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

June 1, 2014

Simon McGrath looks at theories that microglia, the brain’s immune cells, might be overactive and driving the symptoms of ME/CFS and fibromyalgia.

In Part 1, he described how the body reacts to infection or wounding with a “sickness response” that partly resembles ME/CFS, and how the microglia are the last step in the physiological mechanisms that lead to sickness response.

Could microglia be behind the symptoms of ME/CFS?                   Artist’s image of a microglia.  © 2012 Hagop Kaneboughazian

Sickness response is a good thing, helping us survive by resting to fight off infection. But it evolved as a short-term response, and may be harmful if it sets in for the long-term, perhaps playing a role in ME/CFS.

Overactive microglia?

So how could sickness response get stuck in the on position? One possibility is that a chronic infection continues to trigger it, but a chronic infection should exclude an ME/CFS diagnosis.

The last step in the chain, the microglia, are the focus of two other theories which see microglia activated when they should be in their normal, patrolling state.

ME/CFS and fibromyalgia are often referred to as neuroimmune diseases because of the frequent finding of immune dysfunction and widespread symptoms implicating the brain.

Microglia are cells that potentially connect the immune system to the nervous system, responding to immune activation to effectively “turn on” sickness response in the brain. The idea that inappropriate microglial activation could play a major role in ME/CFS is fascinating.

The activation could be due to earlier priming, a severe initial infection, a disturbance in the immune system resulting from problems in the microbiome, autoimmunity or even chronic infection. Microglial activation could be the common endpoint of many different routes to ME/CFS and fibromyalgia.

Microglial research is poised to become a new front in understanding ME/CFS and fibromyalgia, particularly as high-tech tools are developed to probe the state of microglia in the brain.

Dubbo studies: severity of acute illness is key

The Dubbo group in Australia has done research suggesting that in sudden-onset CFS, the severity of the initial infection triggers long-term activation of microglia.

They studied patients with infectious mononucleosis or related infections and found that the stronger the initial sickness response, the greater the chances that a patient would go on to develop CFS.

The CFS did not seem to be caused by continuing high cytokine levels. While cytokine levels were initially elevated, they dropped back to normal levels. But, the researchers suggested, the severity of the initial cytokine response might have got the microglia “stuck” in an activated mode, locking the brain into an extended sickness response.

Interferon-gamma, a proinflammatory cytokine that can activate microglia, seemed to play a particularly important role. Patients with two copies of the most active interferon-gamma gene version were likely to be sicker initially and about three times more likely to develop CFS at six months.

This hypothesis got some support from a recent small study which found that microglia in the brains of ME/CFS patients were activated — exactly what the Dubbo hypothesis predicts.

Microglial ‘Priming’ theory

Professor Hugh Perry

Professor Hugh Perry

A second way that microglia could cause a continuing sickness response is by becoming over-reactive. Hugh Perry, Professor of experimental neuropathology from the University of Southampton, and Dr. Jarred Younger of Stanford University have independently proposed that the problem starts with “priming” of microglia by a variety of factors, including previous infections, obesity, chronic stress, and age.

Primed microglia are hypersensitive — a bit like a primed or armed bomb — so they react too easily and/or too aggressively, which could lead to long-term sickness response. So an infection or other trigger that would lead to no long-term problems in someone with “normal” microglia could lead to ME/CFS or fibromyalgia in someone with primed microglia.

Primed microglia are measurably different from patrolling ones, with very different receptors on their cell surface. Fewer of the receptors that respond to “keep calm” signals from healthy neurons and more receptors that respond to any “shoot now” signals. The result is an excitable, trigger-happy microglial cell.

Much of the work on priming has been done on animals, since the only sure way to detect priming is to physically examine them. However, studies looking at brains of people who have died of neurodegenerative disease also reveal primed microglia.

Perry believes that priming is an important factor in these illnesses because it could lead to an overly-aggressive immune response, damaging tissue instead of helping it heal.

At the recent International Symposium for CFS/ME in Australia Perry suggested that priming of microglia could be behind this illness as well (though he doesn’t think neurones degenerate in ME/CFS the way they do in the other illnesses he studies). Once primed, Perry argues, an infection could send the microglia into a permanently activated state, triggering a long-term sickness response.

Dr. Jarred Younger

Younger, a pain researcher at Stanford, independently developed a very similar theory, which he described at the Stanford Symposium and IACFS/ME conference in March. He primarily focused on fibromyalgia in the IACFS/ME talk, but believes the same mechanism could be behind ME/CFS. Priming could lead to the ME/CFS and fibromyalgia in two possible ways, says Younger:

  • Similar to Perry’s view, microglia might get “stuck” in the activated state: “they fail to revert to their former patrolling state and are therefore constantly producing chemicals that cause ME/CFS symptoms. Microglia are long-lived cells (many, many years), so microglia stuck in [an activated] state can cause problems for a long period of time.”
  • Or, primed microglia may react when they shouldn’t, producing the flares characteristic of ME/CFS and FM as they become fully activated and pump out the chemicals that cause sickness.

What I find fascinating is that Perry and Younger independently came up with very similar ideas of microglial priming. They came at it from different directions: Perry is the microglia expert in neurodegenerative diseases, Younger is the fibromyalgia expert looking at how core biological processes might explain the illness. When ideas converge like this, it’s often a good sign.

The Microglia Priming hypothesis, as explained by Dr Jarrod Younger

The Microglia Priming hypothesis for fibromyalgia and ME/CFS, © Dr. Jarred Younger. Reproduced with permission.

As yet, there is no hard evidence of microglial activation in fibromyalgia, but that might be about to change: Younger recently reported that a microglial-activation PET study — similar to the recent one on ME/CFS — is currently under way at Harvard.

However, activation is not the same as priming, and there is currently no way to detect “primed” microglia in living humans. Until there is, there won’t really be a way to put this theory to the test. If larger studies show there is consistent activation of microglia, there may well be more attention on the priming hypothesis.

Intriguing treatment possibilities

If microglial activation is a factor in ME/CFS, then it could be treatable — one reason there is so much interest in this line of research.

