Dual microglia effects on blood brain barrier permeability induced by systemic inflammation, 2019, Hiroaki Wake et al.

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Moderator note:
Copied from this thread:
"Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia... van Campen et al, 2020
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There is this new article but sorry if it is old study news, I'm new to posting -- thought it was apropos:
https://www.eurekalert.org/pub_releases/2020-02/nu-tso022720.php
News Release 28-Feb-2020

Two sides of a coin: Our own immune cells damage the integrity of the blood-brain barrier
Nagoya University

IMAGE: Microglia express tight junction molecule (CLDN5) to maintain BBB integrity in early phase and molecule for phagocytosis (CD68) to impair the BBB function in late phase of systemic inflammation. Microglia... view more

Credit: Hiroaki Wake

The blood-brain barrier is a layer of cells that covers the blood vessels in the brain and regulates the entry of molecules from the blood into the brain. Increases in blood-brain barrier "permeability," or the extent to which molecules leak through, are observed in several neurological and psychiatric disorders; therefore, understanding the regulation of blood-brain barrier permeability is crucial for developing better therapies for such disorders.

In a study recently published in Nature Communications, a research team led by Prof. Hiroaki Wake of Nagoya University Graduate School of Medicine shows that microglia -- the resident immune cells of the brain -- initially protect the blood-brain barrier from damage due to "systemic inflammation," a condition of chronic inflammation associated with factors like smoking, ageing, and diabetes, and leading to an increased risk of neurodegenerative disorders. However, these same microglia can change their behavior and increase the blood-brain barrier permeability, thereby damaging it.
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The article, "Dual microglia effects on blood brain barrier permeability induced by systemic inflammation," was published in the journal Nature Communications at DOI: 10.1038/s41467-019-13812-z.
https://www.nature.com/articles/s41467-019-13812-z

Abstract
Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood–brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.

 

[stuck]

Hello everyone, I'm fairly new here -- I love a lot of your posts, and your group has helped me so much since I have been ill to make sense of what I'm experiencing and that I'm not alone, that this Thing is a Thing, not just me losing my mind or making stuff up...
Trish separated the article I posted yesterday into this thread (gosh I have my own thread, it's so overwhelming!)

Anyway, the theory that make sense to me -- but I need help sorting, is -- I'm not sure how Jarred Younger's work evaluated inflammation in the brain, this article seemed to focus on what worries me about what I experience with the illness, I FEEL like there is a membrane leak - where energy and signals flow backwards from where they need to go.

Like in the morning, I say I want to get up, but the gear shifting is reversed - like heavy gravity rather than light as a feather pop out of bed.
Other symptoms make me think there is something afoul with the liquid surrounding the brain, I learned about this fluid when my ex had a brain abscess -- a rare situation -- and the infectious specialist pushed to drill a hole in his skull. I didn't know this until then but when they do that, the encasement fluid runs out, and so do all the current memories (he would have permanent amnesia of that time).

Knowing this, fast forward a couple decades and I have these symptoms where I lose my thoughts - this blasted "brain fog" but it isn't the normal fog of sleepy or confusion, it's like a disappearance of what I knew I was working on, or thinking about, or experiencing... which seems to me like we've blown a gasket.

My dad was a mechanic, I remember taking off the manifold and replacing it, without it, there was spewing oil all over the inside of the hood.

As I am desperate to get my life back, I feel this overarching need to solve this illness even though my field is definitely not medicine.

If any of you understand the work of Jarrad Younger, and how this new work, (if it's new) could apply -- could we be afflicted by a leaky brain illness?

 

[Jonathan Edwards]

could we be afflicted by a leaky brain illness

Probably not. Blood brain barrier leakage shows up on standard MRI and is not seen in ME/CFS.
It also produces characteristic clinical signs that are not features of ME/CFS.

I am afraid that an awful lot of publications on 'systemic inflammation' are based on poor understanding of very basic physiology (I spent my career working on inflammation in autoimmune disease). Mouse studies like this are very hard to interpret anyway.

I think it very likely that there are physiological problems in the brain in ME/CFS but 'neuroinflammation' is a vague buzzword that I don't think takes anybody forward.

 

[stuck]

Thanks very much, Jonathan. Still think there is something awry in the barrier. As you said: "very likely that there are physiological problems in the brain in ME/CFS".

To me it's like there is a pump valve backwards. In the article I wasn't as focused on systemic inflammation as much -- was more interested if they had specific key bits on how signaling happens and those signals can get fouled.

I hoped this study could feed into what Younger was doing with his pet scans to evaluate the signaling and integrity of the barrier(s) -- specifically why we must lie down and why the headache/stuffiness symptoms occur -- these headaches/stuffiness are not NORMAL like the headaches or stuffiness I had prior to getting ill, so they are produced by some buildup.

For my personal experience, as stressors cause the PEM there is a dramatic pressure shift in the head and my eyes feel like they will pop out.

