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

[Jonathan Edwards]

Doesnt that depend somewhat on whether the mechinism behind short term resolving Post Viral Fatigue/ Long Covid with PEM is the same as the one behind ME/CFS?

It cannot be the whole mechanism if it does not go on to ME/CFS. The difference between the two also needs a mechanism, surely?

 

[V.R.T.]

It cannot be the whole mechanism if it does not go on to ME/CFS. The difference between the two also needs a mechanism, surely?

Unless it resolves in the same way it sometimes (but rarely) seems to later in the course of illness.

Maybe whatever lever or widget is holding the dysfunctional signalling loop open, as in you and @jnmaciuch's metaphor from a couple of weeks ago (which I may be misremembering), spontaneously lets up the pressure and the system returns to homeostasis?

 

[Creekside]

I suppose what I'm getting at is, if your speculation is correct, what is it about pwME who have a longer time sick that might make it harder for them to be treated than pwME who have been sick a short time? If there is no detectable damage, as you have emphasised before? Some change in immune signalling that occurs later in the disease?

I see it in engineering terms, such as an electrical component shifting its value slightly, which in turn shifts a feedback loop to being more positive. In humans, maybe cell walls change their properties (molecular transport, etc) over time, or with repeated immune system activation. Jonathan's response about bistable systems implies that there are plenty of biological possibilities for these slight (hard to find in patients) changes that affect the overall loop function.

 

[Jonathan Edwards]

I took a look at this 2017 paper and I don’t see where it shows raised serum levels in gamma interferon. The charts I looked at seemed to show a rising gamma interferon that correlated with increased severity. In mild patients it was below the healthy controls and in moderate patients it was about the same as healthy controls and in severe patients it was elevated over healthy controls.

am I interpreting this information incorrectly?

I probably need to look at that again. We discussed it and my memory is that a signal came up for gamma interferon, along with the others, but the wording may have been a bit misleading. A correlation with severity would make sense but clearly is not the same thing. I don't want to put too much on this finding but when I went through papers it seems at least that there was a hint that gamma interferon was as likely a candidate as any.

 

[Creekside]

If I’ve understood the hypothesis correctly, PEM would be a downstream side effect of cellular debris triggering immune activation

That's certainly my belief for physically-induced PEM: muscle cell damage triggers immune activation, which somehow triggers glial activation, resulting in "sickness behaviour" symptoms. Cognitive exertion triggers the glial cells more directly, resulting in a shorter delay for PEM.

If that’s the case, would this hypothesis potentially allow for ME/CFS without PEM?

I certainly hope so, since I managed to stop my PEM, while still retaining the baseline ME symptoms.

 

[Kitty]

Still looking at the first few sections of the paper.

Female Predominance
Despite problems with diagnostic ascertainment, the prevalence of ME/CFS is consistently reported as between twice and four times greater in females than in males[12] ...

... Female predominance is consistently seen for antibody-mediated processes in a way not often seen outside diseases of female organ systems such as the uterus or breast. Such ratios are not seen in T cell-mediated diseases like psoriasis or ankylosing spondylitis (where the ratio is reversed)[21].

[My bolding]

Is it plausible that some of the sex difference could be exaggerated by males being more likely to recover than females?

If we don't have good figures for people who recovered in the first two years or so, it raises the possibility of a hidden population. Perhaps not especially likely, but as the apparent sex differences look important, it's worth asking the question.

 

[Creekside]

Does it necessarily mean harder to treat in ME/CFS? I read it as meaning that once the abnormal pattern's got established, there's less chance of it flipping back to normal on its own.

Less likely, but not impossible. I had several temporary full remissions in the first few years of my ME, but managed to get another couple in maybe year 10 or so? The factors of a complex feedback loop can change the opposite (beneficial) way too. It would be interesting to know whether any PWME started getting temporary (or permanent) remissions decades after developing ME.

 

[V.R.T.]