Perry and Younger pointed to the potential of microglial inhibitor drugs to calm down the overactive cells or prevent activation in the first place. No microglial inhibitors have been proven to treat ME/CFS or fibromyalgia, but Younger has already run an intriguing small study of low-dose naltrexone (LDN) for fibromyalgia with encouraging results.

The exact mechanism for LDN is uncertain, but Younger has pointed to evidence that at the low doses used naltrexone’s main role is probably to inhibit activation of microglia. Other drugs have been shown to inhibit microglial activation in animals, but not yet in humans.

This is definitely an area to watch.

 

Thanks to @searcher who reported on Dr Younger’s work from Stanford and IACFS/ME, and helped me get the science right in this piece.

Simon McGrath tweets on ME/CFS research:

 

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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.

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35 comments

{ 35 comments… read them below or add one }

Firestormm June 1, 2014 at 2:43 pm

Nice piccie of the microglia :)

Another solid article @Simon I shall read in detail tomorrow when my eyes are rested.

Thanks.

Butydoc June 1, 2014 at 3:09 pm
Simon

Simon submitted a new blog post:

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

Simon McGrath looks at theories that microglia, the brain's immune cells, might be overactive and driving the symptoms of ME/CFS and fibromyalgia.

In Part 1, he described how the body reacts to infection or wounding with a “sickness response” that partly resembles ME/CFS, and how the microglia are the last step in the physiological mechanisms that lead to sickness response.

[caption][​IMG] Could microglia be behind the symptoms of ME/CFS? Artist's image of a microglia. © 2012 Hagop Kaneboughazian[/caption]
Sickness response is a good thing, helping us survive by resting to fight off infection. But it evolved as a short-term response, and may be harmful if it sets in for the long-term, perhaps playing a role in ME/CFS.

Overactive microglia?

So how could sickness response get stuck in the on position? One possibility is that a chronic infection continues to trigger it, but a chronic infection should exclude an ME/CFS diagnosis.

The last step in the chain, the microglia, are the focus of two other theories which see microglia activated when they should be in their normal, patrolling state.

ME/CFS and fibromyalgia are often referred to as a neuroimmune disease because of the frequent finding of immune dysfunction and widespread symptoms implicating the brain.

Microglia are cells that potentially connect the immune system to the nervous system, responding to immune activation to effectively "turn on" sickness response in the brain. The idea that inappropriate microglial activation could play a major role in ME/CFS is fascinating.

The activation could be due to earlier priming, a severe initial infection, a disturbance in the immune system resulting from problems in the microbiome, autoimmunity or even chronic infection. Microglial activation could be the common endpoint of many different routes to ME/CFS and fibromyalgia.

Microglial research is poised to become a new front in understanding ME/CFS and fibromyalgia, particularly as high-tech tools are developed to probe the state of microglia in the brain.

Dubbo studies: severity of acute illness is key

The Dubbo group in Australia has done research suggesting that in sudden-onset CFS, the severity of the initial infection triggers long-term activation of microglia. They studied patients with infectious mononucleosis or related infections and found that the stronger the initial sickness response, the greater the chances that a patient would go on to develop CFS.
The CFS did not seem to be caused by continuing high cytokine levels. While cytokine levels were initially elevated, they dropped back to normal levels. But, the researchers suggested, the severity of the initial cytokine response might have got the microglia "stuck" in an activated mode, locking the brain into an extended sickness response.

Interferon-gamma, a proinflammatory cytokine that can activate microglia, seemed to play a particularly important role. Patients with two copies of the most active interferon-gamma gene version were likely to be sicker initially and about three times more likely to develop CFS at six months.

This hypothesis got some support from a recent small study which found that microglia in the brains of ME/CFS patients were activated — exactly what the Dubbo hypothesis predicts.

Microglial 'Priming' theory

[caption][​IMG] Professor Hugh Perry[/caption]

A second way that microglia could cause a continuing sickness response is by becoming over-reactive. Hugh Perry, Professor of experimental neuropathology from the University of Southampton, and Dr. Jarred Younger of Stanford University have independently proposed that the problem starts with "priming" of microglia by a variety of factors, including previous infections, obesity, chronic stress, and age.

Primed microglia are hypersensitive — a bit like a primed or armed bomb — so they react too easily and/or too aggressively, which could lead to long-term sickness response. So an infection or other trigger that would lead to no long-term problems in someone with "normal" microglia could lead to ME/CFS or fibromyalgia in someone with primed microglia.

Primed microglia are measurably different from patrolling ones, with very different receptors on their cell surface. Fewer of the receptors that respond to "keep calm" signals from healthy neurons and more receptors that respond to any "shoot now" signals. The result is an excitable, trigger-happy microglial cell.

Much of the work on priming has been done on animals, since the only sure way to detect priming is to physically examine them. However, studies looking at brains of people who have died of neurodegenerative disease also reveal primed microglia.

Perry believes that priming is an important factor in these illnesses because it could lead to an overly-aggressive immune response, damaging tissue instead of helping it heal.

At the recent International Symposium for CFS/ME in Australia Perry suggested that priming of microglia could be behind this illness as well (though he doesn’t think neurones degenerate in ME/CFS the way they do in the other illnesses he studies). Once primed, Perry argues, an infection could send the microglia into a permanently activated state, triggering a long-term sickness response.

[caption][​IMG] Dr. Jarred Younger[/caption]

Younger, a pain researcher at Stanford, independently developed a very similar theory, which he described at the Stanford Symposium and IACFS/ME conference in March. He primarily focused on fibromyalgia in the IACFS/ME talk, but believes the same mechanism could be behind ME/CFS. Priming could lead to the ME/CFS and fibromyalgia in two possible ways, says Younger:

  • Similar to Perry’s view, microglia might get "stuck" in the activated state: "they fail to revert to their former patrolling state and are therefore constantly producing chemicals that cause ME/CFS symptoms. Microglia are long-lived cells (many, many years), so microglia stuck in [an] state can cause problems for a long period of time."
  • Or, primed microglia may react when they shouldn't, producing the flares characteristic of ME/CFS and FM as they become fully activated and pump out the chemicals that cause sickness.

What I find fascinating is that Perry and Younger independently came up with very similar ideas of microglial priming. They came at it from different directions: Perry is the microglia expert in neurodegenerative diseases, Younger is the fibromyalgia expert looking at how core biological processes might explain the illness. When ideas converge like this, it's often a good sign.

