1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
Hunting down the cause of ME/CFS & other challenging disorders - Lipkin in London
In a talk to patients in London on 3rd September, Dr. W. Ian Lipkin described the extraordinary lengths he and his team are prepared to go to in order to track down the source of an illness, with examples ranging from autism to the strange case of Kawasaki disease.
Discuss the article on the Forums.

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

Discussion in 'Phoenix Rising Articles' started by Simon, Jun 1, 2014.

  1. Simon

    Simon

    Messages:
    1,451
    Likes:
    4,635
    Monmouth, UK
    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.
    [​IMG] 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 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
    [​IMG] 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.

    [​IMG] 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] 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]
    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:



    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
     
    Last edited: Jun 2, 2014
    alex3619, merylg, Esther12 and 9 others like this.
  2. Firestormm

    Firestormm Guest

    Messages:
    5,824
    Likes:
    5,976
    Cornwall England
    Nice piccie of the microglia :)

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

    Thanks.
     
  3. Butydoc

    Butydoc President

    Messages:
    95
    Likes:
    298
    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
     
    NK17, rosie26, SOC and 2 others like this.
  4. aimossy

    aimossy Senior Member

    Messages:
    2,425
    Likes:
    3,072
    NZ
    Thank you Simon, for both articles, complicated = explained!
     
    Simon, Firestormm and rosie26 like this.
  5. rosie26

    rosie26 Senior Member

    Messages:
    1,048
    Likes:
    1,318
    NZ
    Really interesting! Thanks.
     
    Simon, aimossy and Firestormm like this.
  6. Firestormm

    Firestormm Guest

    Messages:
    5,824
    Likes:
    5,976
    Cornwall England
    @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?

    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 :)
     
    Simon and aimossy like this.
  7. rosie26

    rosie26 Senior Member

    Messages:
    1,048
    Likes:
    1,318
    NZ
    How would the Problem that we may have with our B cells fit in with this I wonder ? (as in Rituximab).
     
    aimossy likes this.
  8. Firestormm

    Firestormm Guest

    Messages:
    5,824
    Likes:
    5,976
    Cornwall England
    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
     
    Last edited: Jun 2, 2014
    aimossy and rosie26 like this.
  9. Marco

    Marco Old blackguard

    Messages:
    1,326
    Likes:
    1,010
    Near Cognac, France
    "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.
     
    voner likes this.
  10. searcher

    searcher

    Messages:
    495
    Likes:
    1,241
    SF Bay Area
    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.
     
    Last edited: Jun 2, 2014
    NK17, MeSci, Firestormm and 2 others like this.
  11. Gijs

    Gijs Senior Member

    Messages:
    139
    Likes:
    132
    I don't believe microglial is the (only) cause for ME. It is much more complicated.
     
    Firestormm likes this.
  12. Marco

    Marco Old blackguard

    Messages:
    1,326
    Likes:
    1,010
    Near Cognac, France
    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.
     
  13. lansbergen

    lansbergen Senior Member

    Messages:
    1,096
    Likes:
    538
    I would if there was a test.
     
  14. Simon

    Simon

    Messages:
    1,451
    Likes:
    4,635
    Monmouth, UK
    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.
    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.

    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.

    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.

    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.

    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.
     
    Last edited: Jun 2, 2014
    NK17, searcher, rosie26 and 3 others like this.
  15. Eliza

    Eliza

    Messages:
    11
    Likes:
    29
    Belgium
    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?
     
    NK17 likes this.
  16. Nielk

    Nielk

    Messages:
    5,271
    Likes:
    5,267
    Queens, NY
    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'?
     
    NK17, aimossy and Simon like this.
  17. shannah

    shannah Senior Member

    Messages:
    847
    Likes:
    178

    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.
     
  18. Simon

    Simon

    Messages:
    1,451
    Likes:
    4,635
    Monmouth, UK
    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 :)
     
    aimossy and Nielk like this.
  19. Marco

    Marco Old blackguard

    Messages:
    1,326
    Likes:
    1,010
    Near Cognac, France
    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).
     
  20. cigana

    cigana Senior Member

    Messages:
    617
    Likes:
    206
    UK
    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
     
    NK17 and searcher like this.

See more popular forum discussions.

Share This Page