Intravenous immunoglobulin therapy is mentioned as being expensive but if it helped, even at a couple of grand a go, it would be cheaper than say care costs which can easily be that or more per month. So seems maybe worth investigating while other avenues are being looked at.

This is a very important point. There is a RECOVER long covid IVIG trial but frustratingly it's for POTS. And i think another arm of that trial is exercise...

But yeah IVIG and similar might be a worthwhile thing in the short term if it can keep some people out of a severe state. Care costs and the dangers of severe/very severe outweigh the expense, but from reports its nowhere near universally effective.

There was Efgartigimod as well - the trial failed but a lot of people got better and they were talking about legal action to get at the raw data, and about the fact that the POTS survey they used as a sole outcome measure was not sufficient and people massively improved on tilt testing and in terms of PEM. I know we are skeptical about failed trials with reports of improvement here generally, but if we think IgG lowering is a possible treatment path then I believe that was the mechinism of Efgartigimod.

 

[Creekside]

I wonder whether 'Neuro-immune over-responsiveness' would do better.

I think it would. An over-response could be due to increased inputs, increased sensitivity to normal inputs, increased sensitivity of downstream systems to normal outputs of the immune cells, or some malfunction not yet considered (maybe a protein is being produced at normal rates, but that process also produces larger numbers of defective proteins that cause problems). Neuro-immune malfunction might be more flexible. If you don't know for sure what sort of malfunction is involved, might as well go for honesty.

 

[Jonathan Edwards]

Is it plausible that some of the sex difference could be exaggerated by males being more likely to recover than females?

It is plausible.

 

[Jonathan Edwards]

Neuro-immune malfunction might be more flexible. If you don't know for sure what sort of malfunction is involved, might as well go for honesty.

I think that gets too vague though. I want to emphasise the point that ME/CFS looks as if it would fit with a much wider group of diseases where the immune system is 'trying too hard' which would include standard autoimmune diseases, seronegative spondarthropathies and heritable auto inflammatory syndromes like FMF. I see it as useful to contrast this with a past history of suggestions that ME/CFS is somehow an immune deficiency. I don't see any evidence for that.

 

[voner]

Jonathan,


I did a search for “vigilance” in your document. excluding your references, here is a list of usages of “vigilance” in your document:

• 'neuroimmune hypervigilance'
• 'immune hypervigilance'
• 'health vigilance'
• 'hypervigilance' immune states
• hypervigilance presents as
• acquired hypervigilance signaling
• neural hypervigilance state
• important immune vigilance mechanisms

I, like others, dislike the hypervigilance term because people will make associations with things like anxiety, "it is all in your head", etc. I especially think the part where women have a increased "Health Vigilance“ is suspect for misusage. It sure would be nice to find some different terminology.

 

[voner]

I want to emphasise the point that ME/CFS looks as if it would fit with a much wider group of diseases where the immune system is 'trying too hard' which would include standard autoimmune diseases, seronegative spondarthropathies and heritable auto inflammatory syndromes like FMF.

Perhaps you should just say this and and use it to define what you mean by "hypervigilance" in this context.

 

[Peter T]

I want to emphasise the point that ME/CFS looks as if it would fit with a much wider group of diseases where the immune system is 'trying too hard'

Would then ‘over active’ or ‘over responsive’ immune system be better?

 

[Utsikt]

Is it a peripheral immune intolerance?

I found the concept of immune tolerance on wikipedia. I have no idea if it’s actually a thing.
https://en.wikipedia.org/wiki/Peripheral_tolerancePeripheral tolerance - Wikipedia

 

[hotblack]

I understand people’s concerns with some terms due to misuse by and connotations with things people who have misused them have said or done. At the same time I can’t think of this as being anything other than a biological hypersensitivity or perhaps overreaction, or indeed a hyper-vigilance.

There’s going to be a point when the important thing is to focus on good clear descriptions for the people that will listen rather than being too concerned about what people who already have set and outdated ideas think.

We could even look at it as a nice irony in using their terms but in a biological rather than psychological sense.