[​IMG] [caption]The Microglia Priming hypothesis for fibromyalgia and ME/CFS, © Dr. Jarred Younger. Reproduced with permission.[/caption]As yet, there is no hard evidence of microglial activation in fibromyalgia, but that might be about to change: Younger recently reported that a microglial-activation PET study — similar to the recent one on ME/CFS — is currently under way at Harvard.

However, activation is not the same as priming, and there is currently no way to detect "primed" microglia in living humans. Until there is, there won't really be a way to put this theory to the test. If larger studies show there is consistent activation of microglia, there may well be more attention on the priming hypothesis.

Intriguing treatment possibilities

If microglial activation is a factor in ME/CFS, then it could be treatable — one reason there is so much interest in this line of research.

Perry and Younger pointed to the potential of microglial inhibitor drugs to calm down the overactive cells or prevent activation in the first place. No microglial inhibitors have been proven to treat ME/CFS or fibromyalgia, but Younger has already run an intriguing small study of low-dose naltrexone (LDN) for fibromyalgia with encouraging results.

The exact mechanism for LDN is uncertain, but Younger has pointed to evidence that at the low doses used naltrexone's main role is probably to inhibit activation of microglia. Other drugs have been shown to inhibit microglial activation in animals, but not yet in humans.

This is definitely an area to watch.

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.

[​IMG]

Continue reading the Original Blog Post

Hi Simon,

I find the idea of microglial priming and activation may be the final pathway to cfs/me fascinating. In 2006-7 Dr. Jose Montoya treated a group of patients with Valcye who were diagnosed with cfs/me with some success. He believed that HHV6 or other herpes viruses were causing the disease through chronic ongoing infection. Recently a paper was published by Zhaoging Ding PhD, department of neurology at Stanford entitled " Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuro inflammation." This recent paper would would dovetail very well with the recent theory of microglial priming and activation. This would explain why valcyte has had some success in treating cfs/me even though no infection has been proven. This would also go along with Dr. Lipkin inability to find an infectious agent as a cause for cfs/me. It was also found that acyclovir didn't supress microglial cells. Possibly Valcyte may end up being one of the drugs to treat microglial cell over activation as it primary targets not as a antiviral drug.

Regards,
Gary

aimossy June 1, 2014 at 11:53 pm

Thank you Simon, for both articles, complicated = explained!

rosie26 June 2, 2014 at 12:19 am

Really interesting! Thanks.

Firestormm June 2, 2014 at 12:33 am

@Simon

However, activation is not the same as priming, and there is currently no way to detect "primed" microglia in living humans. Until there is, there won't really be a way to put this theory to the test. If larger studies show there is consistent activation of microglia, there may well be more attention on the priming hypothesis.

Presumably though, if you can 'block' or calm down the microglia response and observe a lessening of ME associated (sickness-response associated) symptoms, you could demonstrate the theory had merit?

Intriguing treatment possibilities


If microglial activation is a factor in ME/CFS, then it could be treatable — one reason there is so much interest in this line of research.

Perry and Younger pointed to the potential of microglial inhibitor drugs to calm down the overactive cells or prevent activation in the first place. No microglial inhibitors have been proven to treat ME/CFS or fibromyalgia, but Younger has already run an intriguing small study of low-dose naltrexone (LDN) for fibromyalgia with encouraging results.

The exact mechanism for LDN is uncertain, but Younger has pointed to evidence that at the low doses used naltrexone's main role is probably to inhibit activation of microglia. Other drugs have been shown to inhibit microglial activation in animals, but not yet in humans.

I hate to say it, but 'sickness behaviour' has been talked about in association with ME for some time (certainly since I have had the diagnosis, so 15 years), and mainly the discourse comes from psychologists/psychiatrists who seem to feel that psychological treatments are (more) useful than drugs – certainly I have never been offered any drugs for this 'response'.

'course we well know the evidence for such things as CBT aint worth the scientific paper it is written on, but how can the above priming and activation theory be used to push aside the psychological explanation/treatments in favour of something that might actually work – in your view?

Finally, are you suggesting that 'pain' is a sickness behaviour/response? Only the study you refer to – and LDN itself – demonstrated if anything a lessening of pain in Fibromyalgia.

Muchos gracias :)

rosie26 June 2, 2014 at 12:40 am

How would the Problem that we may have with our B cells fit in with this I wonder ? (as in Rituximab).

Firestormm June 2, 2014 at 12:48 am
rosie26

How would the Problem that we may have with our B cells fit in with this I wonder ? (as in Rituximab).

Well…. ;)

Here is the naive/layman's attempt at helping….

If an autoimmune disease you have a 'looping' trigger. So, if like Rheumatoid Arthritis you would experience 'flares' e.g. when swellings occur and you feel more sick than normal, when the 'rogue' antibody – by chance – decides 'Hey up. I'm gonna attack them cells today!'.

Something like Rituximab is intended (if other drugs fail) to wipe out your current B-cells and with repeated treatment to hopefully reduce the chance of this 'rogue' antibody being produced again by your bone marrow in new B-cells.

If you can remove or at least reduce the chance of the 'rogue' from occurring, and/or from then 'flaring', you might then break the chain.

On the other hand… it could be something unrelated to B-cells that is triggering such a chain of events: it could be (as Simon said) something in the gut microbiome etc. OR 'we' could now have programmed microglia that are simply 'on alert' all the damn time.

Personally, I think – as we are all different – the answers as to trigger, will be different for each of us – so sub-groups perhaps.

Though for some there may be no trigger identified – and treatment will simply demonstrate that the problem did indeed exist.

But getting access to the treatments – when you can't demonstrate cause – remains a problem.

Edited o_O

Marco June 2, 2014 at 1:32 am

"However, activation is not the same as priming, and there is currently no way to detect “primed” microglia in living humans. Until there is, there won’t really be a way to put this theory to the test. If larger studies show there is consistent activation of microglia, there may well be more attention on the priming hypothesis."

