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

[BurnA]

Certainly if POTS turns out to be autoimmune (and one study which found autoantibodies to the α1, β1 and β2 receptors in POTS suggests it may well be), that would indicate there can at least be autoimmune comorbidities of ME/CFS; however, that does not necessarily imply that autoimmunity occurs as part of the pathophysiology of ME/CFS itself.

There are also other common comorbidities of ME/CFS which are autoimmune or suspected autoimmune, such as Hashimoto’s thyroiditis and Sjögren’s syndrome.


It's also of interest to note that many common comorbidities of ME/CFS tend to be found more frequently in patients with known autoimmune diseases, and this fact might perhaps offer some evidence for an autoimmune etiology of ME/CFS.

Granted it doesnt necessarily imply autoimmunity as part of the pathophysiology of ME/CFS but would it sway you to thinking it might ?

Are there other diseases which are or are not autoimmune yet display autoimmune comorbidities ?

 

[Hip]

Granted it doesnt necessarily imply autoimmunity as part of the pathophysiology of ME/CFS but would it sway you to thinking it might ?

That fact that Hashimoto’s is, and Sjögren’s and POTS possibly are, autoimmune conditions does make me think it is more likely that ME/CFS may involve an autoimmune component, at least in a subset of patients.

Though note that autoantibodies have also been found in ME/CFS as well as these ME/CFS comorbidities.

ME/CFS patients have been shown to have autoantibodies to:

• the muscarinic cholinergic receptor 1 (50% of ME/CFS patients have this)
• the mu-opioid receptor (one of the beta-endorphin receptors)
• the serotonin 5-HT1A receptor (61.5% of ME/CFS patients have this, compared to 5.7% of healthy controls)
• the neurotransmitter serotonin
• microtubule-associated protein 2
• phosphatidylinositol
• insoluble cellular antigens (83% of ME/CFS patients have this, compared to 17% of healthy controls)
• cardiolipin
• Heat shock protein HSP60

For study references for the above, and some more info, see this post.

Though most of the above studies have not been replicated, and even if these results are one day confirmed, I presume it would not necessarily prove that the above autoantibodies actually play a role in the pathophysiology of ME/CFS (but it would be a further step towards such proof).

Are there other diseases which are or are not autoimmune yet display autoimmune comorbidities ?

I don't know. Perhaps @Jonathan Edwards will be able to answer your question. The question is:

If a disease has several common comorbidities that are autoimmune in nature, does this suggest that the main disease itself may also be autoimmune?

And in the same vein: are there are non-autoimmune diseases which have autoimmune diseases as common comorbidities? Or do you usually only find autoimmune comorbidities in diseases that are themselves autoimmune?

 

[Jonathan Edwards]

If a disease has several common comorbidities that are autoimmune in nature, does this suggest that the main disease itself may also be autoimmune?

And in the same vein: are there are non-autoimmune diseases which have autoimmune diseases as common comorbidities? Or do you usually only find autoimmune comorbidities in diseases that are themselves autoimmune?

Comorbidity is a rather vague word. But I cannot think of any non-autoimmune disease that is associated with, or co-occurs more often with, an auto-immune disease. There may be some rare examples. (Autoimmunity can occur after bone marrow transplantation for non-autoimmune disease but that is a bit different.)

 

[Hip]

Comorbidity is a rather vague word.

True, "comorbidity" does have more than one meaning; I am using the meaning: comorbid disease = a secondary disease that statistically is found to occur more often in patients with the primary disease than it does in healthy controls.

For me, one of the most interesting comorbidities of ME/CFS is irritable-bowel-syndrome (IBS): one study found 92% of ME/CFS patients, and 77% of fibromyalgia patients, had IBS in their lifetime (compared to 18% for healthy controls).

So IBS is a very common comorbidity of ME/CFS. Other comorbidities of ME/CFS include: interstitial cystitis, 1 2 chronic prostatitis, 1 and endometriosis. 1

With comorbidities, one can speculate that:

• the comorbidity may play a causal role in the development of the primary disease;
• the primary disease may play a causal role in the development of the comorbidity;
• some third factor present in the patient plays a causal role in the development of both primary disease and comorbidity.

 

[ppodhajski]

Since I cured my ME, IBS, IC with Nutritional Genomics I will say it is autoimmune without a doubt.

 

[BurnA]

Comorbidity is a rather vague word. But I cannot think of any non-autoimmune disease that is associated with, or co-occurs more often with, an auto-immune disease. There may be some rare examples. (Autoimmunity can occur after bone marrow transplantation for non-autoimmune disease but that is a bit different.)

