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

[bobbler]

AI

Is C6S found on the surface of neurons?

Does the heparin bit mean a possible loose link there to the decodeME gene that’s related to ferritin homeostasis?

I’m getting possible complex links between this and iron regulation but risk it could be nonsense because on one bullet it say heparin can act as as strong an inhibitor as Hepcidin for iron, then another bullet notes heparin-iron complexes are being developed as novel approaches to anemia. Ok it seems it suppresses hepcidin so that’s how both could logically make sense.

 

[Jonathan Edwards]

Does the heparin bit mean a possible loose link there to the decodeME gene that’s related to ferritin homeostasis?

It might be heparan sulphate rather than heparin. I doubt there is any link.
Googling quickly suggests that there isn't a heparin sulphate.

 

[V.R.T.]

An unexpected result:

IFNγ-induced memory in human macrophages is sustained by the durability of cytokine signaling itself (J. Exp. Med, February 2026)

Sticky memories of an activated macrophage (associated commentary)

So does this paper suggest that if IFN-y is driving MECFS, JAK-STAT inhibitors might work to break the signalling loop?

 

[Jonathan Edwards]

So does this paper suggest that if IFN-y is driving MECFS, JAK-STAT inhibitors might work to break the signalling loop?

Put like that, maybe, but with an if and a might. (I am not sure whether there are complexities that mean it depends on which inhibitor we are considering.)

 

[Utsikt]

Put like that, maybe, but with an if and a might. (I am not sure whether there are complexities that mean it depends on which inhibitor we are considering.)

I might have misunderstood completely, but didn’t the signalling start up again after stopping the downstream effects ss long as the IFN gamma was still «trapped» in the membrane? Would that mean that you’d have to block JAK-STAT for a long time (assuming it’s the right thing to block)?

From the commentary:

Using a reductionist yet relevant model of human monocyte-derived macrophages stimulated acutely with IFN-γ, they found that long-term maintenance of de novoformed enhancers relied on continued signaling by the JAK–STAT pathway—even if the cytokine was washed out by replacing the culture medium. Inhibition of JAK1/2 with ruxolitinib in cells that were acutely stimulated with IFN-γ and later kept in fresh medium resulted in the loss of H3K4me1 and reduced chromatin accessibility at IFN-γ–induced enhancers (see panel A in figure). Removal of the JAK inhibitor rapidly restored STAT1 phosphorylation, indicating persistent IFN-γ signaling beyond the period of overt cytokine stimulation.

 

[V.R.T.]

I might have misunderstood completely, but didn’t the signalling start up again after stopping the downstream effects ss long as the IFN gamma was still «trapped» in the membrane? Would that mean that you’d have to block JAK-STAT for a long time (assuming it’s the right thing to block)?

From the commentary:

So perhaps the IFN-y itself would have to be targeted in this hypothetical situation? Are there drugs that do that?

 

[Jonathan Edwards]

I might have misunderstood completely, but didn’t the signalling start up again after stopping the downstream effects ss long as the IFN gamma was still «trapped» in the membrane? Would that mean that you’d have to block JAK-STAT for a long time (assuming it’s the right thing to block)?

Somewhere else I think it implies that if there is not continued signalling the IFN-g goes away. A bit confusing. I suspect that kinase inhibition for long enough (days or weeks?) might do the job.

But I can see this may only be part of the story and that for neurons, for instance, other signalling shifts might kick in.

But it would be worth knowing whether there is any information about from other uses of inhibitors that might give clues is to whether there might be a role in ME/CFS.

 

[DHagen]

Somewhere else I think it implies that if there is not continued signalling the IFN-g goes away. A bit confusing. I suspect that kinase inhibition for long enough (days or weeks?) might do the job.

But I can see this may only be part of the story and that for neurons, for instance, other signalling shifts might kick in.

But it would be worth knowing whether there is any information about from other uses of inhibitors that might give clues is to whether there might be a role in ME/CFS.

Is it reasonable to hope that any of the current JAK inhibitor RCTs could be particularly illuminating in this regard?

CLEAR-LC (abrocitinib)
LC-Revitalize (upadacitinib)
REVERSE-LC (barictinib)

 

[hotblack]

The Heparan Sulfate Proteoglycan Metabolic Process was one of the things that popped up from Enrichr when I was looking at the PrecisionLife data

 

[hotblack]

Of note, transient stimulation of macrophages with LPS or type I IFN did not result in persistent STAT1 phosphorylation after washout,

It looks like other than IFN-gamma they also tested with LPS and IFN-beta and didn’t see this persistence. But I wonder if we could see similar persistence from IFN-alpha (I guess unlikely given beta doesn’t) or other cytokines like interleukins?

