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

May 30, 2014

Simon McGrath looks at theories that microglia, the brain’s immune cells, could trigger and perpetuate the symptoms of ME/CFS and fibromyalgia.

sick

‘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.

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.

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.

Thiss blog post will describe the chain of events that lead to sickness response. Part two describes how microglia could get stuck, triggering long-term sickness response and may perhaps be behind 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

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 describes 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.

Part 2: Brain Cells Making us Sick? Messed up microglia could be driving symptoms

 

Simon McGrath tweets on ME/CFS research:

 

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32 comments

{ 32 comments… read them below or add one }

Valentijn May 30, 2014 at 11:42 pm

Thanks for the explanation, @Simon! I especially like using the term "sickness response" … the "behavior" variation is always annoying to see, even when it's describing exactly the same thing :-P

luludji May 31, 2014 at 12:10 am

So I am curious whether this theory also explains my sudden onset allergies….

Sasha May 31, 2014 at 1:40 am

Thanks, Simon – looking forward to Part 2!

And I also agree with 'sickness response' being a better term. Words matter, as we all know to our cost.

Legendrew May 31, 2014 at 10:35 am

Another great article Simon, it's such an interesting area of research that doesn't get anywhere near enough coverage, especially when you consider that it could potentially explain many of the strange features of ME/CFS. I'm looking forward to part 2!

Firestormm May 31, 2014 at 2:19 pm

I like it. Thank you @Simon :)

Simon May 31, 2014 at 2:54 pm

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.

When Ian Lipkin said the microbiome could be causing immune problems, specifically with cytokines – and these in turn could be driving the symptoms, he was referring to the sickness response. I'm pretty-sure people like Nancy Klimas see things in a similar way with immune problems, and particularly changes in pro-inflammatory cytokines leading to mecfs-like symptoms. But after spending rather a long time researching this blog, and trying to explain things simply, I can see why they might gloss over some of the details.

If anyone wants even more detail, here's a great open-access paper by Robert Dantzer, one of the fathers of sickness behaviour:
Twenty Years of Research on Cytokine-Induced Sickness Behavior

Hope to have part 2 up in the next day or so.

Ema May 31, 2014 at 4:29 pm

I am trying heparin because it is supposed to modulate the microglial cells and reduce neuroinflammation (and hopefully help with migraines) and kill babesia all at once.

So far it's just making me dizzy (but so is everything else unfortunately!).

Firestormm June 1, 2014 at 12:32 am
Simon

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.

When Ian Lipkin said the microbiome could be causing immune problems, specifically with cytokines – and these in turn could be driving the symptoms, he was referring to the sickness response. I'm pretty-sure people like Nancy Klimas see things in a similar way with immune problems, and particularly changes in pro-inflammatory cytokines leading to mecfs-like symptoms. But after spending rather a long time researching this blog, and trying to explain things simply, I can see why they might gloss over some of the details.

If anyone wants even more detail, here's a great open-access paper by Robert Dantzer, one of the fathers of sickness behaviour:
Twenty Years of Research on Cytokine-Induced Sickness Behavior

Hope to have part 2 up in the next day or so.

Reminds me that Dantzer is one of the keynote speakers at the CMRC Bristol conference in September along with Lipkin:

http://www.meassociation.org.uk/201…conference-tickets-now-available-12-may-2014/

AbbyDear June 1, 2014 at 1:22 am

i thought another interesting video that showed up after the short clip (in first post) was finished:

Rachael June 1, 2014 at 4:55 am

"For the first time it became clear," says Dantzer. "Sickness behavior is like fear–it is a state that makes the animal reorganize its priorities." Just as the sight of a predator makes animals release hormones that drive the "flight-or-fight" response, infection triggers the release of cytokines, which make the animal rest and conserve its resources to fight the infection. And of course, sickness behavior is not exclusive to rats–think of the last time you got flu.

Read more:
http://www.biopsychiatry.com/immunesystem/index.html

Nielk June 1, 2014 at 5:09 am

Thank you, Simon. So, it seems that this is a usual defensive response by the body when hit with an infection or inflammation. It usually only lasts for a week or two.

Ours lasts for years. Could it not be because our infection/inflammation is continual without any healing?

A.B. June 1, 2014 at 5:12 am

I suspect it will become more and more apparent that depression is a symptom of chronic immune system activation, rather than being caused by "stress" or psychological factors.

Thank you, Simon. So, it seems that this is a usual defensive response by the body when hit with an infection or inflammation. It usually only lasts for a week or two.

No, it's driven directly by immune system activation, and will last as long as the immune system activation.

Nielk June 1, 2014 at 5:52 am
A.B.

I

No, it's driven directly by immune system activation, and will last as long as the immune system activation.

