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

RedFox said:
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.
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I have long been of the view that most of what we see and know so far about ME is the patient's physiological and behavioural reaction to the underlying problem, the attempts to deal with a pathological demand on otherwise normal healthy systems now being forced to operate beyond their sustainable capacity, not the underlying problem itself.
 
Andy said:
@DMissa , is it this research that you will be talking about at UK: Conference: MitOX 2024, 12th April 2024
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That is a hard question to answer because there is a lot going on and not sure exactly which part of it you are referring to (whether my comment or the paper). I will do my best to clarify. I will do so only briefly so as not to derail away from this paper since it mostly concerns my own largely unrelated work, even if Chris is involved.

1) I had and have no involvement with this paper + data nor am I aware of being involved with following up on it directly. I met Jo and Fane while the work was being done but that was about it. The cell lines I have published about are selected from B cells but they are transfected with EBV and imo not directly comparable. I am working with Chris on these lines but I would consider the work separate for this reason. When I said where "we" are at I meant the community in general, from my POV anyway.

2) If you refer to me mentioning cause-effect and mechanism determination, I may have given the wrong impression that it was directly tied to this paper. Maybe not, but I will clarify in case. I was referring to work that I am involved with, while assuming that others are maybe doing similar things (following up published differences by testing how they relate to one another and to pathology: in isolation, in combination, by eliciting them by different approaches, and by using several types of cells, tissues, and even organisms). I don't know if there is such work related to this paper being undertaken. Basically again my comments were general (about this area of the field).

3) The MitOX talk will likely include data collected in collab with Chris. Some may be published by then, first manuscript almost finished. Depending on what makes the cut, aspects of the presented work may be relatable to this paper (since we are also working with unimmortalised immune cells too, as well as other tissues). Trying as hard as I can to get everything written up so regardless it should be in everybody's hands at some point.

PS: I do hope that the good work in this paper is being followed up. Jonathan might know? It may also be private information. Anyway I say this because as a generalist cell biologist I want more people who actually know what they're talking about looking at the metabolism of immune cells in such close detail.

Hopefully this is all clear now.
 
Happy to report that upon another look this paper seems to replicate closely with my own work

I just checked the unadjusted* mito red fluorescence of about 100 ME/CFS LCLs and something like 60 or 70 HC and it is also reduced as seen in the B cells in this paper. Sharing it here because that value probably won't get reported in a paper or used for anything by itself.**

In fact if we take the three things directly related to energy pathways from this paper: 1) mito red fluorescence is down 2) amino acid usage is favoured 3) glycolysis unaffected, all three of those things match the published cell line data. Could suggest that these specific differences persist thru into the lines despite the epigenetic changes induced during immortalisation. Would have been good to check this directly in a fraction of my parental B cells... hard to directly compare as I said in the last comment. But a good sign.

*Mito red was used by itself in this study which means the fluorescence is a function of both mass + MMP.
**Because MitoTracker Red stains membrane but is also MMP dependent (when presenting mass I use mito green, and presenting MMP I use mito red normalised to green to produce a MMP measurement that accounts for differences in mass)
 
Jonathan Edwards said:
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.
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I have a couple questions for you regarding the B cell work..

- CD38 is known to degrade NAD+, removing the NAD+ pool would reduce the speed of ATP production, do you think Daratumumab may have potential by simply removing cells that are more likely to reduce the NAD+ pool?
- CD24 seems to have been identified consistently elevated on B cells in ME cohorts by Jo Cambirdge, no one else is yet to even look at it, what is your opinion on why that could be?
 
MelbME said:
- CD38 is known to degrade NAD+, removing the NAD+ pool would reduce the speed of ATP production, do you think Daratumumab may have potential by simply removing cells that are more likely to reduce the NAD+ pool?
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I don't really see the connection. Like CD20, CD38 is just a useful ligand for identifying cells for antibody-mediated killing. If you kill lots of plasma cells you end up with no antibody production but not much effect on the rest of the body as far as I know.

