Brain Cells Making us Sick? The microglia connection in ME/CFS & Fibromyalgia


(click title to view blog properly)
Simon McGrath looks at theories that microglia, the brain's immune cells, could trigger and perpetuate the symptoms of ME/CFS and fibromyalgia.

'Sickness Behaviour': the immune system releases cytokines in response to infection, which activates microglia in the brain and creates symptoms including fatigue, pain and cognitive problems.

Your dog can’t tell you when she's feeling sick, but even so, you know. She moves slowly, she doesn’t eat, she sleeps a lot, she curls up in a corner by herself. “Sickness behavior" is shared by all mammals, and in humans it’s been shown to include fatigue, cognitive problems, body aches and pains and disturbed sleep. These symptoms might sound very familiar to patients with ME/CFS and fibromyalgia, and several researchers recently have suggested that many core symptoms of these illnesses are the result of sickness behaviour biology gone wrong.

Understanding sickness behaviour first required uncovering some basics of the immune system. In the 1980s, scientists discovered a new molecule called Interleukin 1 that immune cells produce when they fight an infection. It was the first discovered example of a large class of messenger molecules called cytokines that help control the immune response.

Interleukin 1 was tried as a cancer treatment by boosting the immune system (with limited success), and patients reported that they experienced fatigue, pain and other problems that characterise sickness behaviour. This led scientists to the realization that sickness behaviour is driven by some cytokines.

Furthermore, they later discovered that these cytokines act on microglia, the brain’s immune cells, and it is ultimately the microglia that switch sickness response on or off. And the microglia may be where the problem with ME/CFS lies.

Today’s blog post will describe the chain of events that lead to sickness response. Part two will describe how microglia could get stuck, triggering long-term sickness response and may perhaps be behind ME/CFS.

Sickness 'behaviour' - or response
The term “sickness behaviour” might sound like we’re dealing with psychological issues, but it’s actually describing an involuntary, physiological response to being sick.

The term was initially used to describe the behaviour of animals who rest and withdraw when sick, but it’s now used for the symptoms and underlying processes that drive that behaviour. In fact, Dr. Jarred Younger, a Stanford researcher who believes sickness behaviour may play a key role in the biology of Fibromyalgia and ME/CFS (see part two of the blog), would like to see the term sickness “behaviour” replaced by sickness “response.”

The similarities between sickness response and ME/CFS symptoms are imperfect but striking:

Sickness Response | .ME/CFS (Fukuda)

Fatigue | Fatigue

Cognitive problems | Cognitive problems

Disturbed sleep | Disturbed sleep

Headaches | Headaches


Body aches & pains | Muscle & joint pain

Depressed mood | Post-exertional malaise

Pain hypersensitivity | Pain hypersensitivity (FM)

Social isolation | Sore throats

Anhedonia | tender cervical nodes

Post-exertional malaise is notably missing from sickness response, but the big overlap suggests that sickness response could be playing a substantial role in ME/CFS.

The chain reaction that creates sickness response
From an evolutionary perspective, sickness response in response to infection is very useful. It forces us to be still, reserving energy for healing, and causes us to retreat where we’ll be safe from predators.

But it’s meant to be a short-term response of a week or so and if it lasts and lasts, that’s not so useful. If that happens, some part of the chain reaction that leads to sickness response has broken.

Infection almost always occurs in the body rather than the brain itself, because the brain protects itself from infection with a highly selective barrier that bacteria and viruses have a very hard time penetrating.

The blood-brain barrier also keeps out immune cells, though, so when the immune system detects infection in the body, it has only a couple of ways of letting the brain know about it. It releases cytokines that regulate immune response. These are able to pass through some parts of the blood brain barrier, but they can also communicate with the brain by stimulating the vagus nerve in the body, which in turn secretes cytokines into the brain.

The next step in the chain is that the cytokines activate the brain’s own immune cells, the microglia.

Microglia: powerhouse of immune response in the brain


Microglia scan a healthy mouse retina.
Image by Wai Wong/National Eye Institute
Because immune cells like B-cells, T-cells and Natural Killer cells can’t cross the blood-brain barrier, the brain largely relies on its own small, highly adaptable cells called microglia for immune protection. In their 'resting' state, microglia have cell bodies with many long fingers extending from a central cell body (see photo).
These cells are actually on patrol, extending and retracting fingers to 'scan' their territory by touch, lingering at nerve synapses in particular to check their health.

Such patrolling microglia scan their territories every few hours, their bodies remaining in the same place while their scanning fingers are almost a blur by the standards of the brain.

But that’s the quiet life for microglia. Once cytokines or other factors alert microglia to injury or infection, they shift into their activated form, zipping through the brain to where they are needed (see 20" video).


Once there, they spew out chemicals that set up the brain and body for recovery and, most importantly for ME/CFS (and fibromyalgia), that trigger sickness response: for example, neurones involved in perceiving fatigue fire more often.

