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

[OrganicChilli]

It would target the NK cells just the same. The absence of many NK cells from blood doesn't necessarily mean there aren't any. They may be busy in tissues.

How so? Even Fluge and Mella aren't retreating non-responders even though some ended up with more NK cells after unsuccessful treatment.

 

[V.R.T.]

Even Fluge and Mella aren't retreating non-responders even though some ended up with more NK cells after unsuccessful treatment.

Perhaps this is a cost/showing efficacy thing and they will do this at some point if they have reason to think NK cells effect on drug action is the link/cause of the separation

 

[Jonathan Edwards]

How so? Even Fluge and Mella aren't retreating non-responders even though some ended up with more NK cells after unsuccessful treatment.

The question was framed with the premise that the drug was working through NK cell gamm interferon. For all we know the reason for non-responding might have nothing to do with cell numbers - that might have been a fluke.

 

[Timko]

@Jonathan Edwards I have tried IVIG and a Jak-Stat Inhibitor. No effect. Could your theory still hold even if these treatments turn out to have no effect in a broader population? If so, what could explain such a non-response?

 

[Jonathan Edwards]

@Jonathan Edwards I have tried IVIG and a Jak-Stat Inhibitor. No effect. Could your theory still hold even if these treatments turn out to have no effect in a broader population? If so, what could explain such a non-response?

I would not expect IVIG to have nay effect relevant to this theory. If a Jak-Stat inhibitor blocked the effects of gamma interferon, even in hidden environments, then a lack of effect would be against the theory. On the other hand, this theory focuses on how an immune response might trigger a long term neurological response and one possibility is that effects of gamma interferon initially can outlast the presence of cytokine. We have seen at least one study suggesting that.

 

[richie]

FcγRI plays a role in sarcoidosis, I have read. Sarkies are dogged by fatigue, that does not track apparent granulomas, nor ACE levels nor secondary complications like hypercalcemia and we report a PEM-like?/pseudoPEM? and very real post exertional fatigue. I am wondering if this FCgammaRI mechanism may be playing a dual role in sarc - driving aspects of granuloma formation but in the background maintaining an immune hypervigilance, which while not always issuing tissue effects (granulomas), is in many patients adequate to mess things up in a CFS/ME type way.

It is recognised that downstream in sarc different patients develop different complications, which may be the cause of some of the most troubling symptoms. Upstream the properties of differing initial antigens (incl for persistence e.g. borrelia) may create a variety of patient profiles. Might sth similar be going on in ME/CFS cohorts - say, the driving mechanism proposed by JE et al as watermill, some differences from upstream of the mill due to differences in initial antigen etc. and some further downstream effects like observed mito findings. The latter may be little more than passengers in some but in other patients might be key precipitators of that patient's symptoms. They might resolve fully if the central mechanism is sorted out or on the other hand develop "a life of their own".

I wonder if this is in any way relevant to ME/CFS. Apologies if I have displayed scientific ignorance,