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

It is likely that Australian studies I design this/next year will try to answer questions raised by Jonathan's paper

 

Any chance the MRFF funded platform trial can look at some JAK inhibitors?

 

That sounds great, I'd love to be a fly on the wall for some of those hypothesis/method discussions.

 

Same. I’m really interested in which bits people are and are not able to look at and how people can go about testing the ideas. Look forward to hearing more.

 

Didn’t Decode Me report that in their sample that not only were there more women than men, but that the women were more severe than the men?

 

I’ll reiterate that this paper is very accessibly written, thanks again to @Jonathan Edwards , Jo, and Jackie for the work that went into this.

You’ve said elsewhere that your hope is to have a collaborative effort of creating theories, poking holes in them, and seeing what is still viable in the aftermath—in that light, I figure the best compliment I can give is an earnest attempt at this.

The primary issue I see is in the lack of specificity of an interferon gamma-mediated mechanism. Purely theoretically, IFN-g could “prime” a macrophage to be more reactive to FcgRI binding, but the level of interferon gamma stimulation required for this priming would almost certainly also make them more reactive to LPS and PAMPs (bacterial crud, for anyone unfamiliar), oxidized cell free DNA…pretty much anything that activates a TLR or a cytosolic sensor. IFN-g is well known as a pretty broad spectrum sensitizer in that regard.

In which case you’d also have hyper-responsiveness to those other stimulatory signals, which unlike this proposed mechanism, are well known to elicit a macrophage response more typically associated with inflammation wherever those cells are likely to encounter those signals. And yet, only a fraction of pwME report constant GI issues, where you would expect hypersensitized myeloids to react to bacterial pathogens round the clock. I’ve also not seen pwME mention any hyperreactivity to skin wounds mediated by FcgRI on localized dendritic cells.

Do you have indications that a much lower level of IFN-g would be capable of inducing FcgRI “sensitivity” but not sensitivity to everything else? Or something which would indicate a very specific localization for this “priming”? I have not seen anything at all which would hint at either point, but perhaps I am missing an important detail which would make this make sense.

 

Yes, but I envisage the T cell macrophage interaction as occurring within a highly controlled microenvironment within lymph node or spleen, where bacterial products are not expected to be present at levels that would generate inflammation. I am thinking in terms of the study João Fonseca did with us on CD163 expression in RA tissue. Gamma interferon signalling was limited to specific areas, not in B cell clusters, where macrophages were CD163 negative, suggesting a quite specific functional specialisation. Masses of T cells were present elsewhere but had no interferon staining.

 

I don’t follow how interferon gamma expression in only those tissues would then correlate with any ME/CFS symptoms, especially for PEM. You've previously linked interferon gamma to ME/CFS symptoms on the basis that interferon makes people feel lousy. And we know that is true from interferon alpha and beta therapies where type I interferon will be present at high levels in the circulation. But I see no reason to believe that symptomology in those cases is dependent on interferon in the spleen or lymph rather than anywhere else [edit: connected to the circulation].

I’m familiar with that study, my work for nearly 2 years involved characterizing FcgRI+ macrophage subpopulations in synovium at single cell resolution with CD45.1/2 tracing to determine origin. We've confirmed numerous times that the CD163- population is also present in healthy synovium, covering both a subset of tissue-resident CX3CR1+ macrophages as well as all MHCII high CCR2+ BMDM. It is just a much smaller proportion than in RA, where you see a huge influx of those BMDM. I would bet my lunch that's the subpopulation interacting with T-cells--they're already CD163- coming from the circulation, not necessarily induced to lose CD163 from IFN-g. Culemann may have already shown that, I heard he had some things in the pipeline but haven't been keeping up.

So that leads me to another question: If it is a functional specialization causing only macrophages in the spleen/lymph to interact with T-cells in this way, why would those subpopulations only be present in ME/CFS and not in healthy people?

 

My assumption is that in an immune response recognition events involving recruiting T cell clones primarily occur in lymphoid tissue where antigen is brought in by macrophages or dendritic cells to a place where there is a high concentration of memory T cells, some of which might recognise the antigen.

In ME/CFS we don't have any other tissue where we have evidence of any signalling going on locally. Gut is a possibility, since the epithelium provides an interface with vast amounts of antigen and something like half of lymphocytes live in gut wall. But again, they are in microenvironment in Peyer's patches.

I think it likely that malaise with viral infection similarly depends heavily on interactions in lymphoid tissue. How the gamma interferon gets out to sensitise nerves or brain or whatever to produce malaise or PEM is the mystery but it is for viral malaise too. And a subfornical organ that receives T cells primed elsewhere that can signal very locally seems a rather neat possibility.