Maybe not directly but various metabolites produced by activated glia may be detected in CSF or peripheral blood. You could also look at conditions where microglial priming/activation is confirmed (aging and concussion/post concussion syndrome) or suspected (complex regional pain syndrome) for overlapping symptoms. For exmple exercise intolerance/post exertional exacerbation of symptoms in post concussion or autonomic dysfunction in complex regional pain syndrome.

Plus as per @Firestorm 'proof of concept' trials might add to the converging evidence.

searcher June 2, 2014 at 2:12 am

I think one problem with definitively determining based on medication response if activated microglia are to blame for specific symptoms is that there aren't currently any medications that solely target microglia. For example, LDN works on opioid receptors in addition to microglia (although the researchers do think it's helping due to its effects on microglia.) Minocycline is an antibiotic and a microglial inhibitor. Ganciclovir is an antiviral that also inhibits microglia. I have had good luck with Reishi, but it has myriad effects throughout the body. I guess one option is that we can triangulate if a wide range of drugs/supplements that reduce microglial activity are also proven to reduce ME/CFS symptoms.

There's a discussion of this issue at http://www.researchgate.net/post/Microglia_and_minocycline that Dr Younger happened to weigh in on.

Gijs June 2, 2014 at 2:50 am

I don't believe microglial is the (only) cause for ME. It is much more complicated.

Marco June 2, 2014 at 4:14 am
searcher

I think one problem with definitively determining based on medication response if activated microglia are to blame for specific symptoms is that there aren't currently any medications that solely target microglia. For example, LDN works on opioid receptors in addition to microglia (although the researchers do think it's helping due to its effects on microglia.) Minocycline is an antibiotic and a microglial inhibitor. Ganciclovir is an antiviral that also inhibits microglia. I have had good luck with Reishi, but it has myriad effects throughout the body. I guess one option is that we can triangulate if a wide range of drugs/supplements that reduce microglial activity are also proven to reduce ME/CFS symptoms.

There's a discussion of this issue at http://www.researchgate.net/post/Microglia_and_minocycline that Dr Younger happened to weigh in on.

Thanks – that's a very useful discussion.

The flip side of course is that with certain antibiotics, antivirals and even potentially Rituximab, we can't be certain that any benefits reflect and infectious or autoimmune pathology and are not due to microglial inhibition. That's another reason I'd like to see converging evidence.

lansbergen June 2, 2014 at 5:17 am

One possibility is that a chronic infection continues to trigger it, but a chronic infection should exclude an ME/CFS diagnosis.

I would if there was a test.

Simon June 2, 2014 at 6:00 am
Firestormm

@Simon

Presumably though, if you can 'block' or calm down the microglia response and observe a lessening of ME associated (sickness-response associated) symptoms, you could demonstrate the theory had merit?

Yes, that would be supportive evidence though as @searcher points out, hard to find microglia-only drugs. But hey, if such drugs works, that itself would be good, regardless of supporting a theory.

Marco

"However, activation is not the same as priming, and there is currently no way to detect “primed” microglia in living humans…."

Maybe not directly but various metabolites produced by activated glia may be detected in CSF or peripheral blood. You could also look at conditions where microglial priming/activation is confirmed (aging and concussion/post concussion syndrome) or suspected (complex regional pain syndrome) for overlapping symptoms. For exmple exercise intolerance/post exertional exacerbation of symptoms in post concussion or autonomic dysfunction in complex regional pain syndrome.

Plus as per @Firestorm 'proof of concept' trials might add to the converging evidence.

I did ask Prof Hugh Perry about how to prove and he said not yet possible. Even where priming confirmed there are usually so many processes going on it would presumably yield a metabolite signature of the disease in question, rather than of priming specifically. Problem is, there is just so much going on in the brain! There are many cell surface receptors that are linked to priming, and a tracer that picked up those, or a combo of, might be a target for a PET tracer study, like the recent Japanese one indicating microglial activation.

I hate to say it, but 'sickness behaviour' has been talked about in association with ME for some time (certainly since I have had the diagnosis, so 15 years), and mainly the discourse comes from psychologists/psychiatrists who seem to feel that psychological treatments are (more) useful than drugs – certainly I have never been offered any drugs for this 'response'.

'course we well know the evidence for such things as CBT aint worth the scientific paper it is written on, but how can the above priming and activation theory be used to push aside the psychological explanation/treatments in favour of something that might actually work – in your view?

You sure this was sickness behaviour? I have definitely come across psychological explanations focusing on 'illness behaviour' and the alleged benefits of the 'sickness role', but nothing on sickness behaviour/sickness response as described here.

Finally, are you suggesting that 'pain' is a sickness behaviour/response? Only the study you refer to – and LDN itself – demonstrated if anything a lessening of pain in Fibromyalgia.

Yes – well Jarred Younger is, and he's a pain researcher. In fact, someone sent me a great Nature review that highlights evidence for a similar neuroimmune role in pain, also featuring sickness response and microglia (or see What causes chronic pain? Microglia might be to blame). Also, low dose naltrexone is believed to be a microglial inhibitor, and Younger proposes that inhibition is what reduces sickness response and pain as part of that. Which I think is consistent.

rosie26

How would the Problem that we may have with our B cells fit in with this I wonder ? (as in Rituximab).

Indirectly! An autoimmune problem due to B-cell produced anti-bodies would trigger inflammatory cytokines, which would trigger microglia and symptoms as described – but not the primed/'stuck on' situation envisaged by Dubbo group, Perry and Younger. Flares w=could occur as per @Firestormm's comment.

Gijs

I don't believe microglial is the (only) cause for ME. It is much more complicated.

Hi Gijs, thought you'd left! Welcome back.

I agree it is more complicated. First, the microglia story I outlined above with priming/long-term activation still relies on an initial trigger which could include prior infection, particular infections eg EBV, stress, vaccination and more – so not simple. Also, there is the chronic, ongoing cytokine stimulus of normal microglia, eg an autoimmune response. Finally, I'm sure there will be cases of ME/CFS where microglia play no role at all (even if the above theories play out).

With this illness, I don't think anything will ever explain everything, and complex is the name of the game.

