Is the key pathology of ME/CFS in bone marrow?

Creekside said:
I've learned, from teeth and various other pains, that I am really terrible at correctly identifying where the pain is located. I was sure the pain was from one tooth, but it turned out the neighbour was cracked. My present foot pain feels like it's coming from the top of the foot, but it's actually a cyst much lower down, pressing on a nerve there. I expect this misidentification of pain sources is common in humans. So, a poll about bone pain isn't likely to provide useful information.

I have had that "pain in my bones" feeling, but I had that before ME too, and I doubt that it was caused by problems in the bones. I think it's more likely something making the brain cells that process those nerve signals more sensitive.
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I agree. I learned the same thing when I had endometriosis. I seemed to have bladder pain when it was in fact coming from the pouch of Douglas.
 
Creekside said:
I've learned, from teeth and various other pains, that I am really terrible at correctly identifying where the pain is located. I was sure the pain was from one tooth, but it turned out the neighbour was cracked. My present foot pain feels like it's coming from the top of the foot, but it's actually a cyst much lower down, pressing on a nerve there. I expect this misidentification of pain sources is common in humans. So, a poll about bone pain isn't likely to provide useful information.

I have had that "pain in my bones" feeling, but I had that before ME too, and I doubt that it was caused by problems in the bones. I think it's more likely something making the brain cells that process those nerve signals more sensitive.
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I agree with this too. I had ME already before my very severe ME flu triggered onset. I assume the bone pain I felt was from the flu because I know the person that I caught the flu from. I was visiting their place and he said he was really sick with flu and aching bones.

The pain I felt in my shin bone was agonizing and it did feel like the it was in one spot within the bone marrow. A very painful drawing out pain. Never experienced it since or before that. I wouldn't want to experience that again. Whether the bone marrow is caught up in ME I don't know but it is good to hear thoughts about other possibilities even though it is all over my head. Lol.

Thanks for such a good post and I can relate to a lot of what you said.
 
Jaybee00 said:
I just posted this lupus preprint, which includes co-authors from UCL rheumatology @Jonathan Edwards which mentions (I think) that the spleen is a more important factor than bone marrow in Lupus.
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I despair really. These are people in my own deparment and they have clearly never heard of the work Jo Cambridge, Maria Leandro and I did 25 years ago, or indeed understood the reason why we started B cell depletion in lupus in the first place.

The abstract reads as if they understood no b cell immunology.

The spleen will be an important reservoir for short lived plasma cells but if there is a feedback loop there needs to be another arm - which is very likely long lived plasma cells in bone marrow. We explained all this clearly in several reviews in the 2000s but of course nobody reads literature from then.
 
Is it not normal to have the leg/sometimes arm deep aches with normal flu? I have always called it "flu muscle pain", because before ME onset I would get the exact type of muscle pain during any virus.
I wonder if knowing what causes the flu pain could explain a lot about me/cfs as well.
 
Alinda said:
I have always called it "flu muscle pain", because before ME onset I would get the exact type of muscle pain during any virus.
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I don't recall having that feeling from regular cold viruses, but I considered it a signature of flu infections. That's why I thought my first sign of this horrible ME disease was simply a flu, except that the symptoms disappeared too quickly for a flu. I also think of the symptom as "feeling tender" and not wanting to bump into anything (because it would hurt a lot).

Someday maybe we'll know that this sensation is due to certain chemical ratios in specific neurons, or some such thing.
 
So what would be triggering TLR7 inappropriately long term?

It seems that TLR7 binds small bits of single stranded RNA. Maybe there is a link with exosomes and the exosome/autophagy linked gene found in DecodeME?

Is ME/CFS a disease of RNA mishandling where lupus is a disease of DNA mishandling?

Random thoughts...
 
Jonathan Edwards said:
So what would be triggering TLR7 inappropriately long term?

It seems that TLR7 binds small bits of single stranded RNA. Maybe there is a link with exosomes and the exosome/autophagy linked gene found in DecodeME?

Is ME/CFS a disease of RNA mishandling where lupus is a disease of DNA mishandling?

Random thoughts...
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Trigger TLR7 without triggering any signs of the whole cascade we would expect from too much TLR7 triggering?
 
Jonathan Edwards said:
So what would be triggering TLR7 inappropriately long term?
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Detecting and binding the wrong sort of RNA?

To explain the increased symptoms in PEM we presumably need something that reacts to the body's normal responses to physical activity, external stressors, etc.

To explain the phenomenon of feeling better when ill, we need something that can be distracted from generating ME/CFS symptoms by the need to respond to a viral infection. Or not having the capacity to do both at once, at least for 48 hours or so.
 
