- https://en.wikipedia.org/wiki/Autoimmune_hemolytic_anemia
There's an autoimmune disease for hemoglobin carrying cells, but I think anemia would be expected, which I don't think we have evidence for in ME/CFS.
Long-lived plasma cell (LLPC) theory - Similarities between CFS and Lupus?
- Thread starter ryanc97
- Start date
- https://en.wikipedia.org/wiki/Autoimmune_hemolytic_anemia
There's an autoimmune disease for hemoglobin carrying cells, but I think anemia would be expected, which I don't think we have evidence for in ME/CFS.
As a refresher of the criticisms from 2011 about the use of Rituximab for Me/Cfs a letter to the editor is below from Jos Van der meer, Andrew Lloyd, Alistair Miller .
journals.plos.org
Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study
Background Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant...
journals.plos.org
ryanc97
Senior Member (Voting Rights)
I see. So it might not be the oxygen carrier itself.
Possible it is the blood volume or amount? For example the walls of the blood vessel etc. the capillaries.
rapidboson
Senior Member (Voting Rights)
Of available compounds, maybe high enough doses (however much that may be) of apigenin as a known (low potency IC50 ~ 10 uM ) CD38 inhibitor?
Jonathan Edwards
Senior Member (Voting Rights)
As far as I know nobody has convincingly shown that the antibodies produced by plasma cells in brain in MS are directed at myelin or any other self antigen. People just believe that because they believe in the standard mantra. As I have mentioned before, Margaret Esiri showed in the 1990s that any old IgG will stimulate macrophages/microglia to eat myelin. What are found in CSF in MS are antibodies derived from a limited number of clones (oligoclonal). Nobody really knows what most of these are against, or they didn't last time I looked.
Jonathan Edwards
Senior Member (Voting Rights)
Yes, I have already explained that to someone else but no worries, it is getting a bit hectic!!
It is interesting to see that prior comment. It was made in the context of eveyone here assuming that CD38 was just the killing target on plasma cells. I can now see that there are reasons to question that assumption. I have emailed Oystein Fluge to see if he has considered this and what his take is.
I have changed my mind largely because @ryanc97 kept testing all the arguments against daratumumab working and made me run through all the possible interpretations of the data we have. I realised that it might be that ritux does not work and that both cyclo and dara do actually work and that the fact that this does not seem to fit plausibly with any model involving plasma cell subpopulations may be pointing to these drugs both acting some other way. I guess I may have been influenced by thoughts about graft versus host being a useful (but indirect) analogy. But more than anything it was just being put on the spot of trying to find a completely consistent solution - rather as ryanc97 had tried to do for an antibody model.
rapidboson
Senior Member (Voting Rights)
What about in MOGAD? Not produced in the CNS, but anti-MOG nonetheless.
Jonathan Edwards
Senior Member (Voting Rights)
Do you think this is actually robust? For decades I watched while people claimed they had found what the oligoclonal bands were recognising and it kept changing and the main meassgae seemed to be that nobody really knew why they were there. It seems at first sight that it would make sense for it to be a CNS antigen but I don't think that is the only explanation. Moreover, we have the strange fact that most of these antigens are also present in peripheral nerve (which tellingly EAE damages too but MS does not) but there is no demyelination there, despite antibody having much easier access from plasma.
Jonathan Edwards
Senior Member (Voting Rights)
I am not familiar with the details of MOGA but it seems to be quite a different disease, with, as you say, autoantibodies to a myelin associated protein. The AI summary on Google suggest to me that the diagnostic concept may be a bit confused. There may be some enthusiasts for this disease who overinterpret antibody data. But it may be roughly analogous to other recognised autoantibody-mediated CNS diseases like the herpes-linked encephalopathy.
Another thing that is weird about oligoclonal bands is that they do actually occur in other well known brain diseases that are not thought to be autoimmune, but I think at low level and uncommonly.
I don't think we understand what is going on.
What I think we can be reasonably sure of is that plasma cells are not getting into brain and making antibody in Long Covid or ME/CFS because we could measure the bands and CSF studies have already been done and not shown them.