Eliza June 2, 2014 at 6:00 am

I know of at least one patient who did LDN and then started AB treatment.
She's doing so much better now.
If there's no perfect way of altering the primed microglials, it would be the next best thing to alter microglial activity and lessen the cytokine release. For now.
Perhaps LDN is the safest, least invasive way of doing that at the moment?
For some subgroups of patients "trial and error" with LDN does seem to be worthwhile?

What I'm wondering about = how will it effect other major symptoms like gut issues etc.?
What's the link between microglia activation and our consistent immune dysfunctions (nk cell function, cd57, cs14, perforin, elastase, nagalase, …) and other major ME markers?

Nielk June 2, 2014 at 6:56 am

Thank you again, Simon for this fine follow up article.

I had a spect scan done two years ago. I just went back to read the results and it partly reads: "increased uptake in the basal ganglia and thalamus bilaterally". I don't know if there is any connection with 'primed microglia' and 'increased uptake in basal ganglia'?

shannah June 2, 2014 at 7:17 am
Nielk

Thank you again, Simon for this fine follow up article.

I had a spect scan done two years ago. I just went back to read the results and it partly reads: "increased uptake in the basal ganglia and thalamus bilaterally". I don't know if there is any connection with 'primed microglia' and 'increased uptake in basal ganglia'?

There's a comment in regards to the basal ganglia on one of the MRI's I had done which reads, "Dilated perivascular spaces on the ventral aspect of the basal ganglia". No idea what it means or if it relates at all to any of this information.

I was on high dose antibiotics for a couple of years including minocycline, all without any progress at all.

Simon June 2, 2014 at 7:29 am
Nielk

Thank you again, Simon for this fine follow up article.

I had a spect scan done two years ago. I just went back to read the results and it partly reads: "increased uptake in the basal ganglia and thalamus bilaterally". I don't know if there is any connection with 'primed microglia' and 'increased uptake in basal ganglia'?

I'm not familiar with SPECT scans, but if it's similar to PETs then probably not, unless they were using a specific radioactive tracer for microglia. Do you know if they were looking at blood flow or glucose uptake, for instance? Neither of those are markers for microglial activation. In fact a recent brain scan study found evidence for reduced blood flow in basal ganglia of CFS patients. But only when gamblilng :)

Marco June 2, 2014 at 8:41 am

I did ask Prof Hugh Perry about how to prove and he said not yet possible. Even where priming confirmed there are usually so many processes going on it would presumably yield a metabolite signature of the disease in question, rather than of priming specifically. Problem is, there is just so much going on in the brain! There are many cell surface receptors that are linked to priming, and a tracer that picked up those, or a combo of, might be a target for a PET tracer study, like the recent Japanese one indicating microglial activation.

I'm sure he's right and I'm sure it may be difficult to find markers which may be diagnostic – but that does surprise me. E.g. Quinolinic acid (QUIN) is a metabolite of the trycat pathway which (according to wiki which is never wrong ;)) is only produced in the brain by glia http://en.wikipedia.org/wiki/Quinolinic_acid

Elevated QUIN can be measured in cerebrospinal fluid and has been associated with cytokine induced depression and MDD : http://www.jneuroinflammation.com/content/8/1/94 supporting a neuroinflammatory model of depression.

Similar findings in ME/CFS might support a neuroinflammatory model even if not specific to the condition (which I don't believe is a major issue).

cigana June 2, 2014 at 11:23 am

Very interesting :)
From my N=1 I know that curcumin is a microglia inhibitor and it certainly helps me sleep. Other natural microglia inhibitors can be found here: http://www.mdpi.com/1420-3049/16/2/1021/pdf

Esther12 June 2, 2014 at 7:00 pm

Thanks Simon.

Low dose naltrexone is something I've heard people mention for CFS for ages, so I was a bit surprised that my googling didn't bring up any research. I'd have thought that we'd have to be dealing with subsets again as if LDN was significantly helpful for the majority of people surely there'd be more positive word on the grapevine.

RYO June 3, 2014 at 5:23 am

Overall, very interesting concepts re: role of microglia dysfunction in CFS / ME. Similar theory raised in role of vagus nerve in CFS / ME. However, there is "missing piece of puzzle" for those of us that have severe localized muscle weakness and pain. It is true that generalized muscle pain and weakness characterize "sickness behavior" but I have never experienced severe localized muscle symptoms (ie hip girdle area) with previous exposure to illnesses such as influenza. Nor does it explain the muscle fasciculations I have experienced for last 2 years since my initial acute illness.

I have always described to my friends that after my acute illness, it seemed I aged overnight. I went from feeling like someone in their late 30's to a debilitated 90 year old. Some recent news about anti-aging and parabiosis sparked a question re: link between microglia cells and skeletal muscle function.

Does anyone have any information about which cell lines produce GDF11? A study examining whether CFS / ME patients have lower GDF11 levels vs healthy controls would be interesting.

bmoberg337 June 7, 2014 at 5:08 pm
Butydoc
Simon

Simon submitted a new blog post:

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

Simon McGrath looks at theories that microglia, the brain's immune cells, might be overactive and driving the symptoms of ME/CFS and fibromyalgia.

In Part 1, he described how the body reacts to infection or wounding with a “sickness response” that partly resembles ME/CFS, and how the microglia are the last step in the physiological mechanisms that lead to sickness response.

[caption][​IMG] Could microglia be behind the symptoms of ME/CFS? Artist's image of a microglia. © 2012 Hagop Kaneboughazian[/caption]
Sickness response is a good thing, helping us survive by resting to fight off infection. But it evolved as a short-term response, and may be harmful if it sets in for the long-term, perhaps playing a role in ME/CFS.

Overactive microglia?

So how could sickness response get stuck in the on position? One possibility is that a chronic infection continues to trigger it, but a chronic infection should exclude an ME/CFS diagnosis.

The last step in the chain, the microglia, are the focus of two other theories which see microglia activated when they should be in their normal, patrolling state.

ME/CFS and fibromyalgia are often referred to as a neuroimmune disease because of the frequent finding of immune dysfunction and widespread symptoms implicating the brain.

Microglia are cells that potentially connect the immune system to the nervous system, responding to immune activation to effectively "turn on" sickness response in the brain. The idea that inappropriate microglial activation could play a major role in ME/CFS is fascinating.

