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

[Jonathan Edwards]

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.

As far as I know only autologous rescue has been used in lupus. There are 5yr+ remissions but you can get that with rituximab and it is hard to have a clear cut definition of 'cure' in many cases of lupus.

Resetting of an immune loop was of course the reason for us starting to use rituximab in RA and lupus. It seems to work in some ITP cases but for RA the loop never seems to be cleared completely (as yet). I can see that an allogeneic graft might have some extra tumouricidal activity although I am a bit sceptical about some of these claims. As I understand it very few tumours have neoantigens. Most are malignant because they have corrupted gene promoters due to translocations as far as I can see, I guess it is possible that NK killing mechanisms might be more effective with minor MHC mismatches though. But none of that would seem to be much use in the ME context I think.

 

[cigana]

Can you tell the answer to this question based on whether or not a person's symptoms continue to be the same?

For example, Lyme produces characteristic symptoms such as migrating joint pain. If someone is known to have come down with Lyme, but 5 years later they still have the same symptoms as the initial infection, wouldn't that be an argument that it was the infection that was still causing the problem?

I don't know if it is possible for an autoimmune cause of MESEID to continue just by chance to produce exactly the same symptoms as the initial infection.

 

[Jonathan Edwards]

Can you tell the answer to this question based on whether or not a person's symptoms continue to be the same?

For example, Lyme produces characteristic symptoms such as migrating joint pain. If someone is known to have come down with Lyme, but 5 years later they still have the same symptoms as the initial infection, wouldn't that be an argument that it was the infection that was still causing the problem?

I don't know if it is possible for an autoimmune cause of MESEID to continue just by chance to produce exactly the same symptoms as the initial infection.

There is very little evidence that true autoimmunity is triggered by infection. The diseases that we know are triggered by infection and go on relapsing and remitting over years are the spondarthropathy associated syndromes - reactive arthritis, inflammatory bowel problems and psoriasis. What seems to happen with these is that an initial infection in a particular T cell homing zone jiggers up the T cells that home to that zone, with some spill over into, most typically, joints (actually ligamentous entheses) and nailbeds. So the clearest example would be infection acquired via the urethra leading to mucosal T cell activation and chronic urethritis. Dysentery may also lead to an illness with chronic low grade bowel inflammation as part of a spondarthritis, although it is generally true that the long term symptoms are not restricted to the site of entry of the organism. Nevertheless, since the T cell reaction occurs both acutely (when it is often the presenting problem, maybe 3 weeks after actual infection) and chronically and is much the same the answer to your question is yes, there are diseases where the chronic reaction looks just like the acute illness.

 

[Eeyore]

@Jonathan Edwards

First, I second your call to always keep discussions friendly! We are all here for the truth (or should be) and hopefully the diverse backgrounds and knowledge brought by people here will further that end. We're all on the same team.

I can see that an allogeneic graft might have some extra tumouricidal activity although I am a bit sceptical about some of these claims. As I understand it very few tumours have neoantigens. Most are malignant because they have corrupted gene promoters due to translocations as far as I can see, I guess it is possible that NK killing mechanisms might be more effective with minor MHC mismatches though.

This is a bit off topic, but there is clear evidence that allogeneic can offer cures to otherwise incurable cancers (e.g. multiple myeloma - which is never cured any other way). I can send you some papers / links if necessary. I don't think that it has to do with neoantigens and agree with you that tumors don't generally express neoantigens to the best of my knowledge. Certainly the obvious mechanism, which is probably relevant, is enhanced NK cell killing through partial HLA mismatch. What's curious though is that you get increased effect from syngeneic transplants too (for the non-docs out there, that means stem cells from identical twins, so there are no antigen mismatches). We do know that tumors have methods of immune evasion. The secretion of certain cytokines (probably TGF-beta) seems to promote immune tolerance through enhanced expression of foxp3. Curiously, we do now know that cd8 cells do play an important role in tumor control - which I recognize is not consistent with my previous statement of tumors lacking neoantigens, and I'm not exactly sure why this is the case. It may be known and I just don't know it - I don't follow the research actively enough. The role of tumor associated macrophages modifying the microenvironment to be more tumor-friendly may be part of the immune dysregulation that can be reset - but I don't know that with any certainty. Tumor associated macrophages seem to secrete a lot of TGB-beta and promote immune tolerance through induction of foxp3 inducible tregs (sorry - I know you hate cd4 subsets!)

