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Cytokines in the Cerebrospinal Fluids of Patients with CFS/ME

Discussion in 'Latest ME/CFS Research' started by A.B., Mar 3, 2015.

  1. A.B.

    A.B. Senior Member

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    Cytokines in the Cerebrospinal Fluids of Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

    Peterson D., Brenu E.W., Gottschalk G., Ramos S., Ngyuen T., Staines D., Marshall-Gradisnik S.

     
    Last edited: Mar 3, 2015
    adreno, L'engle, melamine and 8 others like this.
  2. Marco

    Marco Grrrrrrr!

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    The reduction in IL10 in CSF is interesting but a bit of a missed opportunity I think to assay for metabolites of neuroinflammation.
     
  3. Scarecrow

    Scarecrow Revolting Peasant

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    The other Hornig et al. paper due to be published soon is expected to show increased IL-10. This is a sample of 60, I think, and as with the plasma study, short and long-duration patients were subgrouped. However,
     
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  4. Never Give Up

    Never Give Up Collecting improvements, until there's a cure.

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  5. A.B.

    A.B. Senior Member

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    I have added them. It's from the Griffith University, Australia.
     
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  6. August59

    August59 Daughters High School Graduation

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    This seems a little concerning to me that cytokine testing of CSF from 2 different labs has different results?

    Could there be this much variance in testing methods? I've always been suspicious of the accuracy of many lab test (I'm referring to high throughput labs though!)

    I suppose the selection criteria could have an impact? The Lipkin CSF study was divided into subsets?
     
  7. nandixon

    nandixon Senior Member

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    The authors of the paper in the original post mention a 2005 study that found increased IL-10 as well:
    Reference 37 is here:
    Spinal Fluid Abnormalities in Patients with Chronic Fatigue Syndrome

    (Fukuda criteria was used for diagnosing CFS in both studies.)
     
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  8. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Lol my doctor said you couldnt test for cytokines, and she has a research project on cytokines. Im confused. Is it correct that cytokines are understudied?

    Very interesting papers btw.
     
  9. greeneagledown

    greeneagledown Senior Member

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    Pretty tiny sample size -- only 5 healthy controls. That's pretty close to an uncontrolled study. The Lipkin study will have a lot more statistical power.
     
  10. Never Give Up

    Never Give Up Collecting improvements, until there's a cure.

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    After seeing the Younger findings of intrapatient Leptin/cytokine/fatigue variability, one would think that every researcher would implement similar design strategies when looking at cytokines, they are transient little things, after all.
     
  11. Snow Leopard

    Snow Leopard Hibernating

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    This study also didn't cover the few extra cytokine/growth factors that I'm currently interested in...
     
  12. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    There are several things missing from this paper that make it difficult to interpret. We are not told how CSF was obtained from 5 healthy people (and why no more). We are not given any data on most of the cytokines and even for the IL-10 we are not give the p value as far as I can see. We are not told about statistical methods, like whether Bonferoni was used.

    For me, interpretation of data like this starts when you have lots of comparator findings to give you a feel for the territory - as a pharmacologist would look for a dose response curve. A single data point is hard to make sense of. As I have mentioned before in the context of the Hornig/Lipkin study, I personally think histograms with error bars are a problem for making use of data like these. I think it should all be done with scatter plots so that we can see population overlap and bimodality and lots more.
     
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  13. deltaforce

    deltaforce

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    Regarding sample size, may be its a pilot study.

    Does anyone find connection with JNK interesting? Anybody using Xeljanz?
    I ask this because from where I see it, even if you inhibit JNK, you would still need to upregulate IL-10, unless IL-10 levels and JNK levels work via a feedback loop. How one can do that? Hence, if anyone is using Xeljanz, one can very roughly extrapolate the idea into, just take Xeljanz or you need more than that.
     
  14. Jon_Tradicionali

    Jon_Tradicionali Alone & Wandering

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    Lipkins finding was right actually.

    Increased il10 is a feature of CFS. It is a mediator of chronic viral infection and EBV, CMV and herpesviruses in general produce il10 mimicking proteins in order to promote chronic persistence. It is a very important part of CFS pathogenesis and one which could yield similar results to that of HepC and HCMV which were shown to be eliminated once it's mediators were inhibited. Il10 is the protein responsible for viral persistence and Tcell exhaustion, which has been shown time and time again in CFS patients. I've absolutely no idea why more focus has not been set on this protein considering it fits the bill in every way possible.
     
  15. halcyon

    halcyon Senior Member

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    But Lipkin and Peterson both found diminished IL-10?
     
  16. Jon_Tradicionali

    Jon_Tradicionali Alone & Wandering

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    "Dr. Lipkin identified increased IL-10"
    http://simmaronresearch.com/2013/09...markers-few-viruses-chronic-fatigue-syndrome/

    "IL-10 and IL-17A secretion was elevated at T2 in comparison to the T1 and T3"
    http://mecfsassist.weebly.com/blog/...s-decreased-immune-function-in-mecfs-patients

    "Compared to healthy individuals, CFS/ME patients displayed significant increases in IL-10"
    http://niceguidelines.blogspot.co.uk/2011/05/immunological-abnormalities-as.html?m=1


    A quick google search yields multiple study results of increased IL-10. Including studies by Lipkin, Peterson and others also.