That said, maybe something like “due to the combination of these factors there is an increased likelihood of reactivity with selected antigens” or something does the job? A bit wordy though. “Lower threshold for affinity/binding?” I’ve also just found out about the word “avidity” so will suggest that for novelty value!

 

[Jacob Richter]

Thank you Jonathan - and coauthors - for this fascinating paper.

I'm especially interested in how this hypothesis could be tested or refined through long-read whole genome sequencing, as in the proposed largescale SequenceME study.

I'm not an immunologist or a geneticist but I ran the paper summary, plus specifications for Oxford Nanopore's sequencing technology, through some LLMs and here's a synthesis of what they produced. I'm not qualified to judge the accuracy of the content below but it seems compelling; which is to say: one of the many useful things this paper does is reinforce the case for SequenceME.

It would be great to hear thoughts from others more qualified.

***
LLM summary

Long-read whole genome sequencing could be valuable for testing this paper’s hypothesis in several key ways:

1. Comprehensive Immune Gene Analysis: Long-read sequencing could provide complete characterization of the complex immune gene regions that short-read sequencing often misses or assembles incorrectly:

• Full resolution of the FcγR gene cluster (FCGR1A, FCGR1B, FCGR2A, etc.) on chromosome 1, including copy number variations and structural variants
• Complete assembly of HLA class I and II regions, which are notoriously difficult to phase and analyze with short reads
• Detailed characterization of interferon gene clusters and their regulatory regions
• Analysis of T cell receptor (TCR) and B cell receptor (BCR) gene segments

2. Structural Variant Detection: The paper suggests individual variation in immune responses. Long reads excel at detecting:

• Large insertions/deletions in immune regulatory regions
• Complex structural rearrangements that could affect FcγRI expression or function
• Copy number variations in immunoglobulin gene regions
• Inversions or translocations affecting immune gene networks

3. Haplotype Phasing and Linkage Analysis: Long reads can phase variants across entire genes and regulatory regions, allowing researchers to:

• Determine which combinations of immune gene variants occur together on the same chromosome
• Identify specific haplotypes associated with ME/CFS susceptibility
• Analyze linkage between FcγRI variants and other immune system polymorphisms

4. Regulatory Region Analysis: The hypothesis involves "hypervigilant" immune activation, suggesting dysregulated gene expression:

• Complete sequencing of promoter and enhancer regions for FcγRI and interferon gamma genes
• Detection of variants in long-range regulatory elements that short reads miss
• Analysis of methylation patterns in immune gene regulatory regions (using Nanopore's native base modification detection)

Specific Advantages for ME/CFS Research

1. Resolution of "Dark" Genomic Regions: Many immune system genes contain repetitive sequences and complex structures that are poorly characterized by short-read sequencing. Long reads could reveal previously hidden variants relevant to the FcγRI-interferon gamma pathway.

2. Personalized Immune Profiles: The paper notes that "specific B or T cell receptor species or affinities for particular antigens may vary from individual to individual." Long-read sequencing could create detailed immune genetic profiles for each patient, potentially identifying subgroups with distinct mechanisms.

3. Integration with Functional Studies: The comprehensive genomic data could be correlated with:

• FcγRI expression levels and binding affinity measurements
• Interferon gamma production assays
• T cell activation profiles
• Autoantibody screening results

Expected Outcomes
Long-read sequencing is more time-intensive than short-read approaches, but the comprehensive data justifies the investment. This approach could:

• Identify specific genetic variants predisposing to the proposed "neuroimmune hypervigilance"
• Reveal biomarkers for patient stratification and personalized treatment approaches
• Provide molecular targets for the therapeutic interventions the authors suggest might be worth exploring
• Support or refute the hypothesis by demonstrating whether ME/CFS patients have distinct patterns in FcγRI and interferon-related genes

 

[Jonathan Edwards]

I'm not an immunologist or a geneticist but I ran the paper summary, plus specifications for Oxford Nanopore's sequencing technology, through some LLMs and here's a synthesis of what they produced.

