What evidence is there that ME/CFS is more autoimmune than chronic infection?

Hip

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It seems some people believe these systems are digital, when they are in fact analogue.
What do you mean precisely?


I don't think making references to people's sanity or insanity is a constructive way to argue. In fact, it would seem to be in the category of ad hominem attacks, which as we know are often used by those who are losing the argument.
They are not making any such references. "Sanity at last" is an English idiom, meaning something like "at last a sensible comment".
 

adreno

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What do you mean precisely?
I mean that those cytokines are not switches that turn on a specific state. Biological systems are complex and dirty (analog). It is really just some statistical approximations trying to demarcate different states, or syndromes.

You are thinking black and white; turn on abc and you get sickness behaviour (or ME). It is too simple a model to explain a complex syndrome like ME.

In other words, ME is not simply sickness behaviour.
 
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Hip

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Trouble is, TNFa, IL-1b and IL-6 are hugely non-sepcific. They figure strongly in rheumatoid arthritis and ankylosing spondylitis, to mention the first two inflammatory diseases to come to my mind.
Significant fatigue can be part of the picture of these two diseases though, so that does suggest some sickness behavior may be occurring as a result of these cytokines.

However, because I assume in these two disease cytokines are not produced in close proximity to the vagus nerve which detects them, the effects of these cytokines on the vagus will be much reduced. I understand that it is IL-1β from infections/inflammation that the vagus nerve specifically detects, and then responds by activating sickness behavior. IL-1β is a paracrine and autocrine cytokine that does not travel far in the body.


Though if ME/CFS does have both autoimmune and infectious subsets, then I think it would be very interesting to try to figure out how the autoimmune processes in the autoimmune subset might trigger sickness behavior, because if we can, that might lead to a universal theory of ME/CFS, which stands to explain how both autoimmune and infectious processes can lead to sickness behavior, and thus ME/CFS symptoms.

Chronically induced sickness behavior might be the central pathophysiological mechanism of ME/CFS, with various "inputs", like infection or autoimmunity, serving to activate this mechanism.

Sickness behavior won't explain all symptoms of ME/CFS; it does not seem to explain orthostatic intolerance for example; but may explain a large bulk of ME/CFS symptoms.



why does it go on being chronic when cytokine production from initial infection would be expected to be brief. I realise that one option is cytokine production confined to brain, and that could be brain stem attached to vagus nerve, but in my experience something as local as that would show some other tell tale signs if there were ongoing infection.
In Michael VanElzakker's paper, he posits a low level chronic infection of the vagus constantly secretes the sickness behavior cytokines IL-1β, TNF-α and IL-6. Because this infection is within the vagus itself, there will be very high levels of these cytokines locally in the nerve, activating the nerve.

Specifically, VanElzakker thinks the glial cells that surround the vagus nerve will harbor the infection. Interestingly enough, coxsackievirus B is known to be able to infect glial cells, and when it does, it specifically secretes exactly these three IL-1β, TNF-α and IL-6 cytokines.
 
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Hip

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You are thinking black and white
I am simply explaining the details of Michael VanElzakker's vagus nerve infection hypothesis for ME/CFS, or variations thereof.

Certainly the activators of sickness behavior are more complex than just the vagus nerve route that is the central part of VanElzakker's theory.

If you are interested in the complexities of sickness behavior activation by cytokines, then here goes:

First of all, sickness behavior symptoms can be triggered when IL-1β, TNF-α and IL-6 are released within the brain. So brain inflammation, brain infection and microglial activation which releases these cytokines can directly induce sickness behavior. Autopsies of ME/CFS patients have shown enterovirus infections in the brain tissues, so these brain infections could be one source of sickness behavior in ME/CFS.


In addition, there are also at least four known pathways by which peripheral infection and inflammation in the body can be detected, and the information transmitted to the brain in order to activate sickness behavior.

1 ➤ The vagus nerve pathway detailed earlier is one of the four pathways, and is the main and most important pathway. It is also referred to as the neural pathway of sickness behavior activation.

The other three pathways by which peripheral infection and inflammation can activate sickness behavior in the brain involve messages conveyed by these inflammatory cytokines in the blood circulation. These three pathways are called the humoral pathways of sickness behavior activation.

These three other pathways are essentially three different routes that IL-1β, TNF-α and IL-6 in the blood can either cross the blood-brain barrier and enter the brain to activate sickness behavior, or transmit a signal across the BBB to activate sickness behavior.

2 ➤ The first of the three routes is via active transport of the cytokines IL-1β, TNF-α and IL-6 across the blood-brain barrier and into the brain, where they then activate sickness behavior;

3 ➤ the second of the three routes is where these cytokines in the blood activate endothelial cells and perivascular macrophages in the blood vessels of the brain, which then release prostaglandin E2 within the brain, which promotes neuroinflammation and sickness behavior;

4 ➤ and the last of the three routes is where these cytokines (and also LPS) in the blood activate macrophages on the circumventricular organs and the choroid plexus of the brain, which then in turn promotes neuroinflammation and sickness behavior.

So this last route indicates that LPS in the blood, deriving from say a leaky gut, could activate sickness behavior. So in some ME/CFS patients with gut issues, this last route might be part of the picture of how their ME/CFS symptoms / sickness behavior arise.


Source: Cytokine, Sickness Behavior, and Depression
 
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alex3619

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What evidence is there that ME/CFS is not due to chronic infection and that drugs like rituximab are making things better not worse or masking the problem?
Masking the problem long term. Unlikely if the phase three trials are successful. However it is the case there are a few patients who cannot be treated with Rituximab until ongoing infections are cleared. Active infections.

There is a concern that low grade infections are going to be an issue with some patients, the kind that do not show up on regular testing. That might include Lyme. Its not clear however that all Lyme is Lyme.

So if Lyme is the cause of the ME symptoms, then it might be a concern. If Lyme is a continuing trigger it might be a concern. But if what we think of as chronic Lyme is more ME with Lyme then it might also be the case that rebooting the immune system might help fight it, or that if the symptoms are Lyme triggered, but the Lyme is no longer a big issue, then the Lyme pathogen is largely irrelevant.

That is why we have phase 3 trials. The evidence is more important than speculation.

Given the prevalence of Lyme disease and the large number of patients who have taken Rituximab for lymphoma, r. arthritis etc., then I would think a Lyme issue might have shown up. I have not read of it. Maybe it just goes unreported, the way Lyme cases get treated. Maybe it doesn't happen.
 

SOC

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As for me, I've never had any of the usual infectious suspects so none of those can explain my illness.
None? As in no exposure to EBV or CMV or HHV6 or HSV or VZV? That would be extremely unusual and reason to look carefully at your immune system. If you are testing antibody-negative to all those, it might be because you're not producing antibodies rather than that you've never been exposed to any of these extremely common viruses.
 

msf

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Haha, I just looked up Esther Crawley, one of the doctors Prof. Edwards mentioned as being located near the New Forest, and found that she supervised a trial of the Lightning Process in children with ME (the completely inappropriately named SMILE study).
 

msf

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Oops, I didn't notice the stress there. I take this last comment back, although I would like to know where the idea that ME consists of 'up to 15 different diseases' came from. This to me sounds just as contentious as saying that there is only one cause.
 

msf

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And I don't think there are any active researchers on PR, for the reason alex 3619 suggested.