It takes a lot of physical pressure relief (bridge of nose, back of neck, jawlines, etc) and baking soda, cold packs, elevated legs to assist in recovery. All these point to some dysfunction that is a physical valve kind of thing, or a leaky balloon or a gasket gone afoul.

Obviously I didn't spend my career with inflammation in autoimmune illnesses, so have zero idea how to diagnose or fix ME. But I have a NEED to fix me, thus the newbie desperation and my own stubbornness to dig at hypotheses that make sense in my head.

I've spent over a year lurking and so talking to anyone outside my immediate family about this is new. I am still hopeful this will be read by someone who can figure out some avenue that explains it all -- obviously it isn't an easy answer or would have been solved long ago.

 

[Tdlcraig]

Probably not. Blood brain barrier leakage shows up on standard MRI and is not seen in ME/CFS.
It also produces characteristic clinical signs that are not features of ME/CFS.

I am afraid that an awful lot of publications on 'systemic inflammation' are based on poor understanding of very basic physiology (I spent my career working on inflammation in autoimmune disease). Mouse studies like this are very hard to interpret anyway.

I think it very likely that there are physiological problems in the brain in ME/CFS but 'neuroinflammation' is a vague buzzword that I don't think takes anybody forward.

Sorry for the late reply. I'd suggest looking in to Chroid Plexus leakage, which is now being investigated with long covid. The inflammation wouldn't show up on an MRI, if it did, it would be a more serious brain condition. It's very mild inflammation caused by B and T cells leaking in to the thalamus, ganglia area. A potential test you could do is having a lumber punch to check WBC, cytokines and proteins. Obviously CFS is a broad term, I'm referring to ME. So fatigue/brain fog alone isn't enough. You'd need to have immune dysregulation symptoms or other auto immune conditions. Further to this, many patients have made dramatic short term recoveries off prednisone, which is treatment for brain inflammation. You could make the assumption this doesn't work long term because it's not stopping the leakage.

 

[Trish]

Hi @Tdlcraig. That sounds interesting. Can you point us in the direction of some research or other published information about Choroid plexus leakage and the investigations for this in long covid - is there a research study happening?

 

[Jonathan Edwards]

Sorry for the late reply. I'd suggest looking in to Chroid Plexus leakage, which is now being investigated with long covid. The inflammation wouldn't show up on an MRI, if it did, it would be a more serious brain condition. It's very mild inflammation caused by B and T cells leaking in to the thalamus, ganglia area. A potential test you could do is having a lumber punch to check WBC, cytokines and proteins. Obviously CFS is a broad term, I'm referring to ME. So fatigue/brain fog alone isn't enough. You'd need to have immune dysregulation symptoms or other auto immune conditions. Further to this, many patients have made dramatic short term recoveries off prednisone, which is treatment for brain inflammation. You could make the assumption this doesn't work long term because it's not stopping the leakage.

The choroid plexus is within the ventricles. Leakage from choroid plexus would mean an increase in fluid, perhaps with cells, going into the intracerebral CSF and out through fourth ventricle into extra cerebral CSF. That would not be inflammation in a meaningful sense (unless there was actual infiltration of choroid tissue which should show on MRI) and no cells would go into basal ganglia or thalamus. To get cells into basal ganglia, surely they would need to diapedese through the grey matter vessels locally. Any significant movement of B or T cells into grey matter would be expected to produce local neurological lesions, which are not seen in ME. I don't see any plausible evidence for this sort of model for ME to be honest.

I would also be interested on what there is on this in Covid - that might well involve choroid changes, although I think the same general principles apply.

 

[FMMM1]

Sorry for the late reply. I'd suggest looking in to Chroid Plexus leakage, which is now being investigated with long covid. The inflammation wouldn't show up on an MRI, if it did, it would be a more serious brain condition. It's very mild inflammation caused by B and T cells leaking in to the thalamus, ganglia area. A potential test you could do is having a lumber punch to check WBC, cytokines and proteins. Obviously CFS is a broad term, I'm referring to ME. So fatigue/brain fog alone isn't enough. You'd need to have immune dysregulation symptoms or other auto immune conditions. Further to this, many patients have made dramatic short term recoveries off prednisone, which is treatment for brain inflammation. You could make the assumption this doesn't work long term because it's not stopping the leakage.

I think "prednisone" is the go to drug for MS etc.; however, it can lead to bone thinning (loss of calcium).

I wonder if "CSF leak" is something that could give the symptoms found in ME; however, it is very difficult to detect a CSF leak (correct?). So "CSF leak" may be a great conspiracy theory - difficult to disprove! I think Cort did an article on "CSF leak in ME" a few years back.

 

[Jonathan Edwards]

I wonder if "CSF leak" is something that could give the symptoms found in ME; however, it is very difficult to detect a CSF leak (correct?). So "CSF leak" may be a great conspiracy theory - difficult to disprove! I think Cort did an article on "CSF leak in ME" a few years back.

Note that CSF leak means CSF getting out of the subarachnoid space. Choroid leak would be an increase of CSF getting in to the space - something unrelated.