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

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


Disturbances of energy metabolism contribute to clinical manifestations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Previously we found that B cells from ME/CFS patients have increased expression of CD24, a modulator of many cellular functions including those of cell stress. The relative ability of B cells from ME/CFS patients and healthy controls (HC) to respond to rapid changes in energy demand were compared. CD24, the ectonucleotidases CD39, CD73, the NAD-degrading enzyme CD38 and mitochondrial mass (MM) were measured following cross-linking of the B cell receptor (BCR) and co-stimulation with either T cell dependent or Toll-like receptor-9 dependent agonists. Levels of metabolites consumed/produced were measured using 1H-NMR spectroscopy and analysed in relation to cell growth and immunophenotype.

Proliferating B cells from patients with ME/CFS showed lower mitochondrial mass and a significantly increased usage of essential amino acids compared those from HC, with a significantly delayed loss of CD24 and increased expression of CD38 following stimulation. Immunophenotype results suggested the triggering of a stress response in ME/CFS B cells associated with increased usage of additional substrates to maintain necessary ATP levels. Disturbances in energy metabolism in ME/CFS B cells were thus confirmed in a dynamic in vitro model, providing the basis for further mechanistic investigations.

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1178882/abstract (Accepted and soon to be published)

 

Is this new data? Haven't seen Fane Mensah doing research into ME for a while. Sorry not able to read well today.

 

Full paper isn't yet available so difficult to tell. Quite possible it is further analysis of existing data, and why Fane might be listed as an author.

 

Yeah the latter is my guess as well. Thanks Andy.

 

It suggests that something is pushing lymphocytes towards a different pattern of metabolism. That could be a signal that is also making PWME feel drained etc. Whether or not it indicates directly a bottleneck to energy production I am less sure about.

It suggests that immune cells are taken up into the pathology, which makes sense. But I don't think it suggests that specific antibodies are relevant particularly.

 

I think the relevance may be that we would not expect B cells to have problems with energy production relating to circulatory/vascular or substrate apply problems. If they have changed their pattern of metabolism it suggests some sort of response to signalling molecules that affect differentiation/maturation.

One possible explanation for ME is that a regulatory disturbance is limited to the CNS - maybe hypothalamic or whatever. If B cells are behaving oddly that gives more support to the idea that the immune system is also dysregulated and that symptoms are based on peripheral processes, as for active infections.

I don't think any very tight conclusions can be drawn but if replicable the findings do give some support to a peripheral immune source of symptoms I think.

 

I am not sure it fits with anything very specifically.
I suspect that the signal would be 'pleiotropic' or in other words would do all sorts of things to all sorts of cells - because that is what these signals tend to do.

 

Has anyone tried to combine this paper with the authors previous one?

CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
https://www.s4me.info/threads/cd24-...-patients-with-me-cfs-2018-mensah-et-al.5983/

The 2018 paper by Armstrong & Mensah starts with "CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow".

Red blood cells (Saha), monocytes (Hanson) and platelets (Jahaniani) have been identified in fairly recent ME/CFS research. These cells also originate in bone marrow.

In the recent NIH ME/CFS Conference, and also the NIH Physiology Working Group Webinar early full body PET scans using the TSPO tracer by James at Stanford showed the bone marrow lighting up
https://event.roseliassociates.com/me-cfs-research-roadmap/recordings/

Similar bone marrow findings have been shown with PET scanning of CD8 cells in Covid convalescence .
First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10569706/

Could the bone marrow be the link to changes in different immune cells types found in ME/CFS?

 

Bone marrow doesn't seem to have been looked at much in ME? Why is that?

To my naive mind it would seem to be an obvious place to at least have a peek as the immune system has been a prime suspect in ME since about forever and many immune cells originate in the bone marrow.

Is/was there some good reason to think going right back to the bone marrow wouldn't be relevant?

Or is it just the practical problems of getting samples or high-tech scans?

 

Bone marrow sampling has a reputation for being one of the most painful procedures in medicine. It need not be too bad but it is not something to do lightly, certainly not repeatedly. There are also sampling problems

 

Ive done it two times with a local anaesthetic, and it was ok. Without the local anaesthetic id imagine it would be horrible just by the sounds i heard haha.

The first time they found some dysplastic cells, and the second time apparantly not. Ive always wondered if the dysplastic cells could have something to do with ME/CFS.

 

I figured one would need to be able to make a convincing case to get the go-ahead for bone marrow biopsies. I guess my question is more, is the lack of bone marrow studies because

a) it's been considered but no good case could be made to justify it, or
b) nobody has bothered to think about it?​

Is there such a thing as bio-banking for bone marrow biopsies, or any other biopsies for that matter, like gastric tissue etc? I'm thinking excess tissue from biopsies taken as part of standard medical investigations, not for any specific study. It seems a waste to subject patients to these invasive procedures and then only do whatever specific test they need at the time when for the same amount of pain one could obtain tissue that may come in useful for research later. Would require a substantial recording & admin system, so I guess it's unlikely to be happening

 

Making a hole in somebody's breast bone is not trivial so before doing a bone marrow one really needs to have some idea what one might be looking for and what it might explain. With nothing very obvious being present in circulating cells it is unclear what one might find.

Moreover, hundreds of people with ME will have had bone marrows over the years for other reasons and nobody has noticed anything unusual. Bone marrow contains different areas with different sorts of cells in varying proportions, so one cannot get much useful numerical data from it, except perhaps in terms of maturation of specific cell lines. You would need about 100 samples to begin to pick up anything statistical I think.

The problem with bone marrows done for other reasons is that the marrow may be abnormal for those other reasons, so unless something new, unique to ME, is found, it isn't much help, and there hasn't been.

It makes sense to consider marrow and Jo Cambridge and I would always consider that if trying to piece together a theory about immune cells, but even in other conditions where you have more to go on it is rarely a viable option. We never did a formal research bone marrow study in autoimmune disease.

 

I'm guessing that if these findings are replicated then it would be worth carrying out a similar study in Lyme, & long covid, i.e. to see if there is evidence of a similar pattern in those diseases.

I assume that if this result replicates then potentially:

• a high proportion of people ME/CFS have the same disease/pathology?
• GWAS [DecodeME] study may have a relatively "pure" population i.e. in terms of the disease(s) causing symptoms of ME?

 

The paper is published now by the way for those that didn't know

 

I've never thought a defect in energy production was the main cause of ME/CFS. I think energy production is impaired because the cells are shifting into a "defensive" state for some reason. Perhaps immune signals.

 

Yes basically where we are at is not knowing which in vitro abnormalities are cause or effect (of pathology or of each other). My guess is that it seems more easily explainable that the differences in energy pathways in immune cells are resultant from sweeping changes to immune cell metabolism due to a "mystery signal" rather than there being an underlying energy problem that changes how the immune cell functions, matures, activates, or whatever, but we have to test from both directions to know for sure. Both are possible until we finish testing this, I just suspect that there are more numerous or obvious or well-described possibilities that would facilitate the former. I reckon it is harder to think of explanations for eg: non-genetic, acquired, underlying mitochondrial dysfunction that would persist into cell culture. But maybe I don't know enough. I should have a chat to Chris about what he thinks of these ideas in relation to this data. I don't want to put a spin on the paper, just musing.

I specifically mean all of this in the context of immune cells only though. We haven't yet studied other tissues in this way enough to say much.

Can confirm (was talking to Chris yesterday) that this is Fane's older data yeah. Really good to see it published.