Notice about a forthcoming paper: A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma

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Very excited that the paper will be coming out tomorrow! Huge thanks to you and Jo Cambridge and Jackie Cliff for all the work you've put into it - and to you, for sticking around for ten years in order to study the problem deeply enough to be able to write it.

rapidboson said:
Would we expect to be able to pragmatically test this hypothesis with a drug like fostamatinib?
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Jonathan Edwards said:
Probably not in that this drug blocks SYK kinase.
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Are there other drugs that might be a pragmatic test?

If the hypothesis is correct, is there a general class of drugs that might be effective, and are any of them non-horrible?

Does the hypothesis point to any non-drug interventions that might help?
 
Sasha said:
If the hypothesis is correct, is there a general class of drugs that might be effective, and are any of them non-horrible?
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We have a short section on possible treatments but members here will probably be able to suggest a lot more. None of them are guaranteed to be from of horribility since most will suppress aspects of the immune response. But we have found drugs that do, that are safe enough to use routinely.
 
Jonathan Edwards said:
We have a short section on possible treatments but members here will probably be able to suggest a lot more. None of them are guaranteed to be from of horribility since most will suppress aspects of the immune response. But we have found drugs that do, that are safe enough to use routinely.
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You mentioned a while back that endemic Covid had changed the landscape of using (I think) the -mab drugs. Would that apply to the ones that you're thinking about? Would they be one-and-done treatments or would we be on them long-term?
 
I should probably wait and go through the paper but if I’m understanding the summary (and I may not as I woke up at half 4 his morning)….
Some B cells create an antibody which binds to this specific receptor (Fc-gamma-RI) on certain cells, which means T cells get interested and fire off messages (interferon gamma, a cytokine) which activates macrophages so they to come in and do their thing and try to swallow up the cells (phagocytosis)? Are the B cells binding to the receptor on macrophages and so helping along a cycle between the T cells and macrophages? Or are the T cells and macrophages just communicating with each other over another tagged cell type?
 
I'm excited to see the paper, thank you.
Jonathan Edwards said:
Jo Cambridge has been involved in the evolution of this for a long time. Jackie Cliff was asked to help on the T cell side and did a great job pulling that aspect together. This isn't specifically her preferred theory, but then I wouldn't say it was for Jo and I either. It is an exercise in seeing how one could make a testable theory that accounted for all the salient facts.
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I was intrigued by this paragraph. Just while we are waiting for the paper, what are your preferred theories and what made you all settle on working on this one?
 
hotblack said:
which activates macrophages so they to come in and do their thing and try to swallow up the cells (phagocytosis)? Are the B cells binding to the receptor on macrophages and so helping along a cycle between the T cells and macrophages? Or are the T cells and macrophages just communicating with each other over another tagged cell type?
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No swallowing up involved, just unhelpful signalling.
B cells do not get near the interaction, only antibodies. The B cells are doing things elsewhere, including making antibodies that gum up the T cell-macrophage conspiracies.
 
I find it entirely unlikely that the proposed mechanism will have been correctly guessed the first time around, especially with the lack of any positive data, but I think what would be very nice would to get a layman understanding of how all the negative findings were used to try to get a story that fits the picture, especially in the case where testing this hypothesis yields further negative results that then have to be incorporated.

I was also wandering whether you or one or your colleagues will be able to present your ideas somewhere amongst colleagues not working in ME/CFS? Not only that some people can try to see if they find loopholes or alternatives on how the picture could look like but also to let people not working in ME/CFS know that there is serious research happening in the field.
 
Hutan said:
I was intrigued by this paragraph. Just while we are waiting for the paper, what are your preferred theories and what made you all settle on working on this one?
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I don't have a preferred theory in the sense of one I would put five pints of Adnam's bitter on it. I rather like the structure of this one but I do not have the sort of confidence that it is right that we had for FcRIIIa in RA. But before we came up with the FcRIIIa story in 1998 we had already published a related story in 1997 that it superseded. So by that measure we might have a story I would put a bottle of The Macallan 25 Years Old on within 12 months.
 
