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

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chillier said:
My understanding was, that could be misremembered, that in neurons you can get mRNA packaged up into riboproteins that can be shuttled along microtubules to the ends of the neurons. In this way you would have a little bit of an ability to quickly respond to signals locally with regulation at the translation level. Maybe this happens in some situations and not others.
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You may be right! It seems not to be the case for e.g. the peptides in the paper I linked (nor for most that I’m familiar with, which granted isn’t that many neuronal proteins), but in theory it seems possible.

[edit: though the time differential gained by translating later wouldn’t be that much compared to simply how much time would be needed to traffic down a long neuron. Translation tends to happen quickly barring some specific circumstances]

[edit on the edit: nope, turns it it can take much longer in the cell than I was thinking. Always good to check the literature before pulling from foggy memory I suppose]
 
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Jonathan Edwards said:
I am not sure that we have good reason to think that the neuron needs to express anything more down at the sensory receptor end. Shifting calcium balance around the cell soma might make more sense - in response to signals from receptor there. These neurons are odd in that they tend to have a single forked axon that functions both as afferent and effect from the cell body. The cell body might seem just to be a source of structural proteins but it might control propagation from one axon fork to the other by modulating calcium at that point?
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I think I see @chillier ’s point though of starting at the time frame of PEM and working backwards. You’re probably right that the neuron doesn’t necessarily need to translate new proteins in order to react to some stimulus, but if there is an important modulatory process where this occurs, it would be a good candidate for a pathological mechanism (or part of one anyways).

It’s the same logic that led me to an interferon response—the timescale seems correct provided you could find an explanation for an initial trigger. Some slow neuronal response might be an alternative answer
 
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Jonathan Edwards said:
If ME/CFS has the sort of mechanism I am suggesting, it is going to be neither of those, because it is not inflammatory.
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This comes up a lot, may I ask for the basis of this statement? I am not challenging it, I just want to understand it. It's not at all within my particular expertise. Every second paper says "inflammation" but I often don't know enough to look in detail at results to understand whether the assays are actually saying what is being interpreted (ie filter out what is meme and what is not). I need a voice that I can trust to make sense of where the consensus information stands.
 
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DMissa said:
This comes up a lot, may I ask for the basis of this statement?
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It is very simple. inflammation is a physiological change based on local blood vessel function that involves a change in calibre, permeability to water and solutes and cell diapedesis. It has been known since Roman times through the signs of: dolor, calor, rubor, tumor (and loss of function). In ME/CFS we can see from looking at the body and, most precisely, analysing tissue fluid content with MRI, that this occurs nowhere.

There is no inflammation.

As pointed out in our paper, there may be production of some cytokines that are often seen in inflammation but there is no production of others, and inflammation itself does not occur.

So the need is to construct a model that includes the mediators we think are involved but does not invoke some rag-bag concept of a package deal of events that people like to use as a buzz word but is not relevant.

DMissa said:
I need a voice that I can trust to make sense of where the consensus information stands.
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My credentials are that I did an Experimental Pathology doctorate under Wally Spector and Derek Willoughby at Barts in the 1980s. The department at that time was the premier UK academic centre for inflammation research. I later collaborated with Salvador Moncada's group at the Wellcome Foundation (Moncada had worked with John Vane on the discovery of the action of prostaglandins and the mechanism of action of aspirin, for which John received the Nobel.) I was a founder committee member of the British Inflammation Research Association.

I learned early on that consensus in biomedical science is nearly always wrong. People just don't understand enough detail, so go for the explanation that superficially makes sense despite the fact that after ten minutes analysis you can see it falls apart. The consensus on relevant 'facts' is always heavily skewed by this popular dogma.
 
jnmaciuch said:
I think I see @chillier ’s point though of starting at the time frame of PEM and working backwards.
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Yes, indeed, I think that is crucial. But at the moment the various possible pathways floating round my head do not seem to need any shift at the afferent nociceptor end of the axon. Sensitising at the cell body through FcRI would make some sort of sense, even if a bit mysterious. I am less clear how it would help at the afferent end and that is not where it has been demonstrated so far.
 
Jonathan Edwards said:
I learned early on that consensus in biomedical science is nearly always wrong. People just don't understand enough detail, so go for the explanation that superficially makes sense despite the fact that after ten minutes analysis you can see it falls apart. The consensus on relevant 'facts' is always heavily skewed by this popular dogma.
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Have you ever thought about doing a book (or series of papers) about myths in medicine? PwME seem to have been on the receiving end of a whole ton of these and it's been shocking to learn how the permeate the field.
 