If PEM includes myalgia and weakness all over and was triggered just by using arm muscles to fold linen then we have to rely on a systemic signalling system something like this.

 

I am certainly not suggesting that they are not present in healthy people. The model is based on the idea that everything in people with ME/CFS is at least initially following all the same rules as in normal people. But either because of genetic differences in response thresholds in e.g. MHC interactions or because of expansion of T cell subpopulations that go AWOL, as in psoriasis, a process that normally only occurs in the presence of new antigen such as virus carries on, or simmers under the surface and boils over during PEM.

There doesn't need to be a 'primary target tissue' here. If the cognate aspect (if there is one) involves lowered response thresholds to more or less ubiquitously available proteins then the place where 'maladaptive recognition' events are most likely to occur is lymphoid tissue, since there are masses of the right sorts of cells there.

 

When I say macrophages I don't have very strong feelings about the dividing line with 'dendritic cells'. Having studied cell populations in tissue before we even had dendritic cell markers (or anybody recognised them much) I have continued to take the view that these names are often Procrustean and that there is probably every sort of intermediate cell.

I don't think we knew much about about functions of CD163 in 2000 although I think we did know it was a scavenger. It would seem very reasonable to me that there might be a population of cells that do not express CD163 'in order to' focus on interactions with T cells. It would be useful to know if these cells had high FcRI of course - we never looked at that.

 

What is your basis for this? If that was true, then I don't see how you would be able to mimic viral infection malaise very closely with just type I interferon treatment. That would suggest you can pretty much bypass the interaction part [edit: even if it is the important upstream step in actual viral infection].

No one's looked for non-inflammatory interferon signaling in other tissue. Just like you're proposing in the spleen, interferon signaling need not spill into other immune signaling in the absence of further TLR stimulation.

I don't recall any indications of that--there was no FcRI high/low split that I could see in my data sets. I also tried direct correlations of gene expression levels for the various markers of subpopulations--I don't recall Fcgr1 being highly correlated with any of them indicating subset specificity. ADT data didn't seem to suggest anything either although was spotty (despite generally corroborating the RNA data). CD163 didn't have the best antibody. I'd have to go back to the human datasets to confirm definitively, though, and those are unpublished.

 

Single cell data would agree with you there

 

I also must admit that though I'd be happy to attribute things to a T-cell response, I just don't think there is strong evidence for them above any other cell type. Zhang et al. gave a very weak indication for HLA-C only (and a loss of function mutation, not a gain of function, no less). I don't believe it was actually standalone in the STING networks, though perhaps someone else could correct me on that.

In other conditions mediated by MHC, those haplotypes are far and above the strongest association. The skyscraper that dwarfs everything else in the Manhattan plot. You've alluded on other threads that DecodeME might provide hints once that data is publicly released. If it does happen to show an MHC haplotype that rockets above all the rest, I'll be happy to concede on that. If it is a weak association, though, I remain skeptical of it being proof of the centrality of T cells.

 

If what you ultimately need is enough of a signal to stimulate certain cells around hypothalamus then bypassing earlier steps that generate one signal option isn't a problem, surely?

I agree but I find it hard to think of somewhere else that would fit. It needs to end up signalling systemically and I am unclear how you do that with type I interferons several hours later and without raised plasma levels. The advantage of gamma interferon is that T cells can traffic around and secrete it all over the place. Macrophages probably don't traffic out of tissues and then back into others (except into lymphoid tissues).

That would be intriguing since FcRI is supposed to be gamma interferon responsive.

 

We will see.

 

Perhaps to add that this model was devised some years back and I posted the T cell aspect here about a year ago, long before we had any genetic data. My argument was based on the long term disease dynamics, following intracellular infection and relapsing and remitting very often, or progressing. That could be antibody driven but we had seen evidence against that. It is actually a very similar dynamic to RA (but not in age incidence profile). I think an adaptive immune response is much the most likely explanation for the dynamic, but, as discussed in the paper, it almost certainly would not fit simplistic stories of breakage of tolerance that immunologists mostly feed on.

 

But it does mean that theories which are reliant on T cells (which we have no indication of here) are not on any higher footing than those that propose a positive feedback interferon loops without T cells (for which there is already evidence, such as individuals with high IFN-k in the skin even before cutaneous lupus develops).

 

Why not raise your concerns in a review on Qeios, @jnmaciuch !! They would then be formally published.