Relevant bits from the paper below:

we stimulated human macrophages with IFNγ or LPS for 8 h and performed H3K4me1 CUT&Tag. LPS activates cells via direct TLR signaling as well as the IFNβ–JAK/STAT signaling axis. To identify JAK/STAT-dependent LPS enhancers, we treated macrophages (Fig. 1 A) with LPS in the presence of the JAK inhibitor ruxolitinib at a dose (1 µM) sufficient to block IFNβ–JAK/STAT signaling (Fig. S2).

And later

We stimulated macrophages with IFNγ, LPS, and IFNβ for 8 h, washed out the stimulus, and cultured the cells for 3 days. Immunoblotting showed that acute treatment with each stimulus could induce STAT1 phosphorylation. This phosphorylation did not persist after washout of IFNβ and LPS; however, IFNγ-induced STAT1 phosphorylation persisted for 3 days after the washout

 

[Jonathan Edwards]

It looks like other than IFN-gamma they also tested with LPS and IFN-beta and didn’t see this persistence.

I think it must be gamma. I can feel it creeping up over my chondroitin 6 sulphate even now.

 

[V.R.T.]

An unexpected result:

IFNγ-induced memory in human macrophages is sustained by the durability of cytokine signaling itself (J. Exp. Med, February 2026)

Sticky memories of an activated macrophage (associated commentary)

@jnmaciuch what do you make of this study?

 

[hotblack]

I think it must be gamma. I can feel it creeping up over my chondroitin 6 sulphate even now.

Sounds like a voiceover for a horror movie! Maybe a niche one anyway.

I suppose even if other cytokines don’t have this property, if macrophages and/or the jak-stat pathways are ‘primed’ by gamma, then things can be more easily triggered by non-gamma? As described in your original theory?

 

[hotblack]

If interferon gamma is mainly made by T cells and activated natural killer cells, could what what's going on with daratumumab be more something to do with this and somehow changing the type or makeup of gamma that is made or allowing a reset here somehow? Could the people with more NK cells actually be a sign that for them the NK cells are producing unhelpful gamma and killing them off helps other parts of whatever loops involving gamma may be going on to settle down?

I’m still a bit more interested in some of the other mechanisms of daratumumab and CD38 (than the LLPC/antibody/etc theories but wondered about this angle too.

 

[Jonathan Edwards]

Could the people with more NK cells actually be a sign that for them the NK cells are producing unhelpful gamma and killing them off helps other parts of whatever loops involving gamma may be going on to settle down?

Certainly could be.
The apparent lack of functional NK cells in old studies might even mean that they are too busy somewhere else.

If you give people steroids their neutrophil counts go up, not because there is inflammation needing neutrophils but because neurtophils have been made too lazy to bother leave the circulation looking for it. It is all too easy to misinterpret blood cell levels.

 

[V.R.T.]

If interferon gamma is mainly made by T cells and activated natural killer cells, could what what's going on with daratumumab be more something to do with this and somehow changing the type or makeup of gamma that is made or allowing a reset here somehow? Could the people with more NK cells actually be a sign that for them the NK cells are producing unhelpful gamma and killing them off helps other parts of whatever loops involving gamma may be going on to settle down?

I’m still a bit more interested in some of the other mechanisms of daratumumab and CD38 (than the LLPC/antibody/etc theories but wondered about this angle too.

If this was the case, what might be useful treatment for low NK cell people?

 

[hotblack]

If this was the case, what might be useful treatment for low NK cell people?

No idea. It depends what the problem is and we still don’t know that. NK cells may be a red herring.

I’m just exploring ideas, although I’ve always been interested in alternative explanations for why daratumumab works. Assuming it works in a particular way then only thinking about other possibilities in 2 or 3 years time seems like a waste of that time.

 

[Jonathan Edwards]

If this was the case, what might be useful treatment for low NK cell people?

I would guess the same. Their NK cells are just a bit more sneaky hiding away.

 

[V.R.T.]

I would guess the same. Their NK cells are just a bit more sneaky hiding away.

The same treatment? How would that work

 

[V.R.T.]

No idea. It depends what the problem is and we still don’t know that. NK cells may be a red herring.

I’m just exploring ideas, although I’ve always been interested in alternative explanations for why daratumumab works. Assuming it works in a particular way then only thinking about other possibilities in 2 or 3 years time seems like a waste of that time.

No absolutely I think we should be thinking about all the possible ways this could work. And what to do about low NK people if it were this way or that.

But of course we know next to nothing currently.