Preprint A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma, 2025, Edwards, Cambridge and Cliff

Thanks so much @Holinger I can take the wrong impression sometimes. Thanks for clearing that up. x

 

I have read the paper twice and came away thinking it would have been nice to have some pointers on next steps to look for evidence that could support this hypothesis. From one of the references it seems in RA researchers knew exactly where to find macrophages - could check the expression of FcγRIII and see that T lymphocytes came after the macrophage activation.

Do self-perpetuating B lymphocytes drive human autoimmune disease?

So how does one go about looking for macrophages in ME/CFS tissue to see (1) if FcγRI is up regulated? (2) Does T-lymphocyte co-location cause the FcγRI up regulation for example. Where do we look? What type of tissue would be needed. Could the PolyBio tissue sample bank be helpful - e.g. skin biopsies for SFN? What other experiments can be done?

 

I haven't read the paper properly yet but if this is tricky to figure out it's important that it gets addressed. I am very interested in testing the ideas in the paper and the more info available the better the design will be

 

Would your model still hold if a significant number of patients had low IFN-γ levels in blood, @Jonathan Edwards? Or asked differently, would it hold in patients with low IFN-γ?

 

I would like to present this paper to my facebook groups. I am thinking if this work is somehow unique and revolutioning. Can we say that it's unique or how to describe it in the best way?

Thank you Jonathan and other members for your hard work. I know that maybe there is still long way before us but after 25 years with this nightmare i feel the first time after a long time a bit optimistic

 

Thanks for all the comments. There are already one or two I (we) will respond to with an updated text. Nobody so far has noticed there is one study cited that has no reference and one reference with no citation! But Qeios have sorted that.

I am not expecting anything in the paper to be very new to members here but I am hoping that it might catch the interest of the wider immunology world who will have had no clue. As someone has said, more than anything it is an exercise in laying out a framework for arguing any model of ME/CFS one might prefer. And although it is long it does seem that people find it intelligible. Immunology doesn't need to be full of obscure jargon. But it is maybe fortunate that Sasha has had a week to bone up on hotdog buns.

I will try to respond to some specifics.

 

I’m sorting an audio version, a few pronunciation questions…

“FcγRI” I’m going for “Fc gamma R one”
“α1β4 integrin traffic domain”, “Alpha one beta four integrin traffic domain”?
“MAIT cells are pronounced “mate” aren’t they?

I think most of the others are initialised, things like GDF15, TNF, IL-6. I’ll knock something together today, it may not be perfect but should be listenable. And if there’s interest I can make fixes later.

Edit: Taking a bit longer than hoped, who knew there were so many ways to say the same thing… FcγRI, Fc-gamma-RI, or is that second a typo or a quote from a paper using a different way or writing things?

 

I appreciate the subtleties here but my statement was designed to make a simple point - that ME/CFS is not congenital. The arguments that follow still apply. And I could argue that if during the prodromal phase they are a bit unhealthy then ME/CFS has already started, if they are healthy then the argument stands!!

And if there is a conversion from prodromal phase we need another event - which is what the paragraph is about.

I agree this is more complicated but I will leave this bit I think.

 

Almost anything that jolts the immune system might have a knock on beneficial effect on a regulatory error I think. An annoying thing about working on theories of mechanism is that quite often the drug that is most practical for patients doesn't necessarily go for the most highlighted target in the theory.

 

Yes, and I say resolution may occur. I don't say that is unusual. I take the point that this could be twisted politically but including all possible nuances is likely to make the text even longer!

May main agenda here is to reset people's minds to think that we should consider the time course of ME/CFS the same way we do for RA or lupus - the expected pattern for a regulatory failure based on genetic risk. If there really is an MHC link then a long term fluctuating course is expected as norm. RA and lupus also resolve spontaneously at times. RA after pregnancy quite often resolves for good after a period of months.

 

Just started on this, armed with my knowledge of hot-dog buns, but already enjoying the 'A little more T-cells' quote at the start...

Thank you so much for this, @Jonathan Edwards, Jo Cambridge and Jackie Cliff.

 

Given that my aunt and my daughter both have severe, moderate/severe ME/CFS and trait wise are scarily alike, this is the most positive thing to happen for years! Thank you @Jonathan Edwards for listening , being curious and exploring possibilities.

 

Jo Cambridge raised this in our discussions and I think we should probably expand on it a bit. The current hypothesis does not predict the sort of clonal dominance that Mark Davis was looking for but the situation is subtle.

When people look for clonal expansions they are generally looking for individual clones having high cell numbers within a sample, which is what you get immediately after meeting a new antigen. Before you get Covid you will have 0.01% of your T cells recognising spike protein peptides, along with 0.01% recognising thousands of other peptides you never met and 0.1% recognising each of the peptides you once met in the past. On meeting Covid the clones recognising spike peptides may expand to 5% of your T cells. A year later they are down to 0.1%. (The numbers are invented.)

In the model the idea is that certain T cell populations will be expanded at some point in life - probably at the time of illness onset but quite possibly earlier in a prodromal phase. All this needs to be is a shift from the 0.01% group to the 0.1% group for T cells that happen to be a nuisance in the relevant genetic and antibody population context. Since we all have clones at both 0.01 and 0.1% levels there is nothing to see. The shift might turn out to be more easily identified but it is hard to say. In the diseases where we are pretty sure that T cell populations are causing pathology there has been pretty little evidence for clonal expansion as far as I know. I am thinking of Reiter's and psoriasis again. Reiter's is problematic because there ought to be a rise in clones recognising the trigger microbe anyway in these people. I have seen suggestion that in psoriasis T cells are recognising a melanocyte antigen but I have not read up about that in enough detail to be sure it is reliable and replicated - or indeed that clonal expansion has been shown.

And of course if MAIT cells are expanded they do not have the same antigen-specific clonality.

Jo and I have spent most of our time on B cells, which is why we recruited Jackie. She seems happy with the MS but I do think maybe this is one of the aspects most worthy of some debate and literature checking here.

The real problem here is that most immunologists have a simplistic view of these diseases as based on T cell recognition of specific peptides in the context of 'molecular mimicry'. As far as I know none of the rheumatic diseases fits that picture at all well, it at all. The problem lies at quite different levels of regulatory failure, and although those may throw up shifts in T cell populations it is much harder to know what.

 

I disagree. Mostly means more than 50%. And from what I have seen these plenty of adults are still only a minority and not much more than 20% of all cases?

Again, I would rather not fiddle about with this because it is irrelevant to the argument being made.

 

Yes, we could put that in.

 

I think proteins are mostly cleared from tissues via lymphatics. We would very much expect lower level of CK in ME/CFS because of lower activity so I doubt this tells us more than that there isn't any over-release.

 

I am not that convinced by these studies and I think they are tangential to the point being made. I don't think we should shy away from invoking neural hypervigilance. I am pretty sure that neural regulation is going to figure much more in future understanding of ME/CFS. I seem to remember that in a recent study the people with high heart rate didn't have so much reduction in cerebral blood flow, but, as I say, I am a bit wary of some of these studies.