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

Seems like the results are not ordered chronologically. For me it's the third result.

 

Apologies, but this kept bothering me. If this model explains ME/CFS symptoms via T cells trafficking around and spewing interferon gamma all over the place, then my original critique still stands:

Interferon gamma would potentiate any circulating myeloid if it had to get in the circulation to cause symptoms.

 

I don't follow that. A T cell is not going to interact with a myeloid cells in the bloodstream. They will be going past each other like F1 drivers.

 

The potentiation doesn’t occur through direct interaction with a T cell, just stimulation of the IFNGR

 

But the receptor isn't going to be stimulated by a T cell going past like Schumacher in a sea of plasma and red cells. I don't know the details of concentrations but my guess is that gamma interferon signalling in a tissue microenvironment is going to be several orders of magnitude more efficient than puffing some out in the breeze and hoping another cell gets a whiff. And any two white cells in blood probably do not get even enough for a whiff for more than fractions of a second.

 

Except that other examples of hypothalmic signaling require a sufficient circulatory concentration. You can induce fever by exogenous IL-1. That indicates that the hypothalmus detects a critical concentration of the cytokine, not specific cells. Similarly, I recall a study posted by someone on another thread showing that injection of a cocktail of cytokines induces myalgia. [Edit: viral infection features detectable levels of type I interferon in the blood]

I've seen some very tentative evidence that e.g. circulatory myeloids make it to the hypothalamus and secrete cytokines locally to induce responses. But when that occurs, it would've been at a sufficient concentration to also observe in the circulation. The idea that a small concentration of IFN-g spewing T-cells would be enough to zip to the hypothalamus and trigger the intensity of symptoms in ME/CFS seems at odds with every other similar example in the literature.

 

But I don't think that is the whole story that we know. Hypothalamic signalling can just be neural - feeling nausea on seeing blood for instance. PEM and other ME/CFS symptoms do not include fever as far as we know so IL-1 signalling is probably not relevant. Yes, you can signal to the hypothalamus with soluble IL-1 or alpha interferon but that doesn't by any means mean it is the only way to signal to it - how about satiety from vagal afferents and indeed fatigue from muscle afferents, as Snow Leopard emphasises. And I don't think we actually know what is needed for signalling malaise during flu.

If cells get to hypothalamus and signal I see no need for that to be reflected in circulation. In a tissue microenvironment tiny amounts will produce useful concentrations - almost like neurotransmitters. If there are bits of hypothalamus that harbour T cells, as it seems there are, then presumably they are there to signal locally so I don't see anything 'at odds' here. Maybe it isn't in the literature but whatever we are looking for isn't in the literature yet!

I don't have any very strong feelings about what is the most likely site for T cells signalling their annoyance but there seem to me to be several options open.