What might cause auto-immune diseases to co-occur ?

 

[Jonathan Edwards]

What might cause auto-immune diseases to co-occur ?

You will find reference to that on other threads over the last couple of years - particularly the one about rituximab and my attachment to IiME. My belief is that you have a genetic predisposition and on top of that there is random generation of autoreactive B cells that happen to be able to keep themselves going through signals through their own antibodies. You don't need any environmental factor, although things like smoking may affect thresholds. The full story is very complicated but we have been through quite a bit of it in past posts.

 

[Forbin]

Could the disease be both infectious and autoimmune?

The Columbia study indicates a chronic upregulation of the immune system in the first three years of the illness. Since many ME patients become ill in the immediate wake of a flu-like infection, it seems likely that an infection by a pathogen (somehow) leads to that upregulation.

Could that chronic upregulation then lead to more opportunities for the kind of random event that results in an autoimmune process?

Conversely, could an autoimmune disease itself produce the kind of upregulated pattern seen in the Columbia study?

[In my own case, although my illness began very distinctly, the symptoms were initially more like "chronic flu" without the upper respiratory features, such as cough and congestion. I only developed potentially autoimmune aspects, such as POTS and something that weirdly mimicked the tissue changes seen in chronic ulcerative colitis for several months, after the first year or two of the illness. This makes me wonder if the disease might begin as an infection leading to chronic upregulation that then enhances the chances of developing autoimmunity.]

 

[Jonathan Edwards]

Could the disease be both infectious and autoimmune?

The Columbia study indicates a chronic upregulation of the immune system in the first three years of the illness. Since many ME patients become ill in the immediate wake of a flu-like infection, it seems likely that an infection by a pathogen (somehow) leads to that upregulation.

Could that chronic upregulation then lead to more opportunities for the kind of random event that results in an autoimmune process?

Conversely, could an autoimmune disease itself produce the kind of upregulated pattern seen in the Columbia study?

[In my own case, although my illness began very distinctly, the symptoms were initially more like "chronic flu" without the upper respiratory features, such as cough and congestion. I only developed potentially autoimmune aspects, such as POTS and something that weirdly mimicked the tissue changes seen in chronic ulcerative colitis for several months, after the first year or two of the illness. This makes me wonder if the disease might begin as an infection leading to chronic upregulation that then enhances the chances of developing autoimmunity.]

The random generation of antibody species that is central to all B cell function would not be encouraged by an infection. It is constant throughout life. However, an infection might favour the engagement of a feedback loop once a suitable random event had occurred. The feedback loop might then evolve to new features over a period of months or years.

 

[Snow Leopard]

The way I see it is that risk factors such as infection can basically add noise or impulses to a signalling system. This can increase the chance of the feedback loops that Jonathan mentions, being induced.

 

[MeSci]

The way I see it is that risk factors such as infection can basically add noise or impulses to a signalling system. This can increase the chance of the feedback loops that Jonathan mentions, being induced.

From a discussion in another thread, I summarised a possible scenario (after correcting myself) thus, with a little elaboration:

Infection causes production of high levels of gamma-interferon.
For some reason high levels of gamma-interferon persist.

This leads to (or makes more likely):

CD64 on microglia/macrophages binds to non-specific antibodies.
Microglia/macrophages are thus primed and become overactive.

I think that @Jonathan Edwards agreed with my summary (more or less!) which I had drafted from the info he had provided.

 

[Snow Leopard]

From a discussion in another thread, I summarised a possible scenario (after correcting myself) thus, with a little elaboration:

Infection causes production of high levels of gamma-interferon.
For some reason high levels of gamma-interferon persist.

This leads to (or makes more likely):

CD64 on microglia/macrophages binds to non-specific antibodies.
Microglia/macrophages are thus primed and become overactive.

Sounds a bit vague to me.

There are literally tens of thousands of possibilities, but very few of them actually lead to disease. Needle in a haystack.

 

[MeSci]

Sounds a bit vague to me.

There are literally tens of thousands of possibilities, but very few of them actually lead to disease. Needle in a haystack.

It was mainly this post of Jonathan's which got me interested.

 

[Snow Leopard]

It was mainly this post of Jonathan's which got me interested.

I thought Jonathan was talking about how the immune system could be activated (and thus mediating symptoms) by circulating antibodies without actually triggering an inflammatory cascade (which might happen if one of the other Fc receptors or complement was the primary binding mechanism of the antibodies in question).