Interesting. As always, AI tends to turn up what you had thought of and a few things that don't quite add up but it is always nice to see what the consensus literature might come up with.

It doesn't seem to mention interferon-responsive genes which I would like to see data on.


One thing that has occurred to me is that genetic studies may well provide very satisfying corroborative evidence for models like this but I am not so sure they will provide Popper's 'dangerous experiments' - the ones capable of destroying your hypothesis and leading you to a better one. I think drug interventions may be needed for that, but if more genetic studies corroborate where to look hard that will be a huge step forward.

 

[Jonathan Edwards]

I found the concept of immune tolerance on wikipedia. I have no idea if it’s actually a thing.

Immune tolerance is a very real thing. You are tolerant of all your own proteins. Mice are not tolerant of foreign proteins but clever tricks can make them tolerant. Sadly those tricks are not so far proving to solve transplant rejection in humans. The practicalities are complicated.

Peripheral tolerance is something people talk about and I have never been sure I really buy as a useful idea in people.

The relevance of tolerance to our model is not great but we introduce what is perhaps a new nuance to tolerance/immunity. The idea is that whether or not you appear to have antibodies to something knocking around depends on what context the antibody is binding in. It may be that in the context of binding to the FcRIII receptor the antibodies just aren't interested enough to mediate 'immunity' to the junk. On the other hand in the context of FcRI they may pass bits of the junk to T cells and mediate a T cell immune response.

Immunology is a bit like a puppet show. You see the puppets moving smoothly around doing what they are supposed to do but what you do not see are all the clever hand movements of the puppeteer that have to be done together to make things work. What appears to be a single integrated immune response orchestrated by macrophages, T cells and B cells is in fact contrived by all sorts of swap-over moves that only work well because everything is aligned right. The system is shimmed up pretty much so that any particular error sufficient to produce major disability only occurs in about 0.5% of people and lethal errors in not more than 0.1%. That is pretty good but isn't perfect.

 

[Arfmeister]

Implications for Treatment

The proposed mechanism for ME/CFS raises several possible options for treatment. All present potential risks in terms of blocking important immune vigilance mechanisms but probably no more than many immunomodulatory treatments currently in use. The main targets implicated are persistent low-affinity IgG antibody populations, FcγRI expression on macrophages, local gamma interferon release (perhaps other cytokines without direct inflammatory actions), and T cell activation or clonal expansies.

I’ll deduct some of the potential treatments based on the paper

Main Targets for Treatment: Persistent low-affinity IgG antibody populations, FcγRI expression on macrophages, local gamma interferon release, and T cell activation or clonal expansion.

Treatment Options Immune supression :

• anti-CD38 (e.g. Daratumumab, Isatuximab) with small molecule agents like mycophenolate or bortezomib to reduce IgG levels.
• Intensive chemotherapy (e.g cyclophosphamide) reduced IgG populations and contributed to ME/CFS improvement - NOT recommended but as a reference
• FcRn blockers (e.g. efgartigimod, rozanolixizumab, etc) reduce total IgG levels by blocking the neonatal Fc receptor, indirectly lowering IgG at FcγRI.
• Intravenous immunoglobulin therapy IVIG may help but is cumbersome and expensive.
• Empalumab (anti-IFN-γ monoclonal antibody) can block gamma interferon production or interaction from T cells.

Targeting T cell populations:

• cyclosporine - Suppress T cell activation; memory cells may persist but become less responsive
• mTOR inhibitors = Rapamycin, evosirolimus
• Alemtuzumab, anti-CD52 T cells = Lemtrada, Campath - Long-term T cell depletion with anti-CD52 proved to be associated with relatively little morbidity in trials for rheumatoid disease
• more subtle approach T cell signalling JAK/STAT pathway = JAK-STAT inhibitors

Maybe in the future heavy duty Teclistamab and CAR-T when more researched and advanced ?