So now we have the full chain of reactions that leads to sickness response:

Infection -> cytokines elevated in blood -> cytokines elevated in brain -> microglia activated -> microglia produce more cytokines -> sickness response

Simple! Thanks for your patience in sticking with all the biology - here's a summary in picture form:
How infection leads to sickness response, via cytokines and microglia.
(Image courtesy of Southampton University, labelling tweaked slightly for clarity.)


Part one of this blog has looked at how the body responds to infection with sickness response, via a chain of events including cytokines and microglia.

Part two will describe new theories about how the microglia could misfire, triggering sickness response for far longer than is intended and even leading to ME/CFS and fibromyalgia. Coming soon!

Simon McGrath tweets on ME/CFS research:



Phoenix Rising is a registered 501 c.(3) non profit. We support ME/CFS and NEID patients through rigorous reporting, reliable information, effective advocacy and the provision of online services which empower patients and help them to cope with their isolation.

There are many ways you can help Phoenix Rising to continue its work. If you feel able to offer your time and talent, we could really use some more authors, proof-readers, fundraisers, technicians etc. We’d also love to expand our Board of Directors. So, if you think you can help in any way then please contact Mark through the Forums.

And don’t forget: you can always support our efforts at no cost to yourself as you shop online! To find out more, visit Phoenix Rising’s Donate page by clicking the button below.

Read the Original Blog Post
 
Last edited:

Comments

I thought it may be useful to see a list of the microglia modulators that Dr Younger shared at the Stanford conference (http://forums.phoenixrising.me/inde...-me-21-march-day-two.29098/page-3#post-443598)
I think that LDN and minocyline (and possibly rifampin) are probably the most commonly used prescription drugs for reducing microglial activation. Reishi may be studied soon in Gulf War Illness.

Note: Dr Younger compiled this list by looking at research on potential microglia modulators; only a few have been studied in humans for their ability to modulate microglia.

Drugs:
  • Naltrexone
  • Dextro-naltrexone
  • Minocycline
  • Ibudilast
  • Dextromethorphan
  • Rifampin
  • Propentofylline
  • Ceftriaxone
  • Glatiramer acetate
  • 3-hydroxymorphinan
  • Dilapimod
  • ATL313
  • BAY 60-6583
  • FP-1 Resolvin D1
  • Resolvin E1
Supplements:
  • Luteolin
  • Panax ginseng
  • Turmeric
  • Resveratrol
  • Gastrodia elata
  • Obovatol
  • Inflexin
  • Piper kadsura
  • Ganoderma lucidum (Reishi)
  • Berberine
  • Epimedium brevicornum
  • Isodon japonicas
  • Stephania tetrandra
  • Stinging nettle
  • Fisetin
  • Pycnogenol
  • Boswellia
  • Kratom
 
Last edited:
I thought it may be useful to see a list of the microglial inhibitors that Dr Younger shared at the Stanford conference (http://forums.phoenixrising.me/inde...-me-21-march-day-two.29098/page-3#post-443598)
LDN and minocyline (and possibly rifampin) are probably the most commonly used prescription drugs for reducing microglial activation. Reishi may be studied soon in Gulf War Illness.

Note: Dr Younger compiled this list by looking at research on potential microglial inhibitors; only a few have been studied in humans for their ability to modulate microglia.

Drugs:
  • Naltrexone
  • Dextro-naltrexone
  • Minocycline
  • Ibudilast
  • Dextromethorphan
  • Rifampin
  • Propentofylline
  • Ceftriaxone
  • Glatiramer acetate
  • 3-hydroxymorphinan
  • Dilapimod
  • ATL313
  • BAY 60-6583
  • FP-1 Resolvin D1
  • Resolvin E1
Supplements:
  • Luteolin
  • Panax ginseng
  • Turmeric
  • Resveratrol
  • Gastrodia elata
  • Obovatol
  • Inflexin
  • Piper kadsura
  • Ganoderma lucidum (Reishi)
  • Berberine
  • Epimedium brevicornum
  • Isodon japonicas
  • Stephania tetrandra
  • Stinging nettle
  • Fisetin
  • Pycnogenol
  • Boswellia
  • Kratom
Might also consider CoQ10, beta blockers, N acetylcysteine, certain anti-virals and ... Rituximab :

http://www.turkishneurosurgery.org.tr/pdf/pdf_JTN_1230.pdf
 
There is something I don't understand. Isn't there a contradiction between the cause of our fatigue being "sickness syndrome" and the research that has shown mitochondrial dysfunction (e.g. Sarah Myhill)? I mean one says we feel fatiguebecause chemical messengers are being fired which increase the perception of fatigue, whereas the other is saying we feel fatigue because we actually cannot produce energy at a sub-cellular level.
 
There is something I don't understand. Isn't there a contradiction between the cause of our fatigue being "sickness syndrome" and the research that has shown mitochondrial dysfunction (e.g. Sarah Myhill)? I mean one says we feel fatiguebecause chemical messengers are being fired which increase the perception of fatigue, whereas the other is saying we feel fatigue because we actually cannot produce energy at a sub-cellular level.
I don't think anyone is claiming that sickness response is responsible for all ME symptoms, but might be involved in some symptoms.
 