EndME said:
I was also wandering whether you or one or your colleagues will be able to present your ideas somewhere amongst colleagues not working in ME/CFS? Not only that some people can try to see if they find loopholes or alternatives on how the picture could look like but also to let people not working in ME/CFS know that there is serious research happening in the field.
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If only there were such venues beyond S4ME! I will no doubt present something along these lines to the UCL Division of Medicine seminars but I rarely get any very intelligent responses there. There are no professional oraganisations that bother with ME/CFS yet. ME/CFS meetings tend to be dominated by rather quirky people who probably wouldn't understand much of this. The days when I would give a seminar to Celltech and have my words repeated at a major event by Keith Peters a few weeks later are long gone. But once we have a bit more genetic data I think opportunities will open up and we will make use of them.
 
Jonathan Edwards said:
No swallowing up involved, just unhelpful signalling.
B cells do not get near the interaction, only antibodies. The B cells are doing things elsewhere, including making antibodies that gum up the T cell-macrophage conspiracies.
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Thanks for the clarification Jonathan. I’ll sit back and wait for the full reveal of The Conspiracy of the Leukocytes
 
Jonathan Edwards said:
If only there were such venues beyond S4ME! I will no doubt present something along these lines to the UCL Division of Medicine seminars but I rarely get any very intelligent responses there. There are no professional oraganisations that bother with ME/CFS yet. ME/CFS meetings tend to be dominated by rather quirky people who probably wouldn't understand much of this. The days when I would give a seminar to Celltech and have my words repeated at a major event by Keith Peters a few weeks later are long gone. But once we have a bit more genetic data I think opportunities will open up and we will make use of them.
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Is there a form of conference lacking that we should be pushing to be created?
 
@Jonathan Edwards I submitted to the analytical framework I have been using the FcRi receptors mentioned, namely CD64, CD32, CD16 in order to identify any associations of interest.

The framework suggested an association of these receptors with MERTK, among others. So i searched and found the following study : https://pubmed.ncbi.nlm.nih.gov/30091033/
From the abstract we read the following :

Mer receptor tyrosine kinase (MerTK) is key for efficient phagocytosis of apoptotic neutrophils (ANs) and homeostasis of IL-10 production by human anti-inflammatory M2c monocytes/macrophages. We asked whether stimulation of M2c surface receptors contributes in turn to MerTK activation. For this purpose, human monocytes/macrophages were differentiated under M1, M2a, and M2c polarizing conditions. The effects of antibody-mediated cross-linking of M2c receptors (i.e., CD14, CD16, CD32, CD163, CD204) on MerTK phosphorylation and phagocytosis of ANs were tested. MerTK expression was also studied by flow cytometry and western blot in the presence of LPS and in M2c-derived microvesicles (MVs). Antibody cross-linking of either CD14 or CD32/FcγRII led to Syk activation and MerTK phosphorylation in its two distinct glycoforms (175-205 and 135-155 kDa). Cross-linked CD14 enhanced efferocytosis by M2c macrophages and enabled M1 and M2a cells to clear ANs efficiently. In M1 conditions, LPS abolished surface MerTK expression on CD14bright cell subsets, so disrupting the anti-inflammatory pathway. In M2c cells, instead, MerTK was diffusely and brightly co-expressed with CD14, and was also detected in M2c macrophage-derived MVs; in these conditions, LPS only partially downregulated MerTK on cell surfaces, while the smaller MerTK glycoform contained in MVs remained intact. Altogether, cooperation between CD14 and MerTK may foster the clearance of ANs by human monocytes/macrophages. CD14 stands between M1-related LPS co-receptor activity and M2c-related MerTK-dependent response. MerTK interaction with CD32/FcγRII, its detection in M2c MVs, and the differential localization and LPS susceptibility of MerTK glycoforms add further new elements to the complexity of the MerTK network.
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I wonder if there is a useful connection between MERTK and your hypothesis.
 
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