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

Discussion in 'ME/CFS research' started by Nightsong, May 27, 2025 at 11:01 PM.

  1. Sasha

    Sasha Senior Member (Voting Rights)

    Messages:
    5,677
    Location:
    UK
    :arghh:, given that I'm about 40 years in.

    Does this happen in RA and other diseases (assuming they're the sort of bistable thing you're talking about) - namely, that the longer you've had it, the harder you are to treat and the less likely you are to go into remission, especially long-term remission?
     
    Last edited: May 29, 2025 at 11:50 PM
    RedFox, MeSci, Peter Trewhitt and 4 others like this.
  2. Sasha

    Sasha Senior Member (Voting Rights)

    Messages:
    5,677
    Location:
    UK
    Struggling to remember what has gone on already so someone may already have raised this but could the two types of ME/CFS (synapse-maintenance vs T cell function) be why there are two age-incidence peaks for ME/CFS? One peak for each type, due to... stuff?

    @Simon M

    [Edit] Was this idea in the paper and I am falsely remembering it as my own?
     
    Last edited: May 30, 2025 at 12:04 AM
    RedFox, Peter Trewhitt and Deanne NZ like this.
  3. Sasha

    Sasha Senior Member (Voting Rights)

    Messages:
    5,677
    Location:
    UK
    @Jonathan Edwards, I have been reading :emoji_hotdog: that as we get into old age, our immune systems get weaker, including T cells forgetting antigens. Would your model predict that PwME would get better in old age? Do we know whether PwME do in fact get better in old age? (We'd expect some masking of improvement by other effects of ageing, of course, but I'd expect to be able to tell the difference, personally.)
     
    RedFox, MeSci, EzzieD and 8 others like this.
  4. Kitty

    Kitty Senior Member (Voting Rights)

    Messages:
    8,244
    Location:
    UK
    Does it necessarily mean harder to treat in ME/CFS? I read it as meaning that once the abnormal pattern's got established, there's less chance of it flipping back to normal on its own.

    It's likely to need a shove from a treatment, but the chances of success wouldn't necessarily be lower than someone who's been ill two or three years. Results might even turn out to be unpredictable, with some old soldiers responding as well as recently ill people, and some of the relative newbies proving more difficult.

    This one hasn't. :rolleyes: Though I haven't got substantially worse either.
     
    RedFox, MeSci, CorAnd and 4 others like this.
  5. Murph

    Murph Senior Member (Voting Rights)

    Messages:
    276
    I've just read the paper and I'd like to praise the writing in it. Clear and accessible, chatty but somehow still formal, it's a rare treat to encounter something so well put together.
     
    RedFox, Lilas, Binkie4 and 14 others like this.
  6. Kitty

    Kitty Senior Member (Voting Rights)

    Messages:
    8,244
    Location:
    UK
    Just started reading the paper through again, and lingered on this part.

    If that second peak in females is sound, presumably we have to consider interplay with sex hormones? Onset in males and females can coincide with reproductive maturity, but the second peak in females also coincides with the start of the hormonal changes that will end their fertility. Male androgen levels begin declining around the same time, but it's a more gradual process.
     
    RedFox, MeSci, CorAnd and 5 others like this.
  7. petrichor

    petrichor Senior Member (Voting Rights)

    Messages:
    329
    This seems like quite a good paper in many ways, particularly how it tries to anchor the hypothesis in features of ME/CFS, and patterns seen in other conditions.

    Apparently when stimulated by interferon gamma macrophages release neopterin https://www.sciencedirect.com/topics/neuroscience/neopterin. This article (https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-11-205) points to some studies that have found elevated neopterin in ME/CFS patients compared to controls, but the differences seem quite modest.

    That may either support or not support this hypothesis, but I thought I'd comment that.
     
    RedFox, MeSci, forestglip and 7 others like this.
  8. Hutan

    Hutan Moderator Staff Member

    Messages:
    32,664
    Location:
    Aotearoa New Zealand
    I've made a thread to look at the evidence for elevated neopterin here:
    Neopterin
     
    RedFox, MeSci, forestglip and 4 others like this.
  9. Sasha

    Sasha Senior Member (Voting Rights)

    Messages:
    5,677
    Location:
    UK
    The treatments considered at the end of paper all seem like heavy-duty immune drugs, to treat the upstream problem. We're likely to be waiting a long time for them, and they might not be suitable for some, plus there might be concerns if they're immunosuppressive, in this time of endemic Covid.

    Are there things other than drugs (or this kind of drugs) that might tackle the upstream problem? Ron Davis has been talking about an 'off switch', and my impression has been that he was talking about a kind of one-and-done treatment, maybe to sort your itaconate shunt out or similar. My impression has been that he wanted to interrupt some sort of metabolic pathway, via the sort of stuff you'd get from a really big Holland and Barrett's, but done in some sort of weird combo and using some of the more recherche vitamins, minerals and whatnot.

    Also, can we predict from the model any treatable downstream effects to improve symptoms and function while we're waiting for the heavy guns? @jnmaciuch has been having apparent personal N=1 success with malate, but needs to keep taking it to get the effects, so I'm wondering if that's an example of an effective non-drug treatment for downstream effects, at least for @jnmaciuch.

    The fact that malate doesn't seem to be working for some (?) but not other (?) people who have tried it might suggest that downstream effects might vary from one individual to another, or that different people might have different biological abilities to benefit from particular treatments. I'm wondering if the model also tells us anything about why we've always seen huge variability in what appears to help people (taking accounts of cause at face value), if we've only got two basic kinds of ME/CFS.
     