Barring genetic regulatory defect, allo is unlikely to be useful in ME. Auto is the more interesting question for ME that is not of genetic cause (and we don't know how much is in each) - but if allo has been done for other reasons and ME disappears that would suggest potentially a genetic defect in ME patients. If auto works, that would suggest that there is no genetic defect, other than perhaps a predisposition, and that a "reset" would fix a self-perpetuating regulatory dysfunction. The parallel is to rituximab, where no one would have treated ME with it since we lack sufficient understanding of etiology, but it was used in patients with both lymphoma and ME, and worked on both. That both gives us information about potential ME treatments as well as information of the pathophysiology.

While much could be deduced if we knew of a number of cases, our lack of data on the subject seems to make it impossible to really glean any useful information. It's something to watch out for though, and if we hear of any examples, or anyone knows of any, that would be a good thing to know.

The long term recurrence of lupus suggests that some minimal residual disease remains post transplant - similar to what is observed in many malignancies.

I know it is not done generally - but I wonder how spondyloarthropathies respond to ASCT. My guess is that they are not cured - the defect seems to be mostly genetic and not antibody-mediated in these cases. I know there are cases of spondyloarthropathies co-existing with myeloid malignancies (probably due to increased inflammation and stimulation of the immune system and cell division) - the rates aren't too much higher though. I think I have read examples in the literature of AS with MM or MDS - then again, the increased occurrence could be a side effect of drugs used to manage the disease.

 

[Eeyore]

@Marco

I do think there is decent evidence to believe that there may be some degree of peripheral demyelination in ME. There definitely seem to be a lot of neurological symptoms.

One symptom I've experienced which can be evidence of axonal degeneration is that I've lost the hair on my lower legs and feet (symmetric). I also have a burning sensation (have had it for years) off and on (but on for months, off for months) occurring at night especially. My feet no longer sweat at night - they are hot and bone dry. My earliest presenting symptoms were mostly neurological: loss of sensation in my hands, especially in the 4th and 5th digits, the development of an intention tremor in both hands, some problems with propioception (I bump into doorways when walking around my house at night) although romberg is negative, etc. These look neurological - and in fact I was initially diagnosed by a neuro as guillain-barre, but I had no weakness at all, and GBS w/o any motor involvement is at best very rare if it exists at all. I developed autonomic dysfunction at this time.

I don't think it was due to infection of schwann cells. I was not tested at the time for any kind of anti-ganglioside antibodies - actually, I never have been - although I plan to do that soon. I suspect there was some degree of damage at the peripheral nerves, but I believe it was immune mediated rather than long-term infectious. The problem seems to have been my body's ability to successfully resolve the inflammatory response after the threat was removed. I don't know if there is ADCC in play here, but if so, I have not yet found the antibodies.

 

[Eeyore]

@cigana - Acute infection in ME generally does not look like the longer term syndrome. Mine certainly did not. My acute illness was unusually severe - the worst I'd ever had probably - but it resolved like a normal virus over a normal time frame - perhaps a few days longer than normal. The fever broke, the cough abated, muscle pains disappeared, etc. There was then a bit of a lag time - only a few weeks - before I started to notice milder and distinctive symptoms - and they were more neurological (which was not present with the initial infection). I also had a low grade fever, dysautonomia, and lots of floaters in my eyes (that's always been a symptom that stumped docs - so they tend to dismiss it rather than even try to explain it).

I don't think acute ME looks like the ME that occurs over the next several years, and even that looks a bit different from the ME you see in patients who have been sick for decades. Long term ME patients tend to be more or less static unless something triggers them (like exercise) and are more comfortable in general than shorter term patients, but they are extremely limited in what they can do and are sort of "living dead."

