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Immune-induced model of CFS - Interleukin-1 in brain may trigger fatigue (2014)

Discussion in 'Latest ME/CFS Research' started by Simon, Jul 11, 2014.

  1. Simon

    Simon

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    I recently blogged about theories that an initial immune problem could lead to in appropriate long-term activation of microglia (the brain's immune cells) and many of the symptoms of ME/CFS :Brain Cells Making us Sick? Messed up microglia could be driving symptoms This new paper is supporting evidence from a rat model:

    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.

    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.]

    The poly-I:C-induced fatigue was associated with serotonin transporter (5-HTT) overexpression in the prefrontal cortex (PFC), a brain region that has been suggested to be critical for fatigue sensation.

    In the present study, we demonstrated that microglial activation in the PFC was important for poly-I:C-induced fatigue in rats, as pretreatment with minocycline, an inhibitor of microglial activation, prevented the decrease in running wheel activity.

    Poly-I:C injection increased the microglial interleukin (IL)-1β expression in the PFC. An intracerebroventricular (i.c.v.) [ie into the brain] injection of IL-1β neutralising antibody limited the poly-I:C-induced decrease in activity, whereas IL-1β (i.c.v.) reduced the activity in a dose-dependent manner.

    5-HTT expression was enhanced by IL-1β in primary cultured astrocytes but not in microglia. Poly-I:C injection (i.p.) caused an increase in 5-HTT expression in astrocytes in the PFC of the rat, which was inhibited by pretreatment with minocycline (i.p.) and rat recombinant IL-1 receptor antagonist (i.c.v.).

    Poly-I:C injection (i.p.) led to a breakdown of the blood–brain barrier and enhanced Toll-like receptor 3 signaling in the brain. Furthermore, direct application of poly-I:C enhanced IL-1β expression in primary microglia.
    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.

    *Microglial Activation in Immunologically Induced Fatigue - 2013
    credit: paper posted on co-cure by Tate Mitchell
    Last edited: Jul 11, 2014
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  2. Firestormm

    Firestormm Guest

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    Thanks @Simon and nice to see you posting again :)

    Now then. This above refers to Interleukin B, but how or is it relevant to Interleukin A and perhaps this study from the MRC and Carmine Pariente: http://forums.phoenixrising.me/inde...nt-fatigue-induced-by-interferon-alpha.13799/

    What I mean to say is do the two Interleukin's - and their association with fatigue-induced symptoms - mean either could be responsible or be involved, and if not, then in what way do the two differ.

    Ha!

    Danke :)
    merylg likes this.
  3. Simon

    Simon

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    Good Q. It's actually interleukin-1beta in this study, Pariente's is using intereferon-alpha which is a different cytokine. However, both are cytokines that can induce fatigue. The Pariente approach has the advantage of looking at humans, and what makes it particularly interesting is that it looks at fatigue that develops after the IFN-a treatment. However, the Pariente study is putting a lot of emphasis on psychosocial indicators, and it isn't yet clear how in-depth it will examine biological factors. Also, rat models allow you to at what's happening in particular brain cells - though that's bad news for the rats.
    Last edited: Jul 11, 2014
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  4. Marco

    Marco Old blackguard

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    @Firestormm

    Excerpts only but see pages 225 and 228 re Poly IC induction of IL1-b; IFN-a and the effects on NK cell activity.

    Fatigue Science for Human Health
    edited by Y. Watanabe, B. Evengard, B.H. Natelson, L.A. Jason, H. Kuratsune

    http://books.google.co.uk/books?id=...UQ6AEwAA#v=onepage&q=5-HTT astrocytes&f=false

    I'd be interested to know if the mildly elevated pro-inflammatory cytokines (low grade inflammation inc IL1_b; IL6 and TNF-a) frequently found in PBMCs might be brain derived rather than a peripheral driver of glial activation.
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  5. IreneF

    IreneF Senior Member

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    Interesting but unconvincing, as much as I could understand it, since we don't know how those rats felt (were they depressed? were they fatigued? did they have upset stomachs?); we now have good evidence that cytokines and their ilk vary depending on the stage of the illness; and if 1/3 of CFS patients were able to return to work after taking an SSRI, it indicates that their illness was depression and not CFS.

    They may have elucidated part of the mechanism of sickness behavior.
  6. natasa778

    natasa778 Senior Member

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    Not necessarily. I wouldn't jump to that conclusion. SSRI may well be doing more than 'just' lifting depression. I have seen SSRIs - as well as 5-htp and tryptophan - improve various symptoms and conditions in people who were not even depressed to start with. Not trying to 'sell' the idea of taking them or anything :) just to say it is totally wrong imo to automatically equate SSRI effects with presence of depression (as in phycho/mental health issue)
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  7. IreneF

    IreneF Senior Member

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    SSRIs may be used for conditions other than depression, but one of the diagnostic issues of CFS is distinguishing it from depression; the fact that *so many* patients allegedly improved on Luvox tells me that the diagnostic criteria used by the author failed to distinguish between the two disorders. Also, I don't think anyone with what we have has ever improved with SSRIs. Correct me if I'm wrong.
  8. SOC

    SOC Moderator and Senior Member

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    Some ME symptoms might improve with an SSRI. A cure from only using an SSRI should mean a misdiagnosis. MDD is an exclusionary condition for ME if treatment for depression relieves all symptoms, which is what appears to have happened in this case.
    Bob likes this.

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