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.