Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease, 2024, Khalid A. Hanafy

[Jonathan Edwards]

Is it fair to say inflammatory cytokines are inflammatory agents?

If they are produced in the brain they might. But that already assumes some inflammation in the brain. Circulating cytokines almost certainly do not cause cells to cross the blood brain barrier. The cells would be quite happy sitting in the blood where the cytokines are. Cytokines do upregulate adhesion molecules but mostly on the endothelial side if they are produced outside the vessel. If cytokines upregulate adhesion molecules on white cells there is no particular reason why they should want to go into brain. Unless there is already pathology in the brain.

I have been involved in inflammation research for about 50 years and simple misconceptions like this become more and more pervasive. Most people do not have any grasp of compartmentalisation of the inflammatory response. A smell of vanilla all along the street would not make you go into a baker to buy cake. You only do that if you smell vanilla just outside the baker's door. Same for white cells. There has to be some misbehaving going on first in the tissue. Except is rare situations like meningococcal septicaemia.

 

[Jonathan Edwards]

overtraining syndrome is real.

Overtraining can produce amenorrhoea in women but I am not sure it has any relevance to anything we are interested in does it?

 

[Creekside]

That doesn't make overtraining the cause of their ME/CFS necessarily.

Not necessarily, but I believe that any activation of the immune system(s) can trigger ME. Whether the cytokines are the result of viral infection or muscle damage, IL-6 is IL-6. I also believe that glial cells activating in response to cytokines is part of the ME trigger. Once triggered, a feedback loop keeps the body in an abnormal state.

 

[Jonathan Edwards]

I also believe that glial cells activating in response to cytokines

Is there any evidence that glial cells respond to circulating cytokines?

 

[poetinsf]

Overtraining can produce amenorrhoea in women but I am not sure it has any relevance to anything we are interested in does it?

OTS produces a set of symptoms identical to MECFS in both men and women. Along with disorders like concussion fatigue, GWI, and some cases of IH/CCI.

If chasing MECFS as viral/post-viral disorder for 40 years produced nothing, another 40 years of the same thing is not likely to produce results. It's time that they seriously look at other similar disorders and look for a common mechanism.

 

[poetinsf]

Is there any evidence that glial cells respond to circulating cytokines?

One theory I'm aware of: proinflammatory cytokines -> BBB breach ->monocyte recruitment by glial cells? Or something like that. There was a Canadian paper on it. I'll post when I find it.

 

[poetinsf]

If cytokines upregulate adhesion molecules on white cells there is no particular reason why they should want to go into brain. Unless there is already pathology in the brain.

No idea on specific physiology, so I'll have to defer to researchers and experts. But Monje's study did show glial activation in hippocampus, presumably same as cancer patients suffering from chemo fog. Was it from inflammation/cytokines? Again, no idea. I'll have to wait the publication on peer-reviewed journal and see how that pans out.

A smell of vanilla all along the street would not make you go into a baker to buy cake. You only do that if you smell vanilla just outside the baker's door.

Where would IL-6 spiking up 100 times the day after exercise fit in this analogy?

 

[Jonathan Edwards]

Where would IL-6 spiking up 100 times the day after exercise fit in this analogy?

It fits perfectly. Nothing happens to your brain.

 

[Jonathan Edwards]

OTS produces a set of symptoms identical to MECFS in both men and women.

A quick look at PubMed suggests that 'overtraining syndrome' is a lot to typical BPS nonsense dreamt up by sports physicians and physios. Exactly the sort of thing S4ME was created to deflate!!

 

[poetinsf]

It fits perfectly. Nothing happens to your brain.

Hmmm, Jonathan says nothing, while Monje says something. I'll have to think about this, man.

 

[poetinsf]

A quick look at PubMed suggests that 'overtraining syndrome' is a lot to typical BPS nonsense dreamt up by sports physicians and physios.!

Right, a quick look at something let's you come to a quick conclusion. That, btw, sounds awfully similar to what people used to say about MECFS. All I can say is, I've been through it and I'm afraid your quick opinions not going to change much.

 

[Sean]

If chasing MECFS as viral/post-viral disorder for 40 years produced nothing, another 40 years of the same thing is not likely to produce results.

