Are Infections Just a Trigger of ME/CFS, or an Ongoing Cause of ME/CFS?

[Sidereal]

@Sidereal - Interesting, similar story with our moms, although mine quit smoking when I was a kid.

Any unusual or interesting health issues with your dad?

He has like 11 diagnoses but no ME/CFS, just typical sequelae of the metabolic syndrome. Me and him also have a very unusual genetic disorder (which does not cause fatigue).

 

[Jonathan Edwards]

It's just the cytokine IL-1β that would have to be at high levels in close proximity to the vagus nerve. I understand it is IL-1β which the vagus specifically detects, and which then causes the vagus to activate sickness behavior in the brain. Levels of IL-1β could be very high next to the vagus, but blood tests would not pick this up, because IL-1β is a paracrine and autocrine cytokine, meaning that it does not travel very far in the body, and only acts locally.

According to VanElzakker's vagus nerve infection and sickness behavior theory of ME/CFS, it's when these cytokines are chronically produced in very close proximity to the vagus nerve — such as when the vagus nerve itself is chronically infected — that you get a very strong cytokine signal being picked up by the vagus, triggering sickness behavior.

If the chronic low level infection is elsewhere in the body, away from the vagus, the cytokine signal will be too weak to trigger the vagus.

I am not entirely clear about this business of the vagus detecting IL-1. Wouldn't that be at the sensory nerve endings where receptors would be? There wouldn't be sensory receptors of that sort near the cell body in the ganglion, I suspect. This theory seems to be a bit vague anatomically! The vaugs nerve is not the same all along. It contains relays of various different sorts of both sensory and motor neurons.

 

[Eeyore]

@Sidereal - Are you very confident that the rare genetic disease you and your father share has no immune system implications, or any possible connection to ME? I don't think fatigue is the criterion we should use - I don't really think fatigue is the main thing in ME. The reason I say this is that I have strong suspicions of connections to my father's genetics as well, although he does not have ME and never really has had anything like it.

@Jonathan Edwards - I really don't think the vagus nerve infection theory makes any sense. I think it's just another attempt to explain why we cannot detect infection in ME patients by saying "see, it's not in the blood, it's in the vagus nerve!" We can play that game all day until we run out of body parts... Again, I think one of the things that has really hampered ME research is the way it presents as infectious. It throws everyone off course. There are examples of autoinflammatory conditions that present as infectious (e.g. reactive arthritis). I'm not sure of any antibody mediated autoimmune diseases present as infectious - perhaps guillain-barre with anti-ganglioside antibodies. I'm sure there are others.

 

[Sidereal]

@Sidereal - Are you very confident that the rare genetic disease you and your father share has no immune system implications, or any possible connection to ME? I don't think fatigue is the criterion we should use - I don't really think fatigue is the main thing in ME. The reason I say this is that I have strong suspicions of connections to my father's genetics as well, although he does not have ME and never really has had anything like it.

I cannot be 100% confident since there are only a couple dozen published papers on this condition. From the case series I've read, it appears to cause only one specific issue and has no immune system or metabolic manifestations whatsoever but who knows what would turn up with further research. I don't think fatigue is the main thing in ME either but no one in the medical community knows what ME is so I presume they would say the patients complained of fatigue if they came in with ME-like symptoms.

 

[Eeyore]

@Sidereal - Well, I'd think there would at least be connections to the immune system, the nervous system, or the ability of cells to generate energy - i.e. at least SOMETHING that might point at our issues.

 

[Jonathan Edwards]

I really don't think the vagus nerve infection theory makes any sense. I think it's just another attempt to explain why we cannot detect infection in ME patients by saying "see, it's not in the blood, it's in the vagus nerve!" We can play that game all day until we run out of body parts... Again, I think one of the things that has really hampered ME research is the way it presents as infectious. It throws everyone off course. There are examples of autoinflammatory conditions that present as infectious (e.g. reactive arthritis). I'm not sure of any antibody mediated autoimmune diseases present as infectious - perhaps guillain-barre with anti-ganglioside antibodies. I'm sure there are others.