 

[Sidereal]

My earliest presenting symptoms were mostly neurological: loss of sensation in my hands, especially in the 4th and 5th digits, the development of an intention tremor in both hands, some problems with propioception (I bump into doorways when walking around my house at night) although romberg is negative, etc. These look neurological - and in fact I was initially diagnosed by a neuro as guillain-barre, but I had no weakness at all, and GBS w/o any motor involvement is at best very rare if it exists at all. I developed autonomic dysfunction at this time.

Almost identical situation here, except my Romberg was positive back when I was really sick. The neurologist who diagnosed POTS had done her PhD on it and said she felt it was autoimmune and in some ways similar to Guillain-Barré. Of course she also thought exercise was the correct treatment. People's seemingly endless capacity for cognitive dissonance never fails to amaze me.

 

[duncan]

Eeyore, I know what acute encephalomyelitis is, and that it can be caused by several discrete pathogens. I am not clear about what acute ME is.

 

[Marco]

@Marco

I do think there is decent evidence to believe that there may be some degree of peripheral demyelination in ME. There definitely seem to be a lot of neurological symptoms.

One symptom I've experienced which can be evidence of axonal degeneration is that I've lost the hair on my lower legs and feet (symmetric). I also have a burning sensation (have had it for years) off and on (but on for months, off for months) occurring at night especially. My feet no longer sweat at night - they are hot and bone dry. My earliest presenting symptoms were mostly neurological: loss of sensation in my hands, especially in the 4th and 5th digits, the development of an intention tremor in both hands, some problems with propioception (I bump into doorways when walking around my house at night) although romberg is negative, etc. These look neurological - and in fact I was initially diagnosed by a neuro as guillain-barre, but I had no weakness at all, and GBS w/o any motor involvement is at best very rare if it exists at all. I developed autonomic dysfunction at this time.

I don't think it was due to infection of schwann cells. I was not tested at the time for any kind of anti-ganglioside antibodies - actually, I never have been - although I plan to do that soon. I suspect there was some degree of damage at the peripheral nerves, but I believe it was immune mediated rather than long-term infectious. The problem seems to have been my body's ability to successfully resolve the inflammatory response after the threat was removed. I don't know if there is ADCC in play here, but if so, I have not yet found the antibodies.

I wasn't suggesting that demyelination is involved just making the narrow point in the context of the vagal hypothesis that demyelination doesn't just lead to loss of sensation. I can't recall the study right now but an impairment of nerve transmission velocity was pretty much ruled out many years ago.

There does appear to be considerable evidence though of autonomic dysfunction and a lot of anecdotal evidence suggesting neuropathy whether due to demyelination or another mechanism.

I have similar symptoms (occasional allodynia, loss of hair on both calves, multiple potentially autonomic symptoms plus higher temperatures rapidly make all symptoms much worse as happens in MS where elevated temperature further reduces nerve transmission velocity.

Where our symptoms appear to differ from MS and therefore demyelination as a likely culprit is in the pattern of symptoms. As I understand it demyelinating lesions strike pretty randomly 'short circuiting' specific nerve fibres but different ones every time. So you may have temporary blindness in one eye in one attack and partial limb paralysis in another. Our symptom pattern seems to be more consistent where symptoms wax and wane but largely the same symptoms. Anecdotally when I overdo things I develop a right leg limp (never injured to my knowledge) which is a reliable indicator that a major crash will soon follow (useless as an early warning though as it's already too late). This pattern repeats every time and never the other leg or another limb. What mechanism might explain this pattern I've no idea.

I still feel that the major problem involves disruption of central signal processing but there may be something else going on that causes structural or functional nerve impairment.

 

[Hip]

The receptors are on the dendrites rather than the axon.

OK. I was a bit confused by this.