1. The dominant paradigm has, until recently, been the psychosomatic one.

2. In no small part due to 1, the post-infectious hypothesis has still not been adequately researched.

3. The emergence of Long-Covid seems to me a pretty good piece of evidence that this is post-infectious. Not definitive, but of considerable weight.

Right, a quick look at something let's you come to a quick conclusion. All I can say is, I've been through it and I'm afraid your quick opinions not going to change much.

He does have a 50 year research and clinical career, with some real successes, behind his opinion.

You have...?

You think we have not heard all this stuff before? You have yet to bring anything new to the table.

 

[Andy]

OTS produces a set of symptoms identical to MECFS in both men and women.

Please could provide reference or references that show this?

If chasing MECFS as viral/post-viral disorder for 40 years produced nothing, another 40 years of the same thing is not likely to produce results.

40 years of biomedical small investigations from the 80s and 90s not being followed sufficiently followed by the BPS model then taking over, ignoring that evidence, and sucking up the majority of the funding - certainly I would not characterise that as sufficient investigation into ME/CFS as a viral/post-viral disorder.

 

[Eddie]

Is there any evidence that glial cells respond to circulating cytokines?

I'm not sure if this answers the question but I did find this in a review paper titled "The semantics of microglia activation: neuroinflammation, homeostasis, and stress"
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-021-02309-6

This work shows that immune cells (often tissue-resident macrophages) in peripheral tissues initiate pro-inflammatory signaling cascades that affect other immune mediators. In particular, circulating cytokines promote IL-1β secretion from macrophages in circumventricular organs, as well as perivascular macrophages and endothelia of the neurovasculature. These pro-inflammatory signals are transmitted to and propagated by microglia in the parenchyma. [85,86,87]. These microglia responses mediate important physiological (e.g., fever) and behavioral (e.g., lethargy) components of sickness that promote survival [88]. This form of microglial activation is transient and occurs without causing overt neuropathology [41, 88,89,90,91,92]. Recent reports indicate that peripheral administration of LPS can cause transient BBB disruption and microbleeds in the brain [90, 92]. These neuro-immune interactions may contribute to the observed changes in inflammatory mediators in the brain, but further studies are needed to define these mechanisms. It is important to emphasize that peripheral infection alters microglia function indirectly, as viral (i.e., poly-IC) or bacterial components (i.e., lipopolysaccharide; LPS) do not typically reach the brain parenchyma, and that effects of LPS will vary depending on the route of administration, dose, and duration of exposure [93].

 

[Jonathan Edwards]

"The semantics of microglia activation: neuroinflammation, homeostasis, and stress"

That looks like someone's make believe story to me.
I would like to see some hard data at relevant levels of cytokine.

The problem is that so much of science writing now is invented drivel trying to sell stories to get grants in.

 

[Creekside]

Is there any evidence that glial cells respond to circulating cytokines?

I never even questioned that. I came across numerous papers claiming that glial cells activated in response to immune activation in the body, so I assumed that was standard knowledge. Other similar claims are that most of the "flu symptoms" are due to glial cells responding to cytokines from t-cells. I recall it being described as something along the lines of: "the brain is critical, so when it gets a signal of infection elsewhere in the body, the brain primes its defenses". I don't recall reading any questioning of those claims.

 

[Jonathan Edwards]

I don't recall reading any questioning of those claims.

The trouble is one doesn't find questioning of such claims because the people who actually understand immunology cannot be bothered to 'question' those who have no clue. You just click on another title and move on.

There are cells in the brain, probably hypothalamus but it is years since I studied this, that response to circulating cytokines via receptors. I assumed that they were neurons but they might be some form of glial cell. But that has nothing to do with the microglia scattered through the brain whose activation would be 'neuroinflammation'. So feeling terrible with flu is due to circulating cytokines, yes, but it has nothing to do with inflammation in the brain. The brain primes the body's defences by shutting down vigorous activity and lying down somewhere warm. It doesn't prime any immune responses inside the brain as far as I know.