I agree with you Eeyore, but I think one has to consider every possibility and work out precisely why it is flawed. For a lot of PWME I think the sense that the disease is infective is quite difficult to counter - particularly without clinical medical training. And I do not think one can discount it entirely. However, I think it is helpful to go through exactly why these theories do not hold a lot of water - as much as anything to get that clear in one's own mind. I realised that my own anatomy of vagal ganglia is a bit hazy, so I looked it up.

Reiter's syndrome, or reactive arthritis, is probably the best example of hit and run we have. The infection lasts a few days but the sequelae go on, with sequential relapses, for months, years or decades. Sympathetic ophthalmia is maybe another - where literally a physical hit to one eye can lead to inflammation developing later in the other eye. In lupus the autoimmune process often either mimics infection or facilitates true intercurrent infection. But to my mind autoimmunity is perhaps not quite hit and run, since we have little evidence for any external trigger at the time of onset. It is more 'the immune system going haywire all of its own accord' with the genesis of persistent autoantibody production through a feedback loop. Like a lot of others I am a bit sceptical about a one off damage theory, although I would not discount it since remissions and relapses might be superimposed by the effects of the normal ebb and flow of immune responses to trivial environmental organisms. But an autoimmune model does have the advantage that we know that the feedback process is constantly shifting and evolving.

I guess my main point is that getting really clear why one should prefer one theory over another is the best route to realising that one particular theory specifically predicts something one might test in the lab to confirm it.

 

[bertiedog]

ohn Chia got similar results with the immunomodulator oxymatrine: in some patients, this herbal extract dramatically reduced viral loads, and led to huge improvements in ME/CFS (you can see Chia's before and after pictures of stomach tissue enteroviral load reduction due to oxymatrine treatment in my post here). In patients who got much better but then discontinued oxymatrine, their ME/CFS returned.

This sort of fits with what I am experiencing. After 9 months of various herbals made by Nutramedix, I have greatly improved. Miles more energy and can do so much more physically. However my CNS can still get easily overstimulated say in hot weather or with too much tea but in general there is a really big improvement.

This past week whilst on a short break in the New Forest I was doing over 10,000 steps daily. Before treatment in September it was half that amount so there has to be some bug/s holding us back.

Pam

 

[Hip]

I am not entirely clear about this business of the vagus detecting IL-1. Wouldn't that be at the sensory nerve endings where receptors would be? There wouldn't be sensory receptors of that sort near the cell body in the ganglion, I suspect. This theory seems to be a bit vague anatomically! The vaugs nerve is not the same all along. It contains relays of various different sorts of both sensory and motor neurons.

That's a point.

This paper gives a good overview of the pathways involved in activating sickness behavior, and it says:

Sensory neurons of the vagus nerves express IL-1 receptors, and circulating IL-1β stimulates vagal sensory activity.

I am not sure exactly where these sensory neurons that express IL-1 receptors are located on the vagus. I could not find any info on it. Presumably though, sensory neurons will be located wherever the vagus innervates tissues or organs, otherwise the vagus would not be able do its job of detecting an infection in these areas. Since the vagus innervates numerous organs through the torso, these sensory neurons I imagine will be found where the vagus enters organs.



One idea that occurred to me: might another way to test this vagus nerve infection theory be via anesthetizing the vagus nerve of ME/CFS patients just beneath the diaphragm? That should temporarily prevent IL-1β-activated sickness behavior signals from the lower half of the vagus nerve reaching the brain, and so might thereby improve ME/CFS symptoms.

Although if the whole length of the vagus was infected, not all IL-1β-activated signals would be blocked by the anesthetic, so ME/CFS symptoms may not disappear entirely; but there may at least be a reduction in sickness behavior signals traveling along this nerve as a result of such anesthetization.