I have found the correct diagram for a sensory neuron — see the image below. In the image, the long dendrite on the right conveys the input signal (from receptors located in the skin in this case) to the neuron cell body, and the cell body then relays and outputs the signal along the axon shown on the left of the diagram.

A Sensory Neuron, Showing the Long Dendrite and the Receptors at its End.
The violet dots on the myelin sheath are the Schwann cells (which make myelin)

​

Jonathan Edwards points out that in sensory neurons, the dendrites are long: several centimeters in length.

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 was proposing that enterovirus may be infecting the Schwann cells (rather than the satellite glial cells). Because the Schwann cells at the far right of the dendrite in the diagram are in fairly close proximity to the IL-1β receptors situated at the end of the dendrite, a chronically infected Schwann cell, constantly secreting IL-1β, could easily be activating these IL-1β receptors, leading to chronic sickness behavior.

This proposal may overcome the problem you identified earlier with the vagus satellite glial cell infection theory, which was the problem of lack of proximity: satellite glial cells are located next to the sensory neuron cell body, which is several centimeters away from the IL-1β receptors; and secreted IL-1β only has a short range.

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.

I understand that Michael VanElzakker had a good friend who got hit with ME/CFS, and this is why he turned his attention to ME/CFS, to try to figured out how this disease arises. But he was sort of moonlighting in this area, because I believe his normal field is PTSD research. PTSD is what he is working on now, and as far as I am aware, he has not got much time for pushing his vagus nerve infection theory of ME/CFS forward.

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.

Could it be that in the case of Mycobaterium leprae-infected Schwann cells, the disruption is so severe that nerve signal transmission function ceases, and this is why you get the loss of feeling in your hands and feet in leprosy, and also why sickness behavior does not get triggered in leprosy, because the nerve is too damaged to transmit any sickness behavior signals to the brain?

Whereas in a low-level non-cytolytic enteroviral infection, the Schwann cells may continue to function normally, but if the chronic infection induces the secretion of inflammatory cytokines including IL-1β, you may get chronic sickness behavior arising.

It says here that Mycobaterium leprae infection actually reprograms Schwann cells to revert to stem cell-like cells, which obviously is a very major change in the function of these Schwann cells. So that's presumably why Mycobaterium leprae is so disrupting to these cells and nerve function.


I just discovered that cytomegalovirus is known to infect Schwann cells (see this page). And Theiler's murine encephalomyelitis virus, from the same picornavirus family as enterovirus, is also known to infect Schwann cells.

My earliest presenting symptoms were mostly neurological: loss of sensation in my hands, especially in the 4th and 5th digits, the development of an intention tremor in both hands, some problems with propioception (I bump into doorways when walking around my house at night) although romberg is negative, etc. These look neurological - and in fact I was initially diagnosed by a neuro as guillain-barre, but I had no weakness at all, and GBS w/o any motor involvement is at best very rare if it exists at all. I developed autonomic dysfunction at this time.

I definitely had a mild loss of sensation in the skin throughout my body soon after first contracting my virus, a symptom which has persisted.

 

[Eeyore]

@Hip - That is a very odd diagram - where did you get it? It's somewhat confusingly labeled and bordering on incorrect - the line that points to the neuron and says dendrite is pointing at the axon. In this case, it's the peripheral axon - the cell body (containing the nucleus) is often central, and there are both central and peripheral axons, going in both directions from the cell body. The dendrite is only the branched part at the end. The myelin sheath does not surround the dendrite - only the axon(s).

I was proposing that enterovirus may be infecting the Schwann cells (rather than the glial cells).

Schwann cells are a type of glial cell. Glial cells are a broad category of non-neuronal cells of the nervous system that are involved in various functions including myelination. Schwann cells are present only in the peripheral nervous system, but have counterparts with similar roles in the CNS (oligodendrocytes).

I have a hard time believing that any schwann cell infection significant enough to induce substantial il-1 production would not impair nerve conduction. That does not seem plausible to me. A low level non-lytic infection might account for persistence, but non-lytic low level infections generally do not cause symptoms. These infections must reactivate to cause illness and significant immune response - the whole point of a non-lytic infection would be stealth and persistence, so if it were triggering an immune response, the immune system would be eliminating the infection and the cells that contained virus. It just doesn't hold together.