 

[Creekside]

Is there any evidence that glial cells respond to circulating cytokines?

https://pubmed.ncbi.nlm.nih.gov/8963753/

"One mechanism by which blood-borne cytokines might affect the function of the central nervous system (CNS) is by crossing the blood-brain barrier (BBB) for direct interaction with CNS tissue. Saturable transport systems from blood to the CNS have been described for interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1ra), IL-6, and tumor necrosis factor-alpha (TNF-alpha). Blood-borne cytokines have been shown to cross the BBB to enter cerebrospinal fluid and interstitial fluid spaces of the brain and spinal cord. IL-2 does not cross the BBB by a saturable transport system. The blood-to-brain uptakes of IL-1 alpha, IL-beta, and IL-1ra are interrelated for most brain sites, but the posterior division of the septum shows selective uptake of blood-borne IL-1 alpha. The saturable transport systems for IL-6 and TNF-alpha are distinguishable from each other and from the IL-1 systems. The amount of blood-borne cytokines entering the brain is modest but comparable to that of other water-soluble compounds, such as morphine, known to cross the BBB in sufficient amounts to affect brain function. CNS to blood efflux of cytokines has also been shown to occur, but the mechanism of passage is unclear. Taken together, the evidence shows that passage of cytokines across the BBB occurs, providing a route by which blood-borne cytokines could potentially affect brain function."


A quick search found papers about circulating cytokines affecting BBB integrity, so if cytokines weaken that barrier, does that mean that circulating cytokines can affect glial cells?

 

[Jonathan Edwards]

A quick search found papers about circulating cytokines affecting BBB integrity, so if cytokines weaken that barrier, does that mean that circulating cytokines can affect glial cells?

It just isn't a real issue as far as I understand things.

It is a bit like saying the money can buy things so the increase in the number of superyachts is due to people being paid more than ten dollars an hour.

Everything has to be kept in perspective - at least to an order of magnitude. This is what these people trying to spin these stories have lost sight of. Fifty years ago we tried to relate things to what we could see clinically and on pathology - in proportion. Nowadays people with no idea of pathology and often not much of clinical practice dream up stories that make no sense.

Part of the problem I think is that the gross pathology we used to see in the 1970s has largely gone. It may to some extent have been replaced by the pathology seen in intensive care medicine with complications of things like heart transplantation. But I can see no useful link between the activation of hypothalamic cells in flu and neuroinflammation. In someone dying of catastrophic sepsis the blood brain barrier will be at risk. In ME I see no possibility of any cytokine storm that could have any significant effect on BBB. The PWME writing posts here are not having delirium or half unconscious with cytokines. They seem to me to be totally on the ball.

And I think that applies to those who are very ill with ME too. Alem Matthees managed to turn the UK FOI system on the BPS people despite being seriously unwell. If your BBB is dodgy that simply isn't possible. You are lucky to know what day it is.

 

[SNT Gatchaman]

But could it be a matter of degree? A chronic low-grade situation that flys under the radar, lacking the associated features that are overt in the acute/ICU context?

It may not be cytokines crossing into brain parenchyma drawing in immune cells, it may be other things affecting BBB integrity, allowing transgression of unexpected substances such as fibrinogen. It may be immune cells accumulating and activating at the CNS borders, eg Brain borders at the central stage of neuroimmunology (2022, Nature)

Quite a few papers in the fields of neurology and psychiatry are working on a dysfunctional BBB as a fundamental mechanism. (I consider these two as largely one field, just that it's been historically divided and neurologists seem mostly happy with that status quo in order to focus on motor, sensory, seizure type symptoms and ignore the part of the brain that does thinking.)

Blood–brain barrier dysfunction in multiple sclerosis: causes, consequences, and potential effects of therapies (2024, The Lancet Neurology)

The Neurovascular Unit as a Locus of Injury in Low-Level Blast-Induced Neurotrauma (2024, International Journal of Molecular Sciences)

The link between neuroinflammation and the neurovascular unit in synucleinopathies (2023, Science Advances)

Brain microvascular endothelial cells and blood-brain barrier dysfunction in psychotic disorders (2023, Nature Molecular Psychiatry)

Blood-brain barrier dysfunction in bipolar disorder: Molecular mechanisms and clinical implications (2022, Brain, Behavior, & Immunity - Health)

Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities (2022, Stroke)

Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke (2019, American Journal of Physiology-Cell Physiology)

Blood–brain barrier leakage years after pre-eclampsia: dynamic contrast-enhanced 7-Tesla MRI study (2022, Ultrasound in Obstetrics & Gynecology)

Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics (2018, Nature Reviews Neuroscience)

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders (2018, Nature Reviews Neurology)

Pericytes of the neurovascular unit: key functions and signaling pathways (2016, Nature Neuroscience)