The activation could be due to earlier priming, a severe initial infection, a disturbance in the immune system resulting from problems in the microbiome, autoimmunity or even chronic infection. Microglial activation could be the common endpoint of many different routes to ME/CFS and fibromyalgia.

Microglial research is poised to become a new front in understanding ME/CFS and fibromyalgia, particularly as high-tech tools are developed to probe the state of microglia in the brain.

Dubbo studies: severity of acute illness is key

The Dubbo group in Australia has done research suggesting that in sudden-onset CFS, the severity of the initial infection triggers long-term activation of microglia. They studied patients with infectious mononucleosis or related infections and found that the stronger the initial sickness response, the greater the chances that a patient would go on to develop CFS.
The CFS did not seem to be caused by continuing high cytokine levels. While cytokine levels were initially elevated, they dropped back to normal levels. But, the researchers suggested, the severity of the initial cytokine response might have got the microglia "stuck" in an activated mode, locking the brain into an extended sickness response.

Interferon-gamma, a proinflammatory cytokine that can activate microglia, seemed to play a particularly important role. Patients with two copies of the most active interferon-gamma gene version were likely to be sicker initially and about three times more likely to develop CFS at six months.

This hypothesis got some support from a recent small study which found that microglia in the brains of ME/CFS patients were activated — exactly what the Dubbo hypothesis predicts.

Microglial 'Priming' theory

[caption][​IMG] Professor Hugh Perry[/caption]

A second way that microglia could cause a continuing sickness response is by becoming over-reactive. Hugh Perry, Professor of experimental neuropathology from the University of Southampton, and Dr. Jarred Younger of Stanford University have independently proposed that the problem starts with "priming" of microglia by a variety of factors, including previous infections, obesity, chronic stress, and age.

Primed microglia are hypersensitive — a bit like a primed or armed bomb — so they react too easily and/or too aggressively, which could lead to long-term sickness response. So an infection or other trigger that would lead to no long-term problems in someone with "normal" microglia could lead to ME/CFS or fibromyalgia in someone with primed microglia.

Primed microglia are measurably different from patrolling ones, with very different receptors on their cell surface. Fewer of the receptors that respond to "keep calm" signals from healthy neurons and more receptors that respond to any "shoot now" signals. The result is an excitable, trigger-happy microglial cell.

Much of the work on priming has been done on animals, since the only sure way to detect priming is to physically examine them. However, studies looking at brains of people who have died of neurodegenerative disease also reveal primed microglia.

Perry believes that priming is an important factor in these illnesses because it could lead to an overly-aggressive immune response, damaging tissue instead of helping it heal.

At the recent International Symposium for CFS/ME in Australia Perry suggested that priming of microglia could be behind this illness as well (though he doesn’t think neurones degenerate in ME/CFS the way they do in the other illnesses he studies). Once primed, Perry argues, an infection could send the microglia into a permanently activated state, triggering a long-term sickness response.

[caption][​IMG] Dr. Jarred Younger[/caption]

Younger, a pain researcher at Stanford, independently developed a very similar theory, which he described at the Stanford Symposium and IACFS/ME conference in March. He primarily focused on fibromyalgia in the IACFS/ME talk, but believes the same mechanism could be behind ME/CFS. Priming could lead to the ME/CFS and fibromyalgia in two possible ways, says Younger:

  • Similar to Perry’s view, microglia might get "stuck" in the activated state: "they fail to revert to their former patrolling state and are therefore constantly producing chemicals that cause ME/CFS symptoms. Microglia are long-lived cells (many, many years), so microglia stuck in [an] state can cause problems for a long period of time."
  • Or, primed microglia may react when they shouldn't, producing the flares characteristic of ME/CFS and FM as they become fully activated and pump out the chemicals that cause sickness.

What I find fascinating is that Perry and Younger independently came up with very similar ideas of microglial priming. They came at it from different directions: Perry is the microglia expert in neurodegenerative diseases, Younger is the fibromyalgia expert looking at how core biological processes might explain the illness. When ideas converge like this, it's often a good sign.

[​IMG] [caption]The Microglia Priming hypothesis for fibromyalgia and ME/CFS, © Dr. Jarred Younger. Reproduced with permission.[/caption]As yet, there is no hard evidence of microglial activation in fibromyalgia, but that might be about to change: Younger recently reported that a microglial-activation PET study — similar to the recent one on ME/CFS — is currently under way at Harvard.

However, activation is not the same as priming, and there is currently no way to detect "primed" microglia in living humans. Until there is, there won't really be a way to put this theory to the test. If larger studies show there is consistent activation of microglia, there may well be more attention on the priming hypothesis.

Intriguing treatment possibilities

If microglial activation is a factor in ME/CFS, then it could be treatable — one reason there is so much interest in this line of research.

Perry and Younger pointed to the potential of microglial inhibitor drugs to calm down the overactive cells or prevent activation in the first place. No microglial inhibitors have been proven to treat ME/CFS or fibromyalgia, but Younger has already run an intriguing small study of low-dose naltrexone (LDN) for fibromyalgia with encouraging results.

The exact mechanism for LDN is uncertain, but Younger has pointed to evidence that at the low doses used naltrexone's main role is probably to inhibit activation of microglia. Other drugs have been shown to inhibit microglial activation in animals, but not yet in humans.

This is definitely an area to watch.

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.

[​IMG]

Continue reading the Original Blog Post

Hi Simon,

I find the idea of microglial priming and activation may be the final pathway to cfs/me fascinating. In 2006-7 Dr. Jose Montoya treated a group of patients with Valcye who were diagnosed with cfs/me with some success. He believed that HHV6 or other herpes viruses were causing the disease through chronic ongoing infection. Recently a paper was published by Zhaoging Ding PhD, department of neurology at Stanford entitled " Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuro inflammation." This recent paper would would dovetail very well with the recent theory of microglial priming and activation. This would explain why valcyte has had some success in treating cfs/me even though no infection has been proven. This would also go along with Dr. Lipkin inability to find an infectious agent as a cause for cfs/me. It was also found that acyclovir didn't supress microglial cells. Possibly Valcyte may end up being one of the drugs to treat microglial cell over activation as it primary targets not as a antiviral drug.