The levels of il-1b sufficient to cause systemic illness response would be more than sufficient to trigger a major immune response against the cells producing them. You can't have it both ways - you're essentially arguing for a level of infection sufficient to cause a major systemic illness with debilitating symptoms, but not enough to trigger an immune response. Furthermore, if the infection of the schwann cells extended further up the axon (i.e. not just a few cells near the dendrite) - which seems likely if any virus were being produced - you'd have major problems with nerve signal transduction.

Lastly, IL-1 production is far from unique - and it can be extremely high in some illnesses, and yet not induce an ME-like syndrome.

 

[Jonathan Edwards]

I agree with your last post @Eeyore, except that I think the diagram is probably OK. The terminology for neuronal components actually gets a bit muddled if you go into it in fine detail. There is an argument for saying that axons are the efferent cables and dendrites the afferent ones. In pyramidal cells there can be a signifcant 'stalk' to the dendritic tree, which is still dendrite. I don't think the presence of myelin changes the nomenclature, but one certainly hears of people talking about peripheral sensory nerve fibres as 'axons'. One thing I have learnt in biomedical research is that the majority of people working in a field tend to get at least a significant amount of their own terminology wrong!! Or maybe nobody quite sorted out how the terminology worked in the first place. I guess axon may be a historical structural term that predates neurophysiology - a bit like 'histiocyte'.

 

[Eeyore]

@Jonathan Edwards

True - I suppose we tend to think of it in terms of a more classic neuron with the nerve body on one end, followed by a long axon, and then a dendrite. I'm not sure exactly what "correct" is either. I suppose it makes some sense to label it in terms of efferent/afferent, although if you do that, then you have myelin on the long, axon-like parts of the dendrite as well as the "axon" - so it's mostly a semantics question. It doesn't really change the anatomy.

I don't think the picture itself looks inaccurate, and was taking issue with the labeling of what dendrite and axon are, but it's reasonable to use that kind of nomenclature too, and I don't think it changes the argument.

 

[halcyon]

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.

I wasn't being adversarial, I'm confused why you think that. I just asked an honest question. I spent quite some time reading trying to answer the question myself but wasn't able to, so I was making sure I was understanding exactly what you were saying, ready to defer to your medical knowledge and training. The answer to that question would be central to whether or not that part of VanElzakker's theory would work. He states:

While latency tends to occur within nerve tissue, upon reactivation,
the viral infection spreads to the extracellular space. There,
satellite glial cells envelop the viral particles [15]. These satellite
glial cells proliferate and activate, releasing neuroexcitatory mediators
such as immune proteins called proinflammatory cytokines,
and other substances which are described below [23,24]. The release
of proinflammatory cytokines is a general response by glia
and other immune cells like interleukin-producing cells (white
blood cells) to encountering any virus or bacteria anywhere in
the body. These locally-released cytokines are detected by the
nearest sensory vagus nerve chemoreceptors, causing an afferent
signal to the brain. The brain then initiates fatigue and several
other symptoms that overlap with CFS (see Table 1). The premise
of the VNIH of CFS is that when a neurotropic virus or any other
pathogen infects the vagus nerve itself, cytokines are released directly
onto sensitive vagus nerve receptors and this normal immune
response becomes pathologically intense.

And you're saying that this detection can't occur because the chemoreceptors don't exist in the same space that the cytokine release is occurring, so this part of his theory is in the trashcan. I'm curious what you think about the other part of his theory where paragangia might be infected. This is non-neural tissue, according to what I read, and VanElzakker claims that this tissue is "dense with proinflammatory cytokine chemoreceptors".

