Notice about a forthcoming paper: A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma

Discussion in 'ME/CFS research news' started by Jonathan Edwards, May 22, 2025.

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  1. Kitty

    Kitty Senior Member (Voting Rights)

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    And Whit Sunday was a Thing.

    Kids got new clothes and everybody went to the park for the Whit Sing. Here's a mini me, modelling Whit 1962 in front of the outside closet.

    Whit Outfit.jpg
     
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  2. Sasha

    Sasha Senior Member (Voting Rights)

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    Very chic, @Kitty! :thumbup:
     
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  3. hotblack

    hotblack Senior Member (Voting Rights)

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    I have been re-reading with more sleep and time to compost things. If I’m understanding the explanation…

    Macrophages are more likely to trigger because this FcgRI receptor has been bound to by an antibody? It’s sort of ‘primed’ by it?

    And this receptor is/can be expressed more when T cells are signalling with Interferon Gamma. Which they do when they get annoyed by various things in this world (I know how they feel).

    And something else that can make T cells do this is macrophages primed as above, binding to an antigen (which they’re more likely to do if there are more of them expressed on cells and more of them are primed). At which point they happily present part of this antigen to the T cells, which say ‘aha, something needs dealing with’. And so on…

    So it’s part probability. Something is nudging parts of this potential loop into a state of being more likely to happen, and once it is, it’s difficult to get all the parts and probabilities down so things balance out again and stop?
     
  4. hotblack

    hotblack Senior Member (Voting Rights)

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    Aha, receptor mediated endocytosis? Or am I suffering from ‘thing I just learnt about’ syndrome?

    edit: since this seems relevant, a description of this can be found here and I’ll post more in the Resources forum
     
    Last edited: May 25, 2025 at 12:58 PM
  5. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    That's the one.
     
  6. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I am fascinated by the fact that neurons in dorsal root ganglia carry FcRI (looking at various papers I think it is probably bona fide).

    What is the point of recognising antigen at the cell body of a nerve that sends signals from somewhere else (your foot maybe) to your brain. Surely it would be more use to tell the brain the foot was not right if the antigen was in the foot?

    There must be some clever reason - maybe all to do with generating myalgia, wherever the antigen might be, for the sake of generating myalgia.

    I am beginning to think that FcRI is an even more likely candidate than I had already wondered.
    An illness mediated by FcRI would tend to always look the same, just as one mediated by FcRIII looks like an inflammatory arthritis, whether RA, lupus or whatever.
     
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  7. V.R.T.

    V.R.T. Senior Member (Voting Rights)

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    So hypothetically speaking FcRI mediated illnesses might 'look the same' but, like with the different arthritises, have enough hetrogenity to account for the diversity in symptoms we see in pwME?
     
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  8. hotblack

    hotblack Senior Member (Voting Rights)

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    Woohoo! Sunday has been a success. Thanks Jonathan and thank you to the greek gods of qeios for the extra time to digest information.
    This is all sounding very intriguing…
     
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  9. hotblack

    hotblack Senior Member (Voting Rights)

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  10. Sasha

    Sasha Senior Member (Voting Rights)

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    I am frantically mugging up on immunology via the fantastic Kurzgesagt book, 'Immune', to be half-ready for the Qeois paper, and am suddenly struck by how forum members here are functioning like dendritic cells bringing interesting bits of stuff to other forum members in the lymph nodes to make sense of and come up with a solution forr. We're like one giant immune system!

    (Or maybe at this point, even a blob of melted ice-cream on the floor would look like an immune system to me, given that I am over-immersed...)
     
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  11. Kitty

    Kitty Senior Member (Voting Rights)

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    Here's your first test then. :D What type of cells don't even bother because they know it's so far out of their ability range they'd do better trying to dance en pointe?
     
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  12. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Yes, invoking an Fc receptor binding has the trick of producing a clinical syndrome that is the same whatever the antigen, but with room for variation perhaps due to background genetics or chance environmental influences.

    T cell diseases can also do this because the T cell receptor does not actually interact with a whole functioning antigen, only with peptides. But if the T cells helped B cells to make specific antibody as well their cover would be blown.
     
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  13. jnmaciuch

    jnmaciuch Senior Member (Voting Rights)

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    Very astute @Sasha! Certainly more astute than my brain’s attempts to do the same thing.

    When I recently learned about the malate-aspartate shuttle, I ended up on a bus that crosses a highway overpass with no pedestrian sidewalks. “It’s just like the MAS crossing the impermeable mitochondrial membrane” I thought in a stroke of genius. An hour later I realized that I had simply thought a shuttle is like a shuttle….somebody call the Nobel prize committee.

    I’m glad you’re enjoying learning immunology so much!!
     
    Last edited: May 25, 2025 at 2:09 PM
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  14. jnmaciuch

    jnmaciuch Senior Member (Voting Rights)

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    Would the corollary, then, be that it tends to look temporally consistent as well? Or would there be room for fluctuation triggered by activity
     
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  15. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    In a strictly Popperian analysis, that could be true - all these nice ideas in the literature being brought in so that they can be refuted and disgorged!!

    What we really want though is to find an idea that we cannot refute. The immune system isn't really interested in that any more than a policeman is interested in the fact that young Jimmy has learnt to ride his bike.
     
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  16. jnmaciuch

    jnmaciuch Senior Member (Voting Rights)

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    Alternatively, the vast amount of ideas get ignored after being determined inconsequential, but some shining bits raise the alarm so that the problem gets attacked head-on!
     
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  17. Sasha

    Sasha Senior Member (Voting Rights)

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    I haven't got to that bit yet but I am already excited that I now know what the first big word means in the paper title (macrophage!). :)
     
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  18. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    A good question. Antibody levels should be rather constant. FcR expression on neurons would probably be rather constant. To get PEM there would need to be another signal that, as Snow Leopard has pointed out, the neuron is sensitised to by having its calcium flux shifted by FcRI interactions. Muscle usage or metabolic shifts or cytokine shifts triggered by activity could all come in.

    But for PEM to persists for weeks there also needs to be some sort of re-setting of the effector mechanism that is quick but can persist. This is where I still think T cells may meed to be involved. In psoriasis a rash can appear overnight and persist for months. It seems to have something to do with T cells getting together in gangs and stirring each other up. We know about mechanisms for gathering cells together but not much about how they might go wrong.

    It doesn't all fall naturally into a clear story for me so far, but I have a sense that at least some of these elements may be critical to story that fits.
     
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  19. Kitty

    Kitty Senior Member (Voting Rights)

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    It is interesting that in a subset of us, PEM starts with 'flu-type symptoms that are indistinguishable from the onset of a virus.

    In moderate PEM that's only going to last two or three days it's mainly felt on the first day. It then fades and morphs into less easily described gruesomeness.
     
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  20. Yann04

    Yann04 Senior Member (Voting Rights)

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    Ooo I read that myself a couple years ago. It was a fun read. Though I was obliviously unnaware my immune system was about to go weird after I got COVID a couple months later.
     
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