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

Patients get rituximab either once every 6 months or once a year, depending on needs - a few go for up to five years between shots.

But the immunosuppressive effect may not be trivial. We did not run into problems until Covid. The problem with Covid is that it seems that people do not produce very good long term immunity, even after vaccination. It is difficult to know whether RA patients ran into trouble with Covid because of their RA or the rituximab though.

 

Does rtx increase cancer risk because of the immunosuppression, and if so, do we know by how much?

 

I'd guess the risk of infection's much more of a threat. If you're really susceptible to a particular type of bug, it can be hairy. There are often helpful drugs, but people's immune systems still need to shoulder much of the work.

 

For as long as I was involved in the post-marketing analysis there was no evidence of increased risk of cancer. Antibodies probably do not control cancers much if at all.

 

That's extremely good news.

When people on immunosuppressive drugs, such as people with RA, attend hospital or a GP surgery, are any precautions taken to protect them from infection, or is that risk treated with the total disregard that it is for the rest of us? I've never understood the lack of protection for those of us who do badly with viral infections, even before Covid.

 

For one of the other possible treatments mentioned (anti CD52, Alemtuzumab) there was this overview of use in MS
https://msddjournal.biomedcentral.com/articles/10.1186/s40893-017-0024-4

 

People often have to carry on going to work or whatever. The only person I know who has rituximab infusions (MS) also cares for three young children and has a succession of people visiting the house for flute lessons. They need that income.

If she'd had a bad reaction or become very vulnerable to infection they'd have had to respond, I guess, but not everyone does.

 

I'm trying to understand this. Are you saying that there is (or could be?) a false/exaggerated signal and that the signal is amplifying the immune signal associated with damage?

I'm not sure I have got this right.

 

It would be easy to assume that all the inappropriate signalling is in the immune system and that the nervous system is just getting all the flack. But there is a faint possibility that the nervous system is contributing by signalling back to keep the inappropriate immune signals coming.

It is very hard to see how the nervous system could regulate a specific adaptive immune response if it is a matter of signalling back to specific clones of cells that are misbehaving. The nervous system cannot pick out the bad cells to signal to. But if the problem consists of essentially normal background immune interactions spilling over a threshold - which is maybe the most likely analysis for ankylosing spondylitis, for instance - then if the nervous system keeps signalling back to all immune cells to keep simmering then there would be a problem.

Neurons have game interferon responsive genes as I understand it. And, as we point out in a tiny sentence in the paper, T cells have receptors for neurotransmitters so there is scope for signalling going the other way. I don't know whether this is likely to be relevant but if genetic studies like the Zhang paper come up with genes potentially involved in nerve synapses then maybe it is.

 

Is it possible that a genetic deviation makes the neurons react to things they otherwise would not react to? Do they react to all types of interferons, or are there some that only react with some?

 

I think so. Don't know about other interferons.

 

They have type I receptors as well. There seem to be very few things [edit: at the downstream levels, at least] that apply to only one type of interferon.

 

Hi all! First comment on this forum..

Wanted to say thanks @Jonathan Edwards. I appreciate the work you and many others do to try to solve this disease. Fills me with gratitude and hope.

Earlier in this thread @JemPD asked the following:

I experience something similar and I'm also curious how this could work. I can run on stress for a bit and feel relatively fine until my body flips into low stress / recovery mode and PEM starts. I have to basically make sure I go into rest mode before I overdo it, then I also feel shit for a bit but I recover fast. If I keep running on stress (especially for multiple days) and wait till I crash I'll be in PEM for a while.

A second (maybe related?) observation is that I generally feel horrible when I wake up but get better as the day progresses and feel the best in the evening. Maybe also related to cortisol levels? Anyone else experience the same?

@Jonathan Edwards I'll leave it to you to decide on the relevance of the above but if you have any thoughts I would love to hear them.

 

Welcome to the forum @Jesse. Both points you raise are the exact same for me.

I don't think this hypothesis paper is intended to explain this kind of thing. The hypothesis is more along the lines of what keeps us locked into a particular "immune" state. i.e. interaction of "junk" antibodies with FcGRI receptors on macrophages that excite T-cells, which produce interferon gamma, which increase expression/activation of FcGRI receptors. As @Jonathan Edwards states, it could be wrong, perhaps dendritic cells instead of macrophages, or completely wrong.

He wants us to think what kind of immune changes could lock us into a disease state based on how ME/CFS presents compared to other diseases. This is one hypothesis.

 

That's fair. Maybe it's too specific. I'm mostly wondering if the hypothesis is congruent with these observations.

Like, if PEM is caused by the immune system putting the brakes on our body, does it make sense that stress hormones can delay this process or even (temporarily) mask/override it.

 

I play scrabble every day with a friend in England who has fairly advanced non-Hodgin lymphoma. Last year she had rituximab treatment and underwent the first infusion in a hospital room with a lot of others receiving infusions for various things. Not one patient or member of staff wore a mask. She was not asked if she had a cold. She insisted on a private hospital room for the second infusion and got it.

The rituximab has made no difference to the progress of her disease. It left her feeling extremely unwell for maybe a few weeks afterwards (I can't remember how long) and has caused (presumably) permanent, severe tinnitus, which is a less common side effect. It will take a year for the ritux to be out of her system and she has her fingers crossed the tinnitus goes away but there's no guarantee apparently.

 

I think very much so. Although it is not emphasised in the paper we do focus a bit on the possibility that the immune signalling does not involve any local changes in muscle itself but may occur elsewhere. Since discussing the paper here we (the forum) have noted that signalling from antibodies and T cells might impact directly on nerves through FcRI or gamma interferon sensitivity, or the T cells might even be interacting with brain in the subfornical organ near the hypothalamus.

That sort of signalling, involving shift in nerve excitability, would very likely be open to temporary suppression by override from adrenaline, cortisol or whatever.

....

I am reminded of previous discussions about a possible analogy between ME/CFS and narcolepsy. Narcolepsy is an irresistible tendency to fall asleep during the day and is strangely also associated with episodes of paralysis when laughing (cataplexy). Unexpectedly, it was discovered to have a very strong genetic association to MHC Class II. It is probably an antibody -dependent autoimmune process.

The immune target in narcolepsy is the prefornical region of brain, not very far away from the subfornical organ.

It is not yet clear whether there is definitely a genetic association to MHC in ME/CFS. Two studies have reported a link but there seems to be inconsistency. Hopefully that will become clear.

 

Interesting, that seems to makes sense! I will say that the more I overdo it, especially physically (i.e. "exercise") the more likely it is PEM does follow swiftly in spite of lots of stress (tired but wired feeling).

Anyways, I have not much more to offer than my personal experiences. The science is definitely over my head, but I'm hoping to get more familiar! Thank you for your reply.

 

Potential DRG involvement keeps tapping at my skull: my moderate-25years-in pwME wife ALWAYS starts PEM with an ache/heaviness in the DRG somewhere around vertebra prominens. Is there good information somewhere about DRG possible involvement?

 

I think it is very unlikely that anything happening in DRG would be felt in that area. The nervous system nearly always refers sensations out to the organs it supplies. Aching in the back is, I suspect, more likely to be a reflection of some dodgy bit of back like discs lighting up because immune signals are operating somewhere else!