 

[Jonathan Edwards]

I wasn't being adversarial, I'm confused why you think that. I just asked an honest question. I spent quite some time reading trying to answer the question myself but wasn't able to, so I was making sure I was understanding exactly what you were saying, ready to defer to your medical knowledge and training. The answer to that question would be central to whether or not that part of VanElzakker's theory would work. He states:


And you're saying that this detection can't occur because the chemoreceptors don't exist in the same space that the cytokine release is occurring, so this part of his theory is in the trashcan. I'm curious what you think about the other part of his theory where paragangia might be infected. This is non-neural tissue, according to what I read, and VanElzakker claims that this tissue is "dense with proinflammatory cytokine chemoreceptors".

I am not sure what paraganglia would be if not neural. I do not know the term.

 

[halcyon]

I am not sure what paraganglia would be if not neural. I do not know the term.

Non-neuronal, sorry.

 

[leokitten]

It's was mentioned in passing in one post in this thread, I have been asking myself the same question:

Are there any autoimmune diseases where patients also tend to have chronic issues with intracellular pathogens?

If such exist then this to me is more proof that this is not necessarily an infectious disease?

 

[Jonathan Edwards]

Non-neuronal, sorry.

OK, I looked it up. They are what I know as glomus cells - in carotid body etc. That would be a different theory I guess. Not a vagus infection but a glomus cell infection. I am not sure that links us to sickness behaviour though. It does make a little bit more sense than the other suggestions but we are still left with the issues about why lots of infections should all zoom in on glomus cells in a way we have never documented before with no structural pathology found.

 

[halcyon]

OK, I looked it up. They are what I know as glomus cells - in carotid body etc. That would be a different theory I guess. Not a vagus infection but a glomus cell infection. I am not sure that links us to sickness behaviour though. It does make a little bit more sense than the other suggestions but we are still left with the issues about why lots of infections should all zoom in on glomus cells in a way we have never documented before with no structural pathology found.

It seems like there are a lot of different viruses that have been documented with tropism for nervous tissue, including several of the ones implicated in ME, so it seems relevant to me. Do herpes nerve infections cause known structural pathology when they reactivate? Again, this is an honest question, I'm not being adversarial.

ETA: VanElzakker claims there are ganglia and paraganglia along all of the branches of the vagus, so it seems like the same theory as best I can tell, but I'm having a lot of trouble understanding the anatomy.

 

[Hip]

Schwann cells are a type of glial cell.

OK, thanks, I did not realize this; I have edited my above post to make things clearer.

I have a hard time believing that any schwann cell infection significant enough to induce substantial il-1 production would not impair nerve conduction. That does not seem plausible to me.

I have not been able to find any info regarding how much normal functionality of a cell remains once it hosts a chronic non-cytolytic enterovirus infection. Though might the fact that these infections have been observed to last many years indicate that the cell must be functioning reasonably well?

A low level non-lytic infection might account for persistence, but non-lytic low level infections generally do not cause symptoms. These infections must reactivate to cause illness and significant immune response - the whole point of a non-lytic infection would be stealth and persistence, so if it were triggering an immune response, the immune system would be eliminating the infection and the cells that contained virus. It just doesn't hold together.

Low level non-cytolytic infections may well cause symptoms and disease, because they are associated with chronic coxsackievirus B myocarditis and dilated cardiomyopathy (and also more tenuously linked to type 1 diabetes).

In adult chronic coxsackievirus B myocarditis, infectious enteroviral particles are rarely found, so there is almost no lytic enterovirus infection in the heart muscle, only a non-cytolytic infection (but for some reason in pediatric cases, you find both lytic and non-cytolytic enterovirus infections). So if enterovirus is causing chronic CVB myocarditis in adults, it is only a non-cytolytic infection that is underpinning this disease.

There does appear to be some immune response associated with these non-cytolytic enterovirus infections, yet the infection is not eliminated: this study found TNF-α in the blood in around one third of patients with dilated cardiomyopathy.

Some researchers think chronic CVB myocarditis may provide a useful model to help understand the chronic coxsackievirus B infections found in ME/CFS.