In the above-quoted study, they refer to animals that were experimentally vagotomized under the diaphragm (so as not to compromise cardiac and pulmonary function), and this prevented sickness behavior occurring when the animals were injected with LPS or IL-1β.

 

[Jonathan Edwards]

I am not sure exactly where these sensory neurons that express IL-1 receptors are located on the vagus. Presumably, sensory neurons will be located wherever the vagus innervates tissues or organs, otherwise the vagus would not be able do its job of detecting an infection in these areas. Since the vagus innervates numerous organs through the torso, these sensory neurons I imagine will be found where the vagus enters organs.

I think we hit a fatal problem here. The sensory neurons have their receptors in the organs they innervate but have their cell bodies many centimetres away up in the ganglia. If the receptors are in the organs then we need the IL-1 to be produced in the organs, not the ganglia. Since these cells innervate most visceral organs that means pretty well anywhere in the abdomen. We are back to infection in viscera, not vagal ganglia. So the 'vagus infection' theory won't do the job it is supposed to do as far as I can see. Getting anatomy right is crucial for these things.

 

[Eeyore]

@Jonathan Edwards

I agree with everything in your post. Actually, when I posted mine, I felt I was being somewhat lazy in not actually explaining why it doesn't make sense. It is something I am critical of others for doing sometimes, but I felt your post did address it from a rational, medically sound perspective. I knew I had looked at it at one point a while ago and thought in more detail and then discounted it, but I didn't remember exactly why, and my own knowledge on vagal anatomy and immune-neurological interactions is also hazy. It's good to have others keep me intellectually honest though, and to hold me to the standards I'd hold others to. After all, if we claim to be scientists, then our pursuit should be the truth above all else.

I think the hit and run theory doesn't preclude other contributing factors creating a predisposition, which may even suggest the trigger is being repeated on an ongoing basis at lower levels (or variable levels). (p.s. Do you use Reiter's and ReA differently? I know some do - but we were taught to not use Reiter's as a term due to his unsavory political affiliations... not that it offends me, it doesn't, was just curious if the terms are synonymous to you.) We know that ReA (and the other seronegative spondyloarthritides) are strongly linked to B27 and some other class 1 alleles. Even so, the patient generally does fine until the infection - which creates a long term illness in some - but not all. Additionally, many with B27:05 (i.e. those known to be associated with ReA, as a few B27 alleles are protective) do not ever have any evidence of pathology. Did they simply not get triggered? Other genes are known to play a role as well. So there is this ongoing, complicated interaction between genes and triggers, and pathology can exist in the absence of current infection, and even the reverse can be true.

I agree that antibody related immunity is different, and more likely involves some problem with clonal deletion of autoreactive lymphocytes. It may be that there can be an infectious trigger (c. jejuni and CMV are known to trigger GBS, which often shows anti-ganglioside antibodies). However, I suspect a predisposition is necessary to develop it, perhaps through HLA types or other immune genes, or some other mechanism - and there may just be a "random" effect in there as well, or it may be tied to the exposure (quantity or location of antigen, etc.)

I think some degree of hit and run with long term damage may be in play, but I don't think that's the entire explanation. I favor an explanation where, at least those with a replapsing/remitting pattern, are re-triggered due to a basic susceptibility factor, which I believe is probably at least partly genetic. However, they may never return to normal health completely, even if they partially recover, reflecting some level of damage. Young people often recover fully - which is true of many illnesses, and represents the ability of younger tissue to heal more efficiently (e.g. a young stroke victim will recover, in general, far more function than an old stroke victim - not just through compensatory mechanisms, but due to increased neural plasticity). I do think something is propagating the cycle, and hope so - as interrupting it could represent a model for treatment. The very fact that rituximab works (assuming the phase 3 trial confirms prior results) argues against static unrepaired damage being the cause.

