The 'writing on the wall' hypothesis

Jonathan Edwards

Jonathan Edwards

Senior Member (Voting Rights)
Thread split from The itaconate shunt hypothesis

A wild card theory I have toyed with for some years is that the pathogenic signalling in ME/CFS may be invisible because it is 'written on the walls' in tissue.

In an underground train (metro) system, travellers need not carry any instructions in their pockets, nor do they need public address systems saying here to go. They read the signs on the walls. 'Northern Line Southbound this way', 'Way Out'.

There is very good evidence that cells do the same. Every tissue has a matrix network of collagen and elastin fibres. The elastic fibres in particular have regularly spaced 'pinboard' sections onto which can attach molecules like TGF beta, complement regulatory proteins CD55 and CD59 and even immunoglobulin receptors (in muscle for instance). If you stain a tissue for LTBP (latent TGF beta binding protein) you will see a complex pattern like a fishnet around all the cells but more in some places than others.

Maybe there is a type of immune response that we might call a 'Fall-out shelter' response, maybe with some similarity to hibernation, normally activated not to react actively to adverse events (inflammation) but to hide away and save resources. And maybe that response is conveyed to cells, and very likely in some tissues more than others, by posting TGF beta and other such things on the elastin pinboards.

In that situation if you looked at cells in tissue culture they would behave normally, at least after a few hours out of the body. You would not find any cytokines in the blood much. But you might find changes in the patterns of signalling molecules painted on tissue fibres using immunochemistry.

An abnormal shift in wall signals might be mediated by dysregulated CD8 T cells, as in psoriasis, for instance. The capricious ups and downs in severity would then be due to the T cells waxing and waning and congregating in different places, just as in psoriasis. But if all the signalling was done with silent wall messages nobody would see what was going on from blood and cell studies.
 
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Jonathan Edwards said:
A wild card theory I have toyed with for some years is that the pathogenic signalling in ME/CFS may be invisible because it is 'written on the walls' in tissue.

In an underground train (metro) system, travellers need not carry any instructions in their pockets, nor do they need public address systems saying here to go. They read the signs on the walls. 'Northern Line Southbound this way', 'Way Out'.

There is very good evidence that cells do the same. Every tissue has a matrix network of collagen and elastin fibres. The elastic fibres in particular have regularly spaced 'pinboard' sections onto which can attach molecules like TGF beta, complement regulatory proteins CD55 and CD59 and even immunoglobulin receptors (in muscle for instance). If you stain a tissue for LTBP (latent TGF beta binding protein) you will see a complex pattern like a fishnet around all the cells but more in some places than others.

Maybe there is a type of immune response that we might call a 'Fall-out shelter' response, maybe with some similarity to hibernation, normally activated not to react actively to adverse events (inflammation) but to hide away and save resources. And maybe that response is conveyed to cells, and very likely in some tissues more than others, by posting TGF beta and other such things on the elastin pinboards.

In that situation if you looked at cells in tissue culture they would behave normally, at least after a few hours out of the body. You would not find any cytokines in the blood much. But you might find changes in the patterns of signalling molecules painted on tissue fibres using immunochemistry.

An abnormal shift in wall signals might be mediated by dysregulated CD8 T cells, as in psoriasis, for instance. The capricious ups and downs in severity would then be due to the T cells waxing and waning and congregating in different places, just as in psoriasis. But if all the signalling was done with silent wall messages nobody would see what was going on from blood and cell studies.
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That's a very interesting idea.

I am not sure though, that ME/CFS cells (we haven't looked at too many celltypes?) behave normally or work as in healthy controls? I guess that is not a neceassary ingredient for your idea to have merit, though.

Are there research methods and technology that could be used to test your idea? I guess you would need tissue of patients?

Maybe somewhat off topic:

I know you don't think much of hEDS as a pathological entity, but recent research points toward the ECM as the potential culprit of this pehontype(s).
 
Ravn said:
Interesting. What sort of study design and technology would you need to investigate this pinboard hypothesis @Jonathan Edwards ?
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I'm assuming that DecodeME [GWAS - common variants] would have clues -- highlighting that the mechanism is immune related? E.g. in Alzheimer's [GWAS] the (3) genes that eventually turned up are immune related - took several DecodeME (GWAS) sized studies to find those genes in Alzheimer's though!
Other thing would be rare variant whole genome sequence studies - e.g. families with 2 or more affected (at least 1 severe) - seems NIH may fund a rare variant study - NIH research roadmap.
 