Jonathan Edwards said:
There is no inflammation.

As pointed out in our paper, there may be production of some cytokines that are often seen in inflammation but there is no production of others, and inflammation itself does not occur.
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Got it.

Jonathan Edwards said:
My credentials are that I did an Experimental Pathology doctorate under Wally Spector and Derek Willoughby at Barts in the 1980s. The department at that time was the premier UK academic centre for inflammation research. I later collaborated with Salvador Moncada's group at the Wellcome Foundation (Moncada had worked with John Vane on the discovery of the action of prostaglandins and the mechanism of action of aspirin, for which John received the Nobel.) I was a founder committee member of the British Inflammation Research Association.

I learned early on that consensus in biomedical science is nearly always wrong. People just don't understand enough detail, so go for the explanation that superficially makes sense despite the fact that after ten minutes analysis you can see it falls apart. The consensus on relevant 'facts' is always heavily skewed by this popular dogma.
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Yep, that's why I am asking you, specifically. ;) Thanks J
 
I am beginning to think that FcRI up regulation on DRG neuron cell bodies might provide a story that would turn some other assumptions on their head and maybe end up making some testing options more attractive.

What if there are a group of T cells whose job it is to lurk around macrophages and dendritic cells in lymphoid tissues until they are presented with some bad peptides and then gear up to make gamma interferon, but instead of just making it there, zip off into the circulation and visit tissues, including nerve ganglia, where they chuck out the interferon. This would provide a way to signal systemically but with a cytokine acting at short range.

The T cells need not stop for long in the tissues they visit. There need not be any apparent increase in T cell numbers in fact. They are just expressing more interferon and up regulating IFN-responsive genes. So there is 'nothing to see here'.

The advantage of this model would be that T cells from blood could probably be shown to be ready to make interferon when sat next to some other cell - maybe macrophage or stroll cells in short term culture.
 
Oh well in that case more questions!

1) How would this all fit in with Ryback et al’s findings of increased IGHV3-30 and skewing in the ratio of IgM to IgG BCRs seen in mild/moderate people and not in severe?

2) The basic mechanism seems to be of different cells all doing largely what we’d expect them to do. Macrophages presenting antigen fragments to T cells, T cells producing cytokines, etc. I haven’t quite got my head around what exactly has gone wrong or why other than some cells being permanently closer to or above an activation threshold so more likely to do things. I can see that it could happen, but don’t yet understand the differentiation between normal and not normal. I assume this will be explained in the paper but thought I may as well ask.
 
hotblack said:
1) How would this all fit in with Ryback et al’s findings of increased IGHV3-30 and skewing in the ratio of IgM to IgG BCRs seen in mild/moderate people and not in severe?
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Pass.

hotblack said:
I haven’t quite got my head around what exactly has gone wrong
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That is the tricky part. One could also ask what has gone wrong in psoriasis, where nobody has found cells doing much they don't normally do. I think the answer must lie in expansion of some group of T cells. It might be one or more 'clones' with a particular antigen receptor specificity but it might be a broader group of 'innate cells'.

I don't pretend to provide a clear answer to this but the answer may lie more in the set up than in anything specific going wrong. That would link to genetic risk. Maybe one should think of the immune system as like a city that over a period of years gradually acquires impenetrable traffic jams at certain points as cars become more popular. Nothing is doing anything other than it usually does, but the system overloads itself. If you introduce certain parking restrictions it may right itself very easily.

For me the key point in this is that to explain the long term dynamic of the illness we need a shifting system that is constantly responding to signals and re-adjusting, which the adaptive immune system does much more than the innate side. For B cell clones in autoimmunity it is fairly easy to see how you can end up with certain specific idiosyncratic errors. For T cell shifts it is more tricky but the possibility is there I think.
 
Jonathan Edwards said:
The T cells need not stop for long in the tissues they visit. There need not be any apparent increase in T cell numbers in fact. They are just expressing more interferon and up regulating IFN-responsive genes. So there is 'nothing to see here'.

The advantage of this model would be that T cells from blood could probably be shown to be ready to make interferon when sat next to some other cell - maybe macrophage or stroll cells in short term culture
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I may have already gotten to a similar conclusion as you via different means. Interested to read your paper, there might be a bit that already aligns with what I am trying to investigate with tissue samples
 
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