Regards,
Gary

Similar studies have been conducted using animal models for quite sometime now. These studies particularly focused on stress induced changes on microglial and consequential release of pro-inflammatory cytokines, mainly IL-1beta.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788324/

It was found in animal models that this response could be blunted by administering Minocycline (anti-inflammatory, commonly used to treat acne). I searched these forums and found a thread form 2010 talking about mixed results using minocycline.

http://forums.phoenixrising.me/index.php?threads/minocyclin.7983/

user9876 June 8, 2014 at 3:13 am
bmoberg337

Similar studies have been conducted using animal models for quite sometime now. These studies particularly focused on stress induced changes on microglial and consequential release of pro-inflammatory cytokines, mainly IL-1beta.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788324/

It was found in animal models that this response could be blunted by administering Minocycline (anti-inflammatory, commonly used to treat acne). I searched these forums and found a thread form 2010 talking about mixed results using minocycline.

http://forums.phoenixrising.me/index.php?threads/minocyclin.7983/

Here is an article talking about the debate over the accuracy animal research and Microglia. They suggest that there are quite a few differences in the way mice microglia bind to different things.

http://phenomena.nationalgeographic.com/2014/04/07/microglia-in-mice-and-men/

Simon June 8, 2014 at 3:22 am
bmoberg337

Similar studies have been conducted using animal models for quite sometime now. These studies particularly focused on stress induced changes on microglial and consequential release of pro-inflammatory cytokines, mainly IL-1beta.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788324/

Thanks, that's very interesting.

For those that want more, this is the study: Acute and Chronic Stress-Induced Disturbances of Microglial Plasticity, Phenotype and Function

The aim of the current review is to critically examine the now substantial literature that has developed around the ability of acute, sub-chronic and chronic stressors to alter microglial structure and function. The vast majority of studies have demonstrated that stress promotes significant structural remodelling of microglia, and can enhance the release of pro-inflammatory cytokines from microglia. Mechanistically, many of these effects appear to be driven by traditional stress-linked signalling molecules, namely corticosterone and norepinephrine. The specific effects of these signalling molecules are, however, complex as they can exert both inhibitory and suppressive effects on microglia depending upon the duration and intensity of exposure.

bmoberg337

It was found in animal models that this response could be blunted by administering Minocycline (anti-inflammatory, commonly used to treat acne). I searched these forums and found a thread form 2010 talking about mixed results using minocycline.

http://forums.phoenixrising.me/index.php?threads/minocyclin.7983/

As @searcher pointed out, the problem is that microglial inhibitors aren't well understood, and usually have other functions too, so it's hard to read too much into results from one inhibitor. I think @Esther12 mentioned similar mixed results with LDN

searcher

I think one problem with definitively determining based on medication response if activated microglia are to blame for specific symptoms is that there aren't currently any medications that solely target microglia. For example, LDN works on opioid receptors in addition to microglia (although the researchers do think it's helping due to its effects on microglia.) Minocycline is an antibiotic and a microglial inhibitor. Ganciclovir is an antiviral that also inhibits microglia. I have had good luck with Reishi, but it has myriad effects throughout the body. I guess one option is that we can triangulate if a wide range of drugs/supplements that reduce microglial activity are also proven to reduce ME/CFS symptoms.

There's a discussion of this issue at http://www.researchgate.net/post/Microglia_and_minocycline that Dr Younger happened to weigh in on.

edit: Here's that comment from Dr Younger:

[​IMG]
Jarred Younger · Stanford University

I do not know of any available agent that selectively suppresses microglia function. There are multiple agents that suppress microglia activity *in addition* to other known effects. Some of those are naltrexone/naloxone, dextromethorphan, 3-hydroxymorphinan, ibudilast, flurocitrate, and pentoxifyline. It is possible that dextro-naltrexone and dextro-naloxone may be more specific to microglia function — check recent work by Linda Watkins, Mark Hutchinson, and their colleagues. I imagine there is more than one pharma group that is currently working on selective microglia inhibitors, so we may see new agents in the next few years.

Leopardtail June 8, 2014 at 3:59 am

It will be interesting to see the results of that study… on microglia

Leopardtail June 8, 2014 at 4:03 am
Leopardtail

It will be interesting to see the results of that study… on microglia

PS Where is part one of this?

MeSci June 8, 2014 at 4:55 am
Leopardtail

PS Where is part one of this?

There's a link to it at the top of the page.

Simon June 8, 2014 at 6:09 am

First, here's a very readable homage to microglia, the subject of this blog
Best Cells Ever – (microglia)

Leopardtail

PS Where is part one of this?

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

user9876

Here is an article talking about the debate over the accuracy animal research and Microglia. They suggest that there are quite a few differences in the way mice microglia bind to different things.

http://phenomena.nationalgeographic.com/2014/04/07/microglia-in-mice-and-men/

Thanks, really interesting stuff: Microglia in Mice and Men

As they point out in the March issue of Trends in Neuroscience, mice and people are separated by 65 million years of evolution, leading to many genetic differences. What’s more, because of pressure from evolving pathogens, “the immune system is a ‘hot-spot’ for evolutionary changes,” the researchers write.

….

The mouse-versus-human question goes way, way beyond microglia. More than 80 percent of drugs that seem promising in mouse models end up failing in clinical trials, as Steve Perrin pointed out in a Nature commentary last month. Perrin’s organization, the ALS Therapy Development Institute, has tested more than 100 compounds in a mouse model of ALS (a motor neuron disease). None of them worked, even those that other research groups had shown to slow disease.