I do completely agree with you that we should explain mechanistically why a given theory doesn't make sense rather than just dismissing it w/o explanation. I took the lazy man's way out - but fortunately you have offered a good explanation as to why the vagal nerve infection is unlikely.

A few somewhat off topic questions I've been pondering - if there is increased cell death for any reason, does that increase the likelihood of autoimmunity developing, as macrophages will clear the debris, and then express self antigens on class II MHC's? Obviously there are mechanisms to prevent this, both in the development and maturation of cells and also later on as well, but I was wondering if there is evidence one way or the other for autoimmunity being connected to partly intact intracellular antigens being presented?

Second, have you ever heard or read, or do you know personally of, any cases of either autologous or allogeneic stem cell transplantation in ME? Does it have any effect? I know it is used in some severe autoimmune diseases such as lupus and systemic sclerosis.

 

[Jonathan Edwards]

A few somewhat off topic questions I've been pondering - if there is increased cell death for any reason, does that increase the likelihood of autoimmunity developing, as macrophages will clear the debris, and then express self antigens on class II MHC's? Obviously there are mechanisms to prevent this, both in the development and maturation of cells and also later on as well, but I was wondering if there is evidence one way or the other for autoimmunity being connected to partly intact intracellular antigens being presented?

Second, have you ever heard or read, or do you know personally of, any cases of either autologous or allogeneic stem cell transplantation in ME? Does it have any effect? I know it is used in some severe autoimmune diseases such as lupus and systemic sclerosis.

Cell death with presentation of nuclear antigens has been a thread in theories of lupus for at least fifty years. It is not clear that increased cell death is ever the driving stimulus, however. The cell death occurs all the time in all of us and in the lupus like illnesses recognition of the released antigens gets screwed up.

Stem cell transplantation, as you know, is not really a treatment in its own right, but merely a way of keeping a person alive after giving them lethal chemotherapy. The treatment is cytotoxic drugs of sufficient power to wipe out the immune system as a whole. I know of no case of this being used in ME. The closest we have is the chemotherapy regimens used in the lymphoma cases Fluge and Mella documented, whose ME got better. The only autoimmune disease where this sort of approach really makes any sense is lupus, I think, because some cases have such a poor prognosis otherwise. In RA it does not better than rituximab. What I think is needed is a way of ablating the immune system without using things like alkylating agents. What is not quite clear is which cells need killing better than we can do at present. We can kill T cells with anti-CD52 and B cells with anti-CD20 but not plasma cells. There are a lot of unanswered questions.

 

[Hip]

I think we hit a fatal problem here. The sensory neurons have their receptors in the organs they innervate but have their cell bodies many centimetres away up in the ganglia. If the receptors are in the organs then we need the IL-1 to be produced in the organs, not the ganglia. Since these cells innervate most visceral organs that means pretty well anywhere in the abdomen. We are back to infection in viscera, not vagal ganglia. So the 'vagus infection' theory won't do the job it is supposed to do as far as I can see. Getting anatomy right is crucial for these things.

That does appear to be a bit of a fatal problem, at least for an infection located in the satellite glial cells.

However, looking at the structure of sensory neurons, I notice that Schwann cells run all the way down the neuron's axon, right up to where the receptors are located. So if the vagus infection was located in the Schwann cells rather than satellite glial cells, do you think that might just get the theory back on the road (at least for the moment). OK, this is not quite Michael VanElzakker' theory as stated in his paper; but it is along exactly the same principles.

I looked for some evidence that enteroviruses could infect Schwann cells, but did not find any (though I read Mycobacterium leprae can infect Schwann cells, and adenovirus has been used as a vector to deliver genes into Schwann cells).

I did read, however, here that schwannomas nearly always posses the coxsackievirus and adenovirus receptor (CAR), so I assume CAR is present in normal Schwann cells. CAR is used by coxsackievirus B for cellular entry. So this suggests that coxsackievirus B may well be able to infect Schwann cells.