Right, but what is driving the immune system activation? For example, I believe that Dr. Chia hypotheses that the pathogen is an enterovirus in the gut that perpetually activates the immune system.

A.B. June 1, 2014 at 6:17 am
Nielk

Right, but what is driving the immune system activation?

Biopsychosocial factors of course… (just kidding). That is the question we don't have an answer for. There are probably many factors.

Rachael June 1, 2014 at 6:36 am

I believe the immune system activation is driven by anything the body deems foreign (viruses, chemicals, alcohol, prescription meds etc) in predisposed individuals; those who are born with up-regulated (superior) immunity. Yesterday's neurasthenia is today's ME/CFS.

"Nervousness of constitution is, indeed, an aid to longevity, and in various ways: it compels caution, makes imperative the avoidance of evil habits, and early warns us of the approach of peril."

https://archive.org/stream/americannervousn00bearuoft#page/22/mode/2up

Firestormm June 1, 2014 at 6:59 am
Nielk

Right, but what is driving the immune system activation? For example, I believe that Dr. Chia hypotheses that the pathogen is an enterovirus in the gut that perpetually activates the immune system.

An autoimmune disease would account for it of course ;)

Simon June 1, 2014 at 8:17 am
Nielk

Thank you, Simon. So, it seems that this is a usual defensive response by the body when hit with an infection or inflammation. It usually only lasts for a week or two.
Ours lasts for years. Could it not be because our infection/inflammation is continual without any healing?

A.B.

No, it's driven directly by immune system activation, and will last as long as the immune system activation.

Nielk

Right, but what is driving the immune system activation? For example, I believe that Dr. Chia hypotheses that the pathogen is an enterovirus in the gut that perpetually activates the immune system.

Firestormm

An autoimmune disease would account for it of course ;)

Right, trying to get part 2 up as soon as I can as it deals with some of these questions – the answer is probably 'all of the above' could be behind long-term sickness response.

But there are 2 broad possibilities for long-term sickness response:

  1. Ongoing immune activation in the body with high levels of pro-inflammatory cytokines that continue to drive sickness response. Chronic infection, autoimmunity and perhaps microbiome issues could count here
  2. microglia that are either 'stuck on' in the absence of cytokine signals, or over-react to minor inflammation that wouldn't normally cause sickness response

Part 2 is looking at the recent hypotheses about over-reacting microglia, though ongoing immune activation eg autoimmunity could plausibly be behind the symptoms of ME/CFS too, via sickness response.

Hope to get part 2 up later today.

Marco June 1, 2014 at 8:33 am

Tempting as it is to fixate on the role the immune system plays in response to infection that's not even half the story as the immune system also responds to physical trauma, ischemia, mental and metabolic/physiological stressors and just plain old daily maintenance plus 'sickness behaviour' isn't the only 'behavioral' response elicited by peripheral cytokine/brain interaction (remember leptin?).

Just for giggles I was interested to know if the exercise related metabolites/channels which the Lights found vastly overexpressed in ME/CFS patients (adrenergic, purinergic, acid sensing and vanilloid) might also trigger microglial activation and surprise – microglia express receptors for (and are activated by) them all :

http://www.researchgate.net/publica…_reactivity_induced_by_repeated_social_defeat

http://www.ncbi.nlm.nih.gov/pubmed/22944319

http://www.ncbi.nlm.nih.gov/pubmed/22674620

http://www.ncbi.nlm.nih.gov/pubmed/1845221

http://www.ajnd.us/files/AJND1204002.pdf

Edited to add : Apologies Simon. Great article and really looking forward to part 2 :)

snowathlete June 1, 2014 at 9:01 am

That's a really helpful and well-written article. Thanks Simon.

searcher June 1, 2014 at 9:26 am

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

Marco June 1, 2014 at 10:03 am
searcher

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

cigana June 1, 2014 at 10:16 am

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.

Valentijn June 1, 2014 at 11:17 am
cigana

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.

A.B. June 1, 2014 at 12:22 pm
cigana

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.

cigana June 2, 2014 at 3:29 am
A.B.

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 :)

MeSci June 8, 2014 at 11:57 am
Simon

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)

:)

Leopardtail June 12, 2014 at 7:01 pm

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?

Leopardtail June 12, 2014 at 7:04 pm
A.B.
cigana

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.

Leopardtail June 12, 2014 at 7:10 pm
cigana

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.

Simon June 13, 2014 at 4:25 am
Leopardtail

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.

Leopardtail June 15, 2014 at 8:27 am
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.

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?

Ema November 22, 2014 at 9:02 pm

Looks like some asthma meds also suppress microglia. They also increase cAMP which seems to be a good thing as well in many cases.

http://www.ncbi.nlm.nih.gov/m/pubmed/9509999/

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