This is an important debate, but it may also be that animal model 'therapies' don't work in humans beccause the original animal work is duff, which is exactly what's argued here (and elsewhere):

Preclinical research: Make mouse studies work : Nature News & Comment
The published data look great – but didn't replicate in animal model testing either:

[​IMG]

osisposis June 8, 2014 at 12:39 pm

FASEB J. 2012 Aug;26(8):3103-17. doi: 10.1096/fj.11-197194. Epub 2012 Apr 19.
Microglia and mast cells: two tracks on the road to neuroinflammation.
Skaper SD1, Giusti P, Facci L.
Author information
Abstract

One of the more important recent advances in neuroscience research is the understanding that there is extensive communication between the immune system and the central nervous system (CNS). Proinflammatory cytokines play a key role in this communication. The emerging realization is that glia and microglia, in particular, (which are the brain's resident macrophages), constitute an important source of inflammatory mediators and may have fundamental roles in CNS disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to proinflammatory signals released from other non-neuronal cells, principally those of immune origin. Mast cells are of particular relevance in this context. These immunity-related cells, while resident in the CNS, are capable of migrating across the blood-spinal cord and blood-brain barriers in situations where the barrier is compromised as a result of CNS pathology. Emerging evidence suggests the possibility of mast cell-glia communications and opens exciting new perspectives for designing therapies to target neuroinflammation by differentially modulating the activation of non-neuronal cells normally controlling neuronal sensitization, both peripherally and centrally. This review aims to provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells, in particular, and the possibility that mast cell-microglia crosstalk may contribute to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerate disease progression, as well as promote pain transmission pathways. We conclude by considering the therapeutic potential of treating systemic inflammation or blockade of signaling pathways from the periphery to the brain in such settings.

http://www.ncbi.nlm.nih.gov/pubmed/22516295

The Mast Cell: A
Cell for All Seasons

Theoharis C. Theoharides, MS, PhD, MD, FAAAAI

http://www.mastcellmaster.com/documents/2014-04/TCT-Research-Overview-3-12-14.pdf

Immunology. 2014 Mar;141(3):314-27. doi: 10.1111/imm.12170.
Mast cells, glia and neuroinflammation: partners in crime?
Skaper SD1, Facci L, Giusti P.
Author information
Abstract

Glia and microglia in particular elaborate pro-inflammatory molecules that play key roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Microglia respond also to pro-inflammatory signals released from other non-neuronal cells, mainly those of immune origin such as mast cells. The latter are found in most tissues, are CNS resident, and traverse the blood-spinal cord and blood-brain barriers when barrier compromise results from CNS pathology. Growing evidence of mast cell-glia communication opens new perspectives for the development of therapies targeting neuroinflammation by differentially modulating activation of non-neuronal cells that normally control neuronal sensitization – both peripherally and centrally. Mast cells and glia possess endogenous homeostatic mechanisms/molecules that can be up-regulated as a result of tissue damage or stimulation of inflammatory responses. Such molecules include the N-acylethanolamine family. One such member, N-palmitoylethanolamine is proposed to have a key role in maintenance of cellular homeostasis in the face of external stressors provoking, for example, inflammation. N-Palmitoylethanolamine has proven efficacious in mast-cell-mediated experimental models of acute and neurogenic inflammation. This review will provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of microglia, neuroimmune interactions involving mast cells and the possibility that mast cell-microglia cross-talk contributes to the exacerbation of acute symptoms of chronic neurodegenerative disease and accelerates disease progression, as well as promoting pain transmission pathways. We will conclude by considering the therapeutic potential of treating systemic inflammation or blockade of signalling pathways from the periphery to the brain in such settings.

http://www.ncbi.nlm.nih.gov/pubmed/24032675

Mast cells in the brain: evidence and functional significance
http://www.sciencedirect.com/science/article/pii/0166223696818637

Mast cells on the mind: new insights and opportunities
http://www.sciencedirect.com/science/article/pii/S0166223613001124

Mast cells, microglia and brain inflammation

http://www.autismfile.com/science-research/mast-cells-microglia-and-brain-inflammation

osisposis June 11, 2014 at 5:26 pm

Leptin, a neuroendocrine mediator of immune responses, inflammation, and sickness behaviors
http://www.sciencedirect.com/science/article/pii/S0018506X12001286

Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287967/

Human mast cells express leptin and leptin receptors.
http://www.ncbi.nlm.nih.gov/pubmed/19241089

Allergy. 2013 Jan;68(1):8-15. doi: 10.1111/all.12043. Epub 2012 Oct 16.
Do mast cells link obesity and asthma?

http://www.ncbi.nlm.nih.gov/pubmed/23066905

Leptin and Mast Cells: A Novel Adipoimmune Link
http://journals.tubitak.gov.tr/medical/issues/sag-01-31-6/sag-31-6-22-0102-7.pdf

osisposis June 15, 2014 at 2:17 pm
Wayne June 25, 2014 at 10:49 pm

Thanks Simon…

Simon June 29, 2014 at 1:29 pm
Simon July 11, 2014 at 5:08 am

A new paper has just been published taking from a rat model that provides support for microglial activation leading to fatigue, as proposed in several of the theories explored in this blog.

In a nutshell, it shows that poly-I:C – which activates the immune system (acts like a super-charged RNA virus), activates microglia long-term, and leads to them producing the cytokine Interleukin-!b. Importantly, their study indicates that Interleukin-1b then acts on astrocytes to trigger fatigue due to over-expression of serotonin transporters.

Simon

Induction of interleukin-1β by activated microglia is a prerequisite for immunologically induced fatigue – Ifuku – 2014
We previously reported* that an intraperitoneal (i.p.) injection of synthetic double-stranded RNA, polyriboinosinic polyribocytidylic acid (poly-I:C), produced prolonged fatigue in rats, which might serve as a model for chronic fatigue syndrome.
[poly-I:C provokes an immune response by mimicking dsRNA viruses.]


We therefore propose that poly-I:C-induced microglial activation, which may be at least partly caused by a direct action of poly-I:C, enhances IL-1β expression. Then, IL-1β induces 5-HTT expression in astrocytes, resulting in the immunologically induced fatigue.

Astrocytes are not neurones, but another type of brain cell that has many important functions, including some immune roles.

alex3619 July 30, 2014 at 4:18 am

I have long been interested in lipopolysaccharide activation of immune responses in ME. I wanted to write a blog on it but my serious blogs are on hold till I improve. LPS has been found elevated in ME patients, though I do not know how reliable the finding is. LPS is a superantigen. It can massively change immune responses. That is because, I think, the immune system reacts to LPS in the blood as though there were a massive bacterial infection. So LPS getting through the gut wall and then the liver detox could easily induce big immune changes on an ongoing basis, and its even possible this is more common after eating … right when leptin levels might change. This is just speculation, but I keep thinking about it.

The microglial theory is looking more and more interesting over time.

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