And it says on this page that Schwann cells posses the decay accelerating factor (DAF) receptor, which can be an aid for certain types of coxsackievirus B to gain cellular entry via CAR.

It also mentions on the same page that Schwann cells do produce IL-1.

In addition, Schwann cells possess β1 integrins, which is what Epstein-Barr virus uses to enter epithelial cells.


Schwann cells are also I believe generally quiescent cells, rather than rapidly dividing cells. It is only in quiescent cells that substantial non-cytolytic enterovirus infections can exist. When a rapidly dividing cell is infected by enterovirus, few non-cytolytic viruses are created.

So this means that Schwann cells could in principle host a non-cytolytic enterovirus infection.

 

[halcyon]

Getting anatomy right is crucial for these things.

So you're asserting that vagal sensory neurons only express cytokine receptors on their axon terminals and none on their cell bodies?

 

[Eeyore]

@Jonathan Edwards -

I mostly agree with that. In treatment of hematologic malignancy, high dose melphalan, cyclophosphamide, or other alkylating agents (or total body irratiation) is the treatment in autologous stem cell transplantation, followed by stem cell rescue. However, in allogeneic it's a bit different - you get some graft vs tumor effect as well. Curiously, syngeneic transplantation often has prognosis superior to autologous, and it's not exactly clear why, but it appears that the new cells are better able to recognize tumor cells w/o any kind of graft on host disease developing, and w/o any immunosuppression required. It seems to imply that there is some sort of self-tolerance effect induced by tumors through an as yet not well understood mechanism that is reversed after transplantation. This effect is thought possibly to be relevant in autologous transplantation too. It suggests the possibility that the immune system can get into a dysfunctional regulatory loop that can be altered by "resetting" it by going back to stem cells. Certainly, as you point out, the primary mechanism of autologous transplantation is the ability to use what would otherwise be lethal conditioning regimens that hopefully overcome the resistance of some cells to alkylating agents. In allogeneic stem cell transplantation, the trend is now towards reduced intensity (non myeloablative) conditioning regimens and the creation of chimeric immune system states. There is still so much to be understood about the mechanisms of immune tolerance induction.

I do not believe stem cell transplantation of any kind has been employed in the treatment of ME - I was more wondering if, much like with rituximab, anyone has treated a patient who had ME and some other illness (e.g. cancer, lupus) where stem cell transplantation is used, and then noted a response to the ME. If in fact this is a disease of the immune system, and especially if it genetically mediated, replacement of the immune system with that of a different person should resolve the illness. I'm not, of course, suggesting such a course be followed w/o much greater understanding of the mechanism as it is not a procedure to be taken lightly and the consequences are potentially very severe. However, if it was incidentally found to have an effect, it might be possible to deduce something.

In lupus, is it autologous transplant, allogeneic, or both that is used? Is it curative, at least in some cases? I believe it's also used in systemic sclerosis (diffuse) sometimes - probably a similar effect to lupus / same basic thinking behind it.

 

[halcyon]

I do not believe stem cell transplantation of any kind has been employed in the treatment of ME

Dr. Cheney was sending people down to Panama to have stem cell therapy a few years ago.

 

[Eeyore]

@Hip - Schwann cells are just the peripheral nervous system's version of oligodendrocytes - their main function is maintenance of the myelin sheath around peripheral nerves. Damage to schwann cells would impair transmission of nerve signals along the axon of the nerves involved. It would therefore impair, rather than enhance, transmission of signals by the nerves. Extensive damage to the schwann cells is detectable actually - you can test peripheral blood for S100 protein. It is always elevated in schwann cell tumors (schwannomas) and should be upregulated if there is damage to schwann cells in general. It's a sensitive, although not specific, method of detecting damage to schwann cells.

Schwann cells themselves do not transmit impulses and are not neurons. Damaging them would not cause enhanced signalling of the CNS from the vagus nerve.

