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

[Utsikt]

As someone who had the same question and had to Google: independent or not influenced by existing ideas or assumptions

Literally, it means in a direction that has nothing in common with what has been indicated before - at right angles. It generates a cotangent of ZERO.

Thank you!

So it’s orthagonal in relation to previous ideas, not the data. That’s what was throwing me off.

 

[Jonathan Edwards]

So it’s orthagonal in relation to previous ideas, not the data. That’s what was throwing me off.

I think what EndME meant was that it was orthogonal in approach. Everyone else was taking the metro here or there and we were suggesting going up the Eiffel Tower.

 

[Utsikt]

I think what EndME meant was that it was orthogonal in approach. Everyone else was taking the metro here or there and we were suggesting going up the Eiffel Tower.

Makes sense, thank you again

 

[wigglethemouse]

Sorry if you have already covered my question in this thread. Can you explain why the "junk antibodies" in this hypothesis paper would not be detectable as a difference in the Andrew Grimson March 2025 antibody paper (thread link) that had a null result.

In the thread of that study linked above you had this to say.

It fits very well with the picture of ME/CFS immunology that is crystallising in my mind.
But it doesn't necessarily mean that B cells are not involved.

 

[Jonathan Edwards]

Sorry if you have already covered my question in this thread. Can you explain why the "junk antibodies" in this hypothesis paper would not be detectable as a difference in the Andrew Grimson March 2025 antibody paper (thread link) that had a null result.

What I hoped we had explained in the paper is that the antibodies we were invoking would not bind with the dissociation constants needed in conditions of a standard autoantibody test. The suggestion is that for steric reasons that we do not claim to know about, these antibodies may engage in interactions in the context of FcRI but not other FcR, complement, or the plastic surfaces of ELISA plates. Because FcRI can immobilise antibody even without antigen binding we know the thermodynamics of engagement are likely to be different. It is a speculation, and likely wrong, but it was a way to try to pull together a range of unexplained features.

 

[Jonathan Edwards]

The other thing is that these low affinity-for-junk antibodies might bind post-translational modification epitopes - like glycated or citrullinated proteins. These would not show up on any standard assays.

 

[ellesa]

Apologies if this is not the right place to ask this, but I am wondering if some recent work in LC aligns with the hypothesis. I am only at the hot dogs and buns stage of learning immunology so I can't do much more than notice when the same words are occasionally repeated, without understanding how they fit together or how often these words would be expected to come up in totally unrelated situations...

The first is the work of Douglas Fraser which was presented at a Long Covid Web webinar in April -

.

The proposed mechanism was summarised in the following diagram, along with the proposed MOA of upadacitinib which is being trialed currently.

The second one is the work of Jie Sun which was mentioned in an article about a successful grant

Dr. Sun’s team has discovered that an immune alarm signal called interferon-gamma can remain switched on after the virus is gone, prompting a prolonged conversation between lung-resident T cells and macrophages that fuels scarring. Over the next five years, the researchers will pinpoint exactly how interferon-gamma from T cells sparks this chronic inflammation, test whether blocking its partner pathway (STAT1) in macrophages prevents long-term damage, and chart the entire molecular chain in search of drug targets.

https://news.med.virginia.edu/featu...ging-and-chronic-diseases-after-viral-injury/

I am hoping that this is showing multiple lines of inquiry converging but I don't know enough to know if this is all just work saying 'the immune system is involved' rather than actual convergence.

 

[Jonathan Edwards]

I am hoping that this is showing multiple lines of inquiry converging but I don't know enough to know if this is all just work saying 'the immune system is involved' rather than actual convergence.

These are relevant mediators but in both cases it looks as if there is an assumption that the events lead to inflammation and in ME/CFS there is no inflammation. It is not the problem. What I think these things show is more or less what EndME was referring to in terms of everyone going back and forth along metro lines of where immunology received dogma says you have to ride (which turns out to be the wrong place). But to see what is actually the problem you need to get a view from the Eiffel Tower.

 

[Jonathan Edwards]

To put that in context @ellesa, maybe I should explain my general view of immunology a bit.

Immunologists have been very good at working out how normal bodies respond to known insults. This has been done with animal experiments where you know what insult you are using.

What immunologists are terrible at is working out what is happening when the response rules go wrong - which is the problem for a lot of diseases we still suffer with after having dealt with infectious diseases. They try to fit human diseases into stories like the animal experiments they do, where you add in some insult and get a response. In human disease there may be no insult at all, just misguided immune cells getting themselves confused.

We had a very positive advisory board meeting for DecodeME this week. I am not allowed to say anything about any results but it included an interesting debate between myself and Chris Ponting about what results might mean if they were this way or that. It reminded me that although immunologists think they have models for multiple sclerosis they have in fact absolutely no idea why the main genetic risk factors for MS make it more likely. They are completely stuck riding up and down from Place de la Concorde to Montmartre without having any clue that where the want to be is ambling through the Tuileries Gardens.

Somewhere amongst all this information out there is a story for ME/CFS that makes sense but it is likely to lie in the raw data, not in the interpretations that immunologists insist on encrusting the data with, especially if it ends up at inflammation. Getting a wide angled view with everything in perpective takes a long time but the best way to do it in my experience is exactly the sort of free exchange of thoughts we have here. Someone suggests something. Someone disagrees. Another person digs up a reference that suddenly reveals new possibilities. We all get a clearer picture and start the next flight of stairs up to get an even better view.

 

[rapidboson]

@Jonathan Edwards Following this hypothesis, would we expect any deterioration with Imunovir / inosine pranobex? (Just revisiting drugs that were in vogue at some point.)

The Czech Wikipedia article on it is pretty thorough (Google Translate).

In the narrow sense, the only synthetic immunomodulator (drug) with proven immunomodulatory and immunopotentiating effects is inosine pranobex. This drug is indicated for the entire spectrum of patients with clinical manifestations of immune deficiency. It has a direct antiviral effect. It modulates the immune system by immunostimulation, or immunooptimization of defensive inflammation [ 6 ] at the cellular level, e.g. by interfering with energy metabolism, cell signaling and proliferation. It modulates components of innate immunity, NK cells and dendritic cells. It suppresses the production of pro-inflammatory cytokines TNF-α and IL-6. It homeostatically and regulatory optimizes the functional polarization of T lymphocyte subsets Th1, Th2, Th17 and Treg. [ 7 ] In clinical studies, isoprinosine normalized impaired cellular immunity by inducing a Th1-type response, which initiates the maturation and differentiation of T lymphocytes. In vivo, it inhibits the synthesis of viral RNA.

Some studies mentioned further down in the article seem to have found increased gamma IFN, IL-2 and IL-10. Others find increased CD25.

This study on ME patients, in which 6/10 improved, does not show this change in cytokines though. But in CD4+ cells and NK cell activity.
I haven't seen newer studies, in the USA it seems very expensive and rare, in Europe it's dirt cheap and OTC.

 

[ellesa]

What immunologists are terrible at is working out what is happening when the response rules go wrong - which is the problem for a lot of diseases we still suffer with after having dealt with infectious diseases. They try to fit human diseases into stories like the animal experiments they do, where you add in some insult and get a response. In human disease there may be no insult at all, just misguided immune cells getting themselves confused.

Thank you, so far what I have learned about immunology is that there is not A -> B -> C, but a combination of {A, B, C, D, E} that needs to happen at the right time for {G, H, I} to happen. And that C, D, E, H or I are not well understood or discovered yet. So is it kind of like everyone assuming that if they see A and B they assume that G is going to happen, even if it turns out, C, D and E are missing.

 

[Jonathan Edwards]

Indeed.