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

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.

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?

 

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.

 

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?

 

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.

 

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.

 

Just to clarify: is this a general statement about results forthcoming, or have you seen specific results?

 

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.

 

It is a general statement about results forthcoming. I have seen some results but that is not for public consumption.

 

Thanks for the clarification Jonathan. I’ll sit back and wait for the full reveal of The Conspiracy of the Leukocytes

 

I also wonder if when having a cold or Covid the opposite can happen. I didn't feel like I had ME for the first 8-10 days of Covid last year.

 

Is there a form of conference lacking that we should be pushing to be created?

 

That's the title of the book, right there.

 

@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 :

I wonder if there is a useful connection between MERTK and your hypothesis.

 

Yes, and that there is tantalising, eminently solve-able puzzle out there begging to be solved.

 

Just a reminder that this is a public thread.