I see that CD38 seems to be a significant NADase, but I am unclear what the significance of that is to metabolic function. In 2000 we didn't use anti-CD38 because we were told CD38 was expressed on other cells, such as cardiomyocytes. It seems to be that anti-CD38 antbodies do not cause major problems with these other cells. So presumably their metabolism carries on as usual.

MelbME said:
- CD24 seems to have been identified consistently elevated on B cells in ME cohorts by Jo Cambirdge, no one else is yet to even look at it, what is your opinion on why that could be?
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Jo was interested in CD24 because in repopulation following rituximab CD24 return behaved strangely. I think particularly in patients with thrombotic thrombocytopenia purpura. There aren't really any other B cell biologists working on ME/CFS as far as I know, now that Amok Bansal has largely retired from research. Even most other immunologists probably have little interest in CD24.


If B cells are relevant to ME/CFS I suspect the story is subtle and not a matter of some obscure specific autoantibody effect. Something that has proven important in lupus is the control of extra follicular B cell survival. It may also be relevant in RA in a different way. The question arises as to whether in ME/CFS the female predominance reflects a shift in maturation control for B cells, analogous to but not the same as in lupus, that allows for the formation of antibody populations that are not autoreactive but 'bad' for some other generic reason. If they were directed against foreign antigens and made by long lived plasma cells then rituximab would make no difference.

Maybe there is another 'quality control' mechanism for antibodies that is defective in people with ME/CFS such that they form antibodies to microbes that get in the way in some non-specific way - maybe by forming complexes of the wrong size or triggering too much ADCC or something. These antibodies might normally be selected against during an immune response through some interaction with CD57+ T cells outside follicles or something (just an illustration).

CD24 might be a marker of such a maturation shift, which might of course also be reflected in a shift in mean values for B cell metabolic pathways.
 
Jonathan Edwards said:
I don't really see the connection. Like CD20, CD38 is just a useful ligand for identifying cells for antibody-mediated killing. If you kill lots of plasma cells you end up with no antibody production but not much effect on the rest of the body as far as I know.

I see that CD38 seems to be a significant NADase, but I am unclear what the significance of that is to metabolic function. In 2000 we didn't use anti-CD38 because we were told CD38 was expressed on other cells, such as cardiomyocytes. It seems to be that anti-CD38 antbodies do not cause major problems with these other cells. So presumably their metabolism carries on as usual.



Jo was interested in CD24 because in repopulation following rituximab CD24 return behaved strangely. I think particularly in patients with thrombotic thrombocytopenia purpura. There aren't really any other B cell biologists working on ME/CFS as far as I know, now that Amok Bansal has largely retired from research. Even most other immunologists probably have little interest in CD24.


If B cells are relevant to ME/CFS I suspect the story is subtle and not a matter of some obscure specific autoantibody effect. Something that has proven important in lupus is the control of extra follicular B cell survival. It may also be relevant in RA in a different way. The question arises as to whether in ME/CFS the female predominance reflects a shift in maturation control for B cells, analogous to but not the same as in lupus, that allows for the formation of antibody populations that are not autoreactive but 'bad' for some other generic reason. If they were directed against foreign antigens and made by long lived plasma cells then rituximab would make no difference.

Maybe there is another 'quality control' mechanism for antibodies that is defective in people with ME/CFS such that they form antibodies to microbes that get in the way in some non-specific way - maybe by forming complexes of the wrong size or triggering too much ADCC or something. These antibodies might normally be selected against during an immune response through some interaction with CD57+ T cells outside follicles or something (just an illustration).

CD24 might be a marker of such a maturation shift, which might of course also be reflected in a shift in mean values for B cell metabolic pathways.
Click to expand...


Thank you. I agree with you on the role of B cells in the disease. I'm more interested in their unusual behaviour, which may be due to the underlying problem or a reflection of that problem.
 
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