There is something I don't understand. Isn't there a contradiction between the cause of our fatigue being "sickness syndrome" and the research that has shown mitochondrial dysfunction (e.g. Sarah Myhill)? I mean one says we feel fatiguebecause chemical messengers are being fired which increase the perception of fatigue, whereas the other is saying we feel fatigue because we actually cannot produce energy at a sub-cellular level.
What makes you think that the cytokines responsible for sickness behaviour don't induce it by acting on mitochondria? Maybe the perception of fatigue isn't just a brain thing but is actually fatigue. In any case, one doesn't necessarily exclude the other. As usual, the situation is unclear and we need more research.
 
What makes you think that the cytokines responsible for sickness behaviour don't induce it by acting on mitochondria? Maybe the perception of fatigue isn't just a brain thing but is actually fatigue. In any case, one doesn't necessarily exclude the other. As usual, the situation is unclear and we need more research.
I considered that might be the case, but the way sickness behaviour is usually explained is as a mechanism to "tell the body it needs to rest to conserve energy to fight the infection" etc. Actually damaging/impairing mitochondria seems like it would not be the best way of telling us we need to rest :)
 
Thanks all :).

In some way this doesn't seem that obvious a story, and I think that's because there's actually quite a lot of biology involved. But I do think it could be incredibly important.
No need for apology
To those who LOVE biology!

(Like me)

:)
 
Two thoughts spring to mind here:
1. This explains why we FEEL sick...
2. How could this explain genuine exhaustion in which one CANNOT override the feeling is is forced to stop (e.g. total loss of muscular strength).

Any thoughts Simon?
 
There is something I don't understand. Isn't there a contradiction between the cause of our fatigue being "sickness syndrome" and the research that has shown mitochondrial dysfunction (e.g. Sarah Myhill)? I mean one says we feel fatiguebecause chemical messengers are being fired which increase the perception of fatigue, whereas the other is saying we feel fatigue because we actually cannot produce energy at a sub-cellular level.
What makes you think that the cytokines responsible for sickness behaviour don't induce it by acting on mitochondria? Maybe the perception of fatigue isn't just a brain thing but is actually fatigue. In any case, one doesn't necessarily exclude the other. As usual, the situation is unclear and we need more research.
High levels of mito activity are needed for immune response (both humeral and febrile). Hence sickness response forcing rest makes biological/evolutionary sense) but sickness repsonse lowering energy production does not - it would destroy immune response as occurs in ME patients.
 
There is something I don't understand. Isn't there a contradiction between the cause of our fatigue being "sickness syndrome" and the research that has shown mitochondrial dysfunction (e.g. Sarah Myhill)? I mean one says we feel fatiguebecause chemical messengers are being fired which increase the perception of fatigue, whereas the other is saying we feel fatigue because we actually cannot produce energy at a sub-cellular level.
I am inclined to agree Cigana, poor mito function inducing sickness response would make sense to protect vital functions. Poor mito function reducing immune response and cause extended symptoms via sickness response would also make sense. Sickness response causing poor mito function would be an evolutionary disaster other than by safe mechanisms such as thyroid hormones and melatonin.
 
Two thoughts spring to mind here:
1. This explains why we FEEL sick...
2. How could this explain genuine exhaustion in which one CANNOT override the feeling is is forced to stop (e.g. total loss of muscular strength).

Any thoughts Simon?
Couple of thoughts from me
1. Microglia/sickness response is unlikely to be a complete explanation. As Jarred Younger stressed in his presentation in California, there is considerable overlap between sickness response and mecfs/FM, but it isn't complete by any means.
2. Also, sickness response doesn't have a single level: it can be mild and it can also be severe and incapacitating. I'm not quite sure of the difference between exhaustion and 'genuine' exhaustion, but it's possible that severe sickness response could explain genuine exhaustion too. So far, though, this central role of sickness response in mecfs is very much a plausible but untested hypothesis.
 
Couple of thoughts from me
1. Microglia/sickness response is unlikely to be a complete explanation. As Jarred Younger stressed in his presentation in California, there is considerable overlap between sickness response and mecfs/FM, but it isn't complete by any means.
2. Also, sickness response doesn't have a single level: it can be mild and it can also be severe and incapacitating. I'm not quite sure of the difference between exhaustion and 'genuine' exhaustion, but it's possible that severe sickness response could explain genuine exhaustion too. So far, though, this central role of sickness response in mecfs is very much a plausible but untested hypothesis.
I think we are pretty much on the same page given your response above Simon.

I refer to "genuine" exhaustion in the true meaning of the term - absolutely no energy left if the house were burning down, one would have to be carried out. I did used to experience that degree of exhaustion as opposed to the severe fatigue accompanying heavy infection that may be mis-labelled as exhaustion.

Hyperbole in general use of language sometimes makes finding the right phrasing with severe ME difficult doesn't it?