I might have forgotten or missed something, but why zero in on TLR7? If we're working with the idea of X chromosome dosage, there are lots of other genes that aren't fully silenced on the second X. For example TLR8 right next to it. From another paper:
We show that incomplete XCI affects at least 23% of X-chromosomal genes
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If we're talking about the recent mouse study, then as jnmaciuch explained, it didn't really show that there was a causal link between TLR7 and the memory issues. They were correlated, but the cause could be any of the many other genes on the X chromosome that they didn't test that could also be correlated with X chromosome dosage and infection like TLR7.
jnmaciuch said:
This paper doesn't provide mechanistic proof of a link between Xist and TLR7 and any other sex-specific differences. They're showing increased levels of Xist and Tlr7 RNA in macrophages and lung tissue in female mice at a couple different time points. I'm not sure why they only show RNA levels in macrophages at 2 dpi, and only show expression in lung tissue homogenate at 42 and 84 dpi.

They do have a single X chromosome model that does not express Xist (X0F), and one convincing figure showing similar behavior to XY males in one of their tests (Fig 7N):
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jnmaciuch said:
The issue is that for this behavioral finding, you can't be sure whether the X0F results are due to Xist specifically or anything else related to X chromosome dosage.
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As far as I can tell, the basis would mainly be that TLR7 appears to be linked to lupus, another female-biased disease, and the mouse study seems to show that like lupus, post-infectious syndromes might also be sex biased due to something on the X chromosome. But it's possible ME/CFS might be different from lupus specifically because the causal gene is something different on chrX.
 
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forestglip said:
I might have forgotten or missed something, but why zero in on TLR7? If we're working with the idea of X chromosome dosage, there are lots of other genes that aren't fully silenced on the second X. For example TLR8 right next to it.
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Sure, maybe TLR8. I suggested TLR7 in the hope that people might find arguments against as much as anything. The SNP patterns seem to suggest it may be possible to make statements about which path steps are common for lupus and ME/FS and which not. It all seems a bit too complicated at present but maybe there are clues to what is doing the equivalent of anti-DNA antibodies in ME/CFS - what is capitalising on a subversive loop facilitated by XX. Maybe it's a TLR8 ligand, but maybe that's RNAs as well.
 
I don’t really see a way to make a TLR story make sense. Interferon is a good candidate to explain symptom etiology in ME/CFS because we know it makes people feel awful in ways that resemble ME/CFS and on its own (barring exceptionally high levels seen in interferonopathies leading calcification), it’s not expected to cause tissue damage. But invoking TLR activation as the source of interferon basically negates that benefit of the theory, because TLR stimulation activates multiple signaling cascades simultaneously—many of which result in cytokines that do cause inflammation and tissue damage. Absence of NFkB-related pathology would be the big one to explain.

You can’t really invoke TLR activation without an explanation for how the majority of downstream signaling pathways get counteracted as well. At most, you might be able to make an argument for this occurring only in brief bursts during PEM so tissues have time to heal adequately outside of PEM, but then you would need a different explanation for what’s causing the constant symptoms outside of PEM.
 
jnmaciuch said:
But invoking TLR activation as the source of interferon basically negates that benefit of the theory, because TLR stimulation activates multiple signaling cascades simultaneously—many of which result in cytokines that do cause inflammation and tissue damage. Absence of NFkB-related pathology would be the big one to explain.
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That seems a reasonable objection but what if TLR7 or 8 was ligated in specific cell populations in very specific places - maybe cells that do not generate things like TNF. It would certainly be an argument against macrophage activation. What about something like gamma delta T cells specifically in bone marrow?
 
Sorry if this has been asked, but if a part of the causation of ME is in the brain, how might a causal loop involving bone marrow and brain work?

Is a model possible where brain and bone marrow (to simplify things) communicate with each other?

Or is it more likely that the brain genes identified by DecodeME make a person more vulnerable to the effects of a disease loop occurring somewhere else in the body?

Where mild ME results from a disease loop involving the immune system and severe ME results from the same disease loop occurring in people whose brains tolerate it much less. The people with more severe symtoms will be more likely to be diagnosed and to take part in a study, so that DecodeME ends up finding that genes involved in brain function are causally related to the illness.
 
Hoopoe said:
Is a model possible where brain and bone marrow (to simplify things) communicate with each other?
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Yes, sorry, I should maybe have given more introduction but it ends up getting a bit longwinded.

We have been thinking of an immune signalling loop producing something like interferons that have an effect of brain just as in flu. The brain may be more susceptible for reasons to do with the 'brain genes' or might set up another loop or a feedback into the immune loop.

The puzzle is where the immune loop is going on if there is no evidence of any inflammation anywhere. My thought was that it might involve signals in bone marrow where immune events occur without necessarily tripping the standard inflammatory response.
 
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