Ravn said:
Interesting. What sort of study design and technology would you need to investigate this pinboard hypothesis @Jonathan Edwards ?
Click to expand...

The first step would be to look at patterns of adsorbed signalling proteins on matrix fibres using biopsies and immunochemistry. Calibrating between individuals would probably be hard. I would look for changes in patterns. One the the best bits of evidence for our rheumatoid theory was that the immunoglobulin receptor CD16 is expressed on macrophages and adsorbed on to elastic fibres at exactly the site where rheumatoid nodules occur. I would not expect anything quite as clear-cut as that for ME/CFS but something equally striking might turn up around muscle or something.

Taking biopsies is not easy but if one knew exactly what was looking for a fairly small series might provide a very useful clue.
 
butter. said:
I know you don't think much of hEDS as a pathological entity, but recent research points toward the ECM as the potential culprit of this pehontype(s).
Click to expand...

We have known for a long time that many EDS genotypes are defects in collagen-related genes - i.e. ECM. But the disease of elastin/fibrillin fibres is Marfan syndrome. The pinboards are on fibrillins as far as I can see.
 
FMMM1 said:
Other thing would be rare variant whole genome sequence studies - e.g. families with 2 or more affected (at least 1 severe) - seems NIH may fund a rare variant study - NIH research roadmap.
Click to expand...
Decode ME collected enough to provide DNA for a GWAS analysis and also a rare variant study (whole genome sequencing, WGS). The vast majority of participants gave consent to the rest of their DNA to be analysed by WGS. The problem is it’s very expensive, but the material is there for a very large WGS, which might be very revealing. As with all GWAS, the data also reveals family connections between participants.
 
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Jonathan Edwards said:
The first step would be to look at patterns of adsorbed signalling proteins on matrix fibres using biopsies and immunochemistry. Calibrating between individuals would probably be hard. I would look for changes in patterns. One the the best bits of evidence for our rheumatoid theory was that the immunoglobulin receptor CD16 is expressed on macrophages and adsorbed on to elastic fibres at exactly the site where rheumatoid nodules occur. I would not expect anything quite as clear-cut as that for ME/CFS but something equally striking might turn up around muscle or something.

Taking biopsies is not easy but if one knew exactly what was looking for a fairly small series might provide a very useful clue.
Click to expand...
What can we do to progress this Jonathan?
 
Jonathan Edwards said:
An abnormal shift in wall signals might be mediated by dysregulated CD8 T cells, as in psoriasis, for instance. The capricious ups and downs in severity would then be due to the T cells waxing and waning and congregating in different places, just as in psoriasis. But if all the signalling was done with silent wall messages nobody would see what was going on from blood and cell studies.
Click to expand...
MelbME said:
I imagine the cells that are lifelong would be of particular interest in this theory.
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So could the signs on the wall change frequently, with the signs directly affecting cell function?

Or would the signs on the wall be permanent, with fluctuations explained by cells' abnormal response to stresses such as exertion under the regime imposed by the signs?
 
Hutan said:
So could the signs on the wall change frequently, with the signs directly affecting cell function?

Or would the signs on the wall be permanent, with fluctuations explained by cells' abnormal response to stresses such as exertion under the regime imposed by the signs?
Click to expand...

Almost nothing is known about turnover of these wall signals. But observations on rheumatoid nodules suggest that the signals are dependent on things like ongoing physical forces - probably a bit like what controls the thickness of skin on the palms of our hands (which may be mediated by exactly these sorts of signals). It is likely that once present regulatory proteins just sit there for months but they may gradually wash out over days or weeks if the tissue is not used mechanically. It may also be that during inflammation everything gets wiped off and repainted over a period of hours.

The nice thing about it is that it would be a mechanism that might explain the peculiar slowish time course of events in ME/CFS and would potentially be completely reversible. But to reverse it one would need to find out what was keeping excessive or insufficient signals painted up on the walls - probably some sort of immune surveillance cell but also possibly nerves. It might even tie in with an acetylcholinesterase role.
 
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