot.
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For plasmapheresis, do you need to know the specific antibody to remove it? Or does it just remove any antibody.


Is it possible the pathogenic antibodies are in the tissues and not removable by plasmapheresis?
 
Jonathan Edwards said:
But in a sense this is already well known. People with antibodies to Sm, Ro, RNP with a diagnosis of lupus or probably lupus can spend much of their lives with the malaise/fatigue side of flu-like symptoms but without fever or raised CRP and nothing else in the way of pathology. If you sit in a lupus clinic you spend a good proportion of your time dealing with this sort of situation. These people may have had episodes of more specific antibody-mediated problem like thrombocytopenia or myositis or arthritis in the past but very often they are left with unremitting 'fatigue'. People with cerebral lupus also often feel really terrible with no evidence of activation of TNF or IL-6 and pretty little to show on any other test until their intracranial pressure rises measurably and they go from hiding under the bedclothes to being unconscious.

A lupus clinic is a good place to dispel any illusions that all 'sickness behaviour' is mediated the same way. After all, people feel unwell having ingested a huge range of inadvisable chemicals, including ethanol, each of which probably mediates feeling terrible in a slightly different way. There must be lots of routes to choose from and an antibody could mimic any one of those.
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I’m well aware of all this, and like I said several times, the specific constraints of being a subtle enough problem to evade all previous screens and investigations, fitting the specific clinical features of ME/CFS where they diverge from general fatigue and unwellness of other antibody mediated diseases, and still having a weird global effect on B cells could ultimately be answerable by an antibody problem—it can never fully be taken off the the table. It just prompts us to consider that other options fit the story better, which I’m sure you would not be opposed to
 
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