    RedFox, MeSci, EzzieD and 6 others like this.
  10. arnoble

    arnoble Established Member (Voting Rights)

    Messages:
    28
    @Jonathan Edwards, and your co-authors, a huge thank you. PWME I know, including my moderate-25+years-in wife, are so grateful for this huge effort and dedication - it gives them hope (in an indifferent world) to see such a clear framework woven from the evidence/hints so far. Setting the scene within the landscape of other conditions gives confidence that your proposals are seeing the big picture, and not digging away in a little hypothesis corner. Each reading of it (now #3) reveals much hidden treasure.
     
    Last edited: May 30, 2025 at 8:31 AM
    RedFox, Lilas, Binkie4 and 11 others like this.
  11. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    17,630
    Location:
    London, UK
    The problem with RA is the accumulation of tissue damage. But it was interesting that with rituximab you could often get complete remission of symptoms even in long standing disease.
    The trouble is that we haven't yet found a way to 'undo' the regulatory error for good, so we don't know the answer. It may be a false concern. For ME/CFS I don't think we have much to go on other than that remissions tend to occur in the first few years if they do.
     
    RedFox, MeSci, EzzieD and 6 others like this.
  12. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    17,630
    Location:
    London, UK
    It's possible. I think the two peaks may be hiding much more complex shifts in incidence with age for many subsets and the way genetic traits get expressed could well be part of that.
     
    RedFox, Lilas, MeSci and 4 others like this.
  13. Sasha

    Sasha Senior Member (Voting Rights)

    Messages:
    5,677
    Location:
    UK
    FWIW, I had a massive remission ten years in, going from bedbound to able to work full-time and live a largely normal life. In retrospect, there were red flags but I'd call it a big fat remission. After some years, I relapsed.
     
    RedFox, MeSci, EzzieD and 3 others like this.
  14. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    17,630
    Location:
    London, UK
    I think the evidence on the immune system getting weaker with age is a bit moot. From a clinical experience point of view I have seen rather little evidence of it. Frail people in their last couple of years of life do succumb to things like pneumonia but often cope with most things very well. My mother shrugged off Covid-19 at 99 without a problem. The shingles virus can reappear but that is a rather unique situation. Some people with diabetes develop 'immune windows' for things like staphylococcus aureus or E. coli and cannot fight them off. I fear that poor Graham may have had that problem. But it is not common.

    It is a reasonable question though. I don't think we would predict improvement of ME/CFS but I think we might expect new ME/CFS to become less common. The immune diseases of old age are mostly antibody mediated - like RA and I think poly myalgia, although nobody has ever sorted that one out.
     
    RedFox, Lilas, Binkie4 and 6 others like this.
  15. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    17,630
    Location:
    London, UK
    Yes, I think that was more the line of thought.
     
  16. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    17,630
    Location:
    London, UK
    Jo Cambridge pointed me to the review by Natalie Conrad we cite. The effect of sex on immune disease is fascinating and complicated. It isn't just oestrogen. It is also other genes on the X chromosome that mediate processes independently of oestrogen levels. You also have to distinguish the ongoing effects of oestrogen from the lifelong effects that determine sexual maturation. Which is presumably why changes in risk of cardiovascular disease with HRT are complicated.

    As Hutan has said, the second peak may not be quite what it seems. There was an apparent second male peak that Snow Leopard pointed out was an artefact. But I do think there are complex things going on. The rise in incidence in teens in boys has a different shape from girls - that has been seen twice I think.

    I don't know why there is so little literature on these epidemiological issues for immune disease. We still have no idea why polymyalgia and temporal arteritis are almost never seen under the age of 50.
     
    RedFox, Lilas, obeat and 8 others like this.
  17. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

    Messages:
    4,385
    Location:
    Belgium
    Would it be useful to get an overview of findings on interferon-gamma in ME/CFS research? It seems to have come up quite a few times. Or would these results not matter too much because the theory only assumes local increases of cytokines?
     
    RedFox, EzzieD, Hutan and 2 others like this.
  18. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    17,630
    Location:
    London, UK
    As I have been arguing in various threads with members such as jnmaciuch and RBP himself, I find it hard to believe that a metabolic switch is upstream. I think the upstream switching of the railway points must be an adaptive immune cell shift. Writing the paper I came to realise just how similar the time course probably is to many well known adaptive immune mediated diseases and if there is an HLA link we are likely to be well in that ball park.

    I sympathise with Ron's personal situation but the supplement soup idea seems to me not very different from my parsnip juice dream.

    But I would not totally discount some physical procedure - even something like cold water immersion! That might seem crazy but if we take neuroimmune signalling seriously, and maybe we should, and the nervous system really does regulate T cells, then an overwhelming neural reflex might do something spectacular. I always remember the fact that if you have an inflamed thumb from hitting it with a fourteen pound hammer by mistake (I have tested this) much the best way to remove the pain is ice, not painkillers.

    But maybe that's just another parsnip juice idea too.
     
    RedFox, Lilas, MeSci and 8 others like this.
  19. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    17,630
    Location:
    London, UK
    I wonder if variable responses to things relates to the last post 178. If neural reflex mechanisms are engaged then the way they engage may vary from person to person on an idiosyncratic basis.

    But I never said 'only two basic kinds'. I suggested that there might be lots of genes each skewing things a bit differently.
     
    RedFox, Lilas, MeSci and 4 others like this.
  20. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    17,630
    Location:
    London, UK
    Absolutely. We did not do an exhaustive search for data on interferons before writing this. The consensus seemed to be that it might be up a bit or correlate to severity but that results were inconsistent. There is probably a wealth of data out there that we have put to one side as hard to be sure about which in the fullness of time will be seen to fit into a bigger picture.
     
    RedFox, Lilas, MeSci and 8 others like this.

Share This Page