Interesting, thanks for taking the time to explain that again.
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jnmaciuch
Senior Member (Voting Rights)
I think it’s the most likely explanation but agree that other explanations could be theoretically possible. Trouble is I can’t come up with an alternative that makes sense.
The best option I’ve heard is that it is different CNS antigens for each patient but something about the MS landscape (or pre-MS landscape, really) just makes the brain a good niche for allowing antibody binding and clonal expansion where it wouldn’t happen in the periphery. Which is rather vague unless it can be explained what that permissive factor is, so I’m not staking much on it
ryanc97
Senior Member (Voting Rights)
Whatever theory for antibodies is just distilled from the two video presentations that Mella and Fluge gave at Charite 2025. It would be interesting to hear their thoughts on alternative possibilities as well and maybe they can do some additional tests in the P2 to validate any possible theories as well.
Jonathan Edwards
Senior Member (Voting Rights)
It is a long time since I looked at this but quite recently there was something more about the CNS being an environment in which rules for B cell survival and death signals are shifted. There isn't much complement around - which can mediate both survival and death for B cells. Proliferating B cells live in a cocoon of CD55 that allows CD21 interactions but not membrane attack formation. B cells normally need VCAM-1 too but I think it has been shown that this is not required in CNS. Something to do with Bcl2 and things.
My guess at present is that EBV gives B clones a bit of an edge for survival. Then some get into CNS and beat the negative signals partly from that and partly because they are making antibodies that interact (maybe weakly) with some other survival ligand - which need not be to do with CNS. Perhaps they hitch hike on to C3 involved in synaptic maintenance or something weird. What would be nice to know is why DQ matters a lot, when very few T helper cells seem to be DQ restricted in their responses. I haven't heard a good answer to that.
Jonathan Edwards
Senior Member (Voting Rights)
Only if you were killing CD38+ cells with NK cells and that is not what I ha din mind. Dara would bind to CD38 and alter the cell's behaviour without needing to be killed. What might be an implication of this model is that you might get an effect with quite small doses of dara that blocked CD38 but did not produce cell killing.
ryanc97
Senior Member (Voting Rights)
So one dose might do the trick? Would it be the case where you need more doses to break any loop under this theory? Like the more the better, basically.
Under LLPC theory at least the effectiveness of each dose drops exponentially due to the NK cell fraticide at least, so the first dose is the most important.
Under LLPC theory at least the effectiveness of each dose drops exponentially due to the NK cell fraticide at least, so the first dose is the most important.
Yes I think that Fluge doesn’t think many Dara injections are needed. That’s why they amended the pilot study to include a week 0 ,week 10 (only if there is no response), week 24 and week 48.
I think the multiple injections protocol came from multiple myeloma where I assume patients are churning out loads of bad plasma cells.
Utsikt
Senior Member (Voting Rights)
In Cyclo P2 (unblinded, no controls), 22/44 (55 %) were classified as responders.
In Dara P1, (unblinded, no controls), 6/10 (60 %) were classified as responders.
Is it common tø have about half as responders with these kinds of drugs?
And why would almost half not respond?
ryanc97
Senior Member (Voting Rights)
I mean under a different theory of the problem maybe different doses would be needed?
Say assuming plasma cells are the problem vs CD38 being the problem
Is the idea that symptom improvement would require antibodies to be stuck to CD38, or that just one of these events is enough to interrupt a positive feedback loop for improvement even after antibodies are gone? Is the former (antibodies stay stuck) possible with the length of time (> year) that people continued to see improvement in the open label study?
The latter is hard for me to imagine. Do we have some other example of where interrupting a positive feedback loop but otherwise not adding or removing anything from the body helps long term with a disease? I feel like the body's homeostasis mechanisms are too robust for this, but would love to see counterevidence.
I (maybe incorrectly) like the idea of something bad being removed more. Why not some antigen specific T cell? Maybe a specific type of Treg that was incorrectly made and is causing trouble? (Unfortunately, I have no idea what "trouble" would mean.)
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