The levels of il-1b sufficient to cause systemic illness response would be more than sufficient to trigger a major immune response against the cells producing them. You can't have it both ways - you're essentially arguing for a level of infection sufficient to cause a major systemic illness with debilitating symptoms, but not enough to trigger an immune response.

I see the point you are making.

Though if we consider chronic hepatitis C infection, this induces IL-1β, and my guess that this cytokine, when detected by the vagus nerve, may be largely responsible for the sickness behavior symptoms present in hep C. Yet these cytokines do not result in the elimination of this virus.

And in this study on a human astrocyte cell line CCF-STTG1, coxsackievirus B formed a persistent infection that did not kill these cells, and caused the secretion of IL-6 and IL-8. Though the study notes that enterovirus infection of the CNS can often end in cell death, and the fact that it does not in this particular cell line must be due to the specifics of the pathogen-host interaction in these cells.

Lastly, IL-1 production is far from unique - and it can be extremely high in some illnesses, and yet not induce an ME-like syndrome.

Could you give please me some examples of these illnesses where IL-1β is extremely high. If blood levels of IL-1β are high, I would have thought that some manifestation of sickness behavior symptoms will appear in the disease.

There can be modulating factors, though, that affect just how much a cytokine like IL-1β activates sickness behavior. Nitric oxide has been shown to reduce LPS-induced sickness behavior. Note that LPS induces an inflammatory response when injected into the abdominal cavity:

When LPS or cytokines are injected into the abdominal cavity, they induce inflammation of the peritoneum. One of the major routes of visceral sensibility is represented by the afferent branches of the vagus nerves. These branches contain in their perineural sheath macrophages and dendritic cells that express membrane TLRs and produce IL-1β in response to an intraperitoneal injection of LPS. Ref: here.

IL-10 and IGF-I also reduce sickness behavior:

IL-10 or insulin-like growth factor I (IGF-I), a growth factor that behaves like an anti-inflammatory cytokine in the brain, attenuates behavioural signs of sickness induced by centrally injected LPS. Ref: here.

So modulating factors like nitric oxide, IL-10 or IGF-1 levels may need to be considered when determining how much sickness behavior is induced by IL-1β.


One important thing to bear in mind is that there are several pathways (which are outlined in this post) that lead to activation of sickness behavior, and the vagus just represents just one of these pathways. The vagus pathways is called the neural pathway; but in addition, there are what are called the humoral pathways of sickness behavior activation.

The way that the vagus nerve neural pathway and the humoral pathways of sickness behavior converge and interact in the brain is not well understood; but it is likely that sickness behavior activation results from a joint effort of these pathways.

Intriguingly, different sickness behavior pathways will tend to activate different features of sickness behavior.

The vagus pathway is more geared to inducing the behavioral features of sickness behavior (like fatigue, depression, anhedonia, cognitive impairment, decreased social interaction), but is less geared to inducing the fever and HPA axis activation of sickness behavior. Ref: here. This is interesting, because ME/CFS patients don't really have raised body temperature (except during PEM where a few patients experience fever), so this suggests that their sickness behavior symptoms are being primarily activated via the vagus pathway, more than any other pathway.

The fever that some ME/CFS patients experience during PEM may be due to the pyrogenic effects of IL-6. We mentioned earlier (here) that IL-6 released during exercise may be responsible for physical exertion PEM. IL-6 also potentiates the behaviorally depressing effects of IL-1β, so this may explain why many aspects of ME/CFS worsen after physical exertion, when there is a huge increase in IL-6 in the blood.



Might there be any autoimmune mechanisms that could lead to the chronic activation of the IL-1β receptors on the vagus nerve, by the way?

I think the core aspect of Michael VanElzakker's theory is the idea that ME/CFS is caused by the chronic activation of sickness behavior. So although he postulates an infection of the vagus nerve is the cause of this chronic sickness behavior, it might be good to explore whether some autoimmune processes may lead to the same sickness behavior activation.

The phenomenal similarity between sickness behavior and ME/CFS symptoms is compelling, and thus I think sickness behavior is a fruitful path to explore in trying to understand this disease.