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.