I'm not sure if this model actually requires elevated gamma-interferon over time, but I guess it is possible that this could increase the risk of initiating such loops early on in the disease. Which I now realise is probably what you were getting at, given the finding in the Hornig study.

 

[MeSci]

I thought Jonathan was talking about how the immune system could be activated (and thus mediating symptoms) by circulating antibodies without actually triggering an inflammatory cascade (which might happen if one of the other Fc receptors or complement was the primary binding mechanism of the antibodies in question).

I'm not sure if this model actually requires elevated gamma-interferon over time, but I guess it is possible that this could increase the risk of initiating such loops early on in the disease. Which I now realise is probably what you were getting at, given the finding in the Hornig study.

Yes - I thought it was relevant to the questions/statements here about whether infection could play a role in triggering ME through this means.

 

[Jonathan Edwards]

I thought Jonathan was talking about how the immune system could be activated (and thus mediating symptoms) by circulating antibodies without actually triggering an inflammatory cascade (which might happen if one of the other Fc receptors or complement was the primary binding mechanism of the antibodies in question).

I'm not sure if this model actually requires elevated gamma-interferon over time, but I guess it is possible that this could increase the risk of initiating such loops early on in the disease. Which I now realise is probably what you were getting at, given the finding in the Hornig study.

I thought MeSci was making a fair summary of ideas we chucked around. Whether they were worth chucking time will tell!

 

[Forbin]

I don't know if this might relate to ME, but this 2012 paper out of Harvard talks about the interrelationship between immune deficiency, a chronically activated immune system and autoimmune diseases. Most of it is over my head, but seems to make a case for uncleared infections leading to chronic immune activation, inflammation and autoimmune disease (it mainly focuses on lupus).

Clinical and laboratory findings consistent with autoimmunity are common in immunodeficient patients. The decreased ability of the immune system to clear infections in these patients can cause perpetual immune system activation and autoimmunity.

Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus
Alexandros P. Grammatikos and George C. Tsokos
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278563/

[My bolding above.]

Naturally, this makes me wonder if the chronic immune activation reported in early ME might be a factor leading to some form of autoimmunity.

 

[Jonathan Edwards]

I don't know if this might relate to ME, but this 2012 paper out of Harvard talks about the interrelationship between immune deficiency, a chronically activated immune system and autoimmune diseases. Most of it is over my head, but seems to make a case for uncleared infections leading to chronic immune activation, inflammation and autoimmune disease (it mainly focuses on lupus).


[My bolding above.]

Naturally, this makes me wonder if the chronic immune activation reported in early ME might be a factor leading to some form of autoimmunity.

This seems like the same old infectious trigger theory that to my mind is obsolete. Immunologists do not seem to be able to move on. I think it is much more likely that the regulatory failure that leads to immunodeficiency also predisposes directly to autoimmune loops. No need to invoke infection, just unstable regulation.

 

[BurnA]

You will find reference to that on other threads over the last couple of years - particularly the one about rituximab and my attachment to IiME. My belief is that you have a genetic predisposition and on top of that there is random generation of autoreactive B cells that happen to be able to keep themselves going through signals through their own antibodies. You don't need any environmental factor, although things like smoking may affect thresholds. The full story is very complicated but we have been through quite a bit of it in past posts.

Comorbidity is a rather vague word. But I cannot think of any non-autoimmune disease that is associated with, or co-occurs more often with, an auto-immune disease.

I came across this on another thread..

I would caution against the idea that bits of evidence for something being autoimmune always 'add up'. If there is autoimmunity to one target then it is probably less likely that there autoimmunity to another target. If it was Colonel Mustard in the Library it probably wasn't Professor Plum in the Conservatory as well, if you see what I mean!

Just wondering, how the last statement ties in with the previous one above it or indeed the relevance to POTS in general. It seems to me you are advising caution in associating 'bits of evidence' adding up to autoimmunity. However do you have any theory on the presence of POTS in PWME ?

 

[Jonathan Edwards]

I came across this on another thread..


Just wondering, how the last statement ties in with the previous one above it or indeed the relevance to POTS in general. It seems to me you are advising caution in associating 'bits of evidence' adding up to autoimmunity. However do you have any theory on the presence of POTS in PWME ?

I think those quotes relate to quite different questions. I do not have very strong feelings about the mechanism for POTS, if indeed PWME generally have POTS rather than some other form of OI. It is all a bit fuzzy to me. If OI occurs across the board in ME then I am tempted to think it is part of a secondary autonomic mechanism rather than being a sign of a specific aetiology, but I don't know. I am not sure that there is good evidence for POTS having an autoimmune basis in general.