 

[Eeyore]

@halcyon - I think that's something different - they weren't (as far as I know) replacing people's immune systems, but rather just injecting random stem cells and hoping they would fix damaged tissue. I don't think there's any proof it works for anything yet - which is why it's being done in Panama and not the US...

I believe the approach is a rather naive one of just thinking you can throw stem cells in and they will know what to do and fix anything that is broken.

I'm more curious as to whether one can "reset" a dysfunctional regulatory loop of the immune system, and what that would mean for understanding of the underlying pathophysiology, rather than actually suggesting a potential treatment.

As Dr. Edwards mentions, if we could find a safer conditioning regimen, autologous stem cell transplantation would become much more common and much more useful. Right now, the drugs we use cause secondary cancers, lung and other organ fibrosis and pathology, and many other serious, long term side effects, and so ASCT is reserved only for diseases that would otherwise be lethal - and even then it's often a last ditch effort. It is used increasingly routinely in the aggressive management of hematologic malignancy, especially in younger, otherwise healthy patients.

 

[Hip]

Damage to schwann cells would impair transmission of nerve signals along the axon of the nerves involved.

If it is a low-level non-cytolytic enterovirus infection, perhaps there will be little damage to these Schwann cells.

Earlier in this thread I posted this study which showed how a non-cytolytic echovirus infection was kept going for 6 years in a human cell line.

 

[Marco]

@Hip Schwann cells themselves do not transmit impulses and are not neurons. Damaging them would not cause enhanced signalling of the CNS from the vagus nerve.

I'm not a fan of the persistent infection theory, I lean towards the possibility of apparent viral onset being a symptom of the underlying problem or perhaps a 'nudge' factor but I don't think you can discount damage to the myelin shealth leading to enhanced signalling.given that many of the efferent functions of the vagal nerve are inhibitory and demyelination may result in enhanced signalling.

Some examples are in peripheral neuropathy affecting both myelinated and non-myelinated nerves where you often find either loss of sensation or allodynia/thermal hyperalgesia. Widespread pain is a frequent problem in (demyelinating) MS and genetic defects in Schwann cells in mice results in a neuropathic pain phenotype :

http://www.ncbi.nlm.nih.gov/pubmed/10839370

 

[Jonathan Edwards]

That does appear to be a bit of a fatal problem, at least for an infection located in the satellite glial cells.

However, looking at the structure of sensory neurons, I notice that Schwann cells run all the way down the neuron's axon, right up to where the receptors are located. So if the vagus infection was located in the Schwann cells rather than satellite glial cells, do you think that might just get the theory back on the road (at least for the moment). OK, this is not quite Michael VanElzakker' theory as stated in his paper; but it is along exactly the same principles.

The receptors are on the dendrites rather than the axon. The anatomy of peripheral sensory neurons is quite confusing because there is both a very long 'input cable' and 'output cable'. Both can be myelinated with Schwann cells, but we have the same problem as before. The glial cells are in contact with structural components of the neuron other than where it is designed to receive signals.

I am not 'asserting that vagal sensory neurons only express cytokine receptors on their axon terminals and none on their cell bodies?' as Halcyon suggests. (That sort of adversarial approach to discussion seems unhelpful. Why can't we discuss this in a friendly constructive way?) I have said I do not know if they do, but it would seem rather surprising if they did, since generally speaking neurons have specialised endings carrying receptors rather than having receptors all over them. As far as I can see when VanElzakker wrote his hypothesis he was a PhD student in a lab in a psychology department. I have no idea if he had any training in neuroanatomy. As Eeyore says, from the point of view of someone with forty years of experience of tissue pathology it all looks pretty implausible. Certainly there are very unusual organisms that infect specific cell types, like mycobaterium leprae, but the point is that they are very unusual. And the effect in leprosy is anaesthesia of hands and feet, NOT sickness behaviour. VanElzakker wants a mechanism that will work for any old organism. That just does not add up to me.