    Below is a model used to prove this:

    "Elevated levels of systemic IL-10 have been associated with several chronic viral infections, including HCV, EBV, HCMV and LCMV. In the chronic LCMV infection model, both elevated IL-10 and enhanced infection of dendritic cells (DCs) are important for viral persistence.......
    Collectively these data point to enhanced infection of DCs as a key trigger of the IL-10 induction cascade resulting in maintenance of elevated IL-10 expression in CD4 T cells and inhibition of LCMV-specific CD4 and CD8 T cell proliferation."

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090855

    To make things more interesting, rituximab depletes IL-10 producing B cells which explains remission and cessation of rituximab results in rapid repopulation of IL-10 producing B cells, which explains relapse.

    The anti-cancer drug cyclophosphamide being trialed by Fluge/Mella also inhibits IL-10.

    These two cancer drugs both inhibit iL-10 and produce remission in many patients. It is this exact mechanism that I propose produces the remission.
     
  17. nandixon

    nandixon Senior Member

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    That particular blog report turned out to be premature/incorrect, since when the study it's referring to was actually published, the level of IL-10 in cerebrospinal fluid was found to be low.

    Here's the actual published study:
    Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome

    And there's a Phoenix Rising thread about it here:
    CFI Spinal Fluid study from Lipkin and Hornig is out.
     
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  18. halcyon

    halcyon Senior Member

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    I'm not sure what's up with that quote. You can see in the figures from the Lipkin CSF study that IL-10 was diminished compared to controls. I believe there weren't any significant IL-10 differences found in the blood study.

    See above regarding the latest Peterson CSF study, "Results: Of the 27 cytokines examined, only IL-10 was significantly reduced in the CFS/ME patients in comparison to the controls."

    The increase in IL-10 secretion was following mitogenic stimulation. The next sentence states "A significant decrease was observed at T2 in the CFS/ME group for IL-10".

    This study was also done by mitogenically stimulating PBMCs and then measuring the cytokine release. The Lipkin studies were just measuring systemic blood/CSF cytokine concentrations.
     
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  19. Jon_Tradicionali

    Jon_Tradicionali Alone & Wandering

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    Zogor-Ndreaj, Shkodër, Albania
    @nandixon

    I was not aware Lipkin had retracted statements he had made during the CDC conference call.
    It clearly states:

    "However, they did find that patients had elevated levels of the TH-2 type cytokines IL-10 and IL-13 and elevated levels of four TH-1 cytokine: IL-1 beta, TNF-alpha, IL-5, and IL-17. Lipkin said this is compatible with a profile of some particular types of response that may provide insights into immunological dysregulation in Chronic Fatigue Syndrome."

    http://phoenixrising.me/archives/19083

    Original Transcript:
    https://docs.google.com/file/d/0B-NT-7M70igudmZVSVJUTnZVclU/edit?pli=1

    As for the Hornig study you linked, there is no mention of iL-10 at all. It was Petersons study which showed decreased iL-10.

    The inconsistencies in iL-10 detection seem to stark and something I firmly believe deserves a deeper investigation.

    @halcyon

    Below is a statement by Natelson after iL-10 was found to be the only elevated cytokine in a study:

    "Spotlight on IL-10…The fairly consistent finding of increased IL-10 levels in ME/CFS is interesting – no other cytokine is found to be upregulated as frequently. That finding (thankfully) fits with some other immune findings in ME/CFS. Interleukin-10, for instance, down-regulates several parts of the immune system ( Th1 cytokines, MHC class II antigens) that play a role in pathogen detection. Interestingly for the EBV theory of ME/CFS and questions of autoimmune problems IL-10 also enhances B cell survival, proliferation, and antibody production. It also appears to be an important immunoregulator in the intestinal tract. A study in mice has shown that interleukin-10 is also produced by mast cells. An NIH investigator is looking at whether mast cells play a role in CFS."

    http://phoenixrising.me/archives/5223


    Original study:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849324/

    As I noted above to Nadixon, iL-10 findings have been nothing short of varied from study to study. However there does seem to be a correlation of slight increase between majority of studies conducted on CFS iL-10.

    One reason for this variation is provided here:

    "Before exercise, CFS had lower CD40L (p<.05) but similar cytokines versus controls. In subgroups based on SF at 48 h, high SF patients (n=11) increased in IL-1β, IL-12, IL-6, IL-8, IL-10, and IL-13 (p<.05) 8 h post-ex. Low SF patients (n=8) showed post-ex decreases in IL-10, IL-13, and CD40L, and controls decreased in IL-10, CD40L, and TNFα (p<.05). Thus, in CFS, cytokine activity may vary directly with SF, which may explain prior inconsistent findings."

    http://onlinelibrary.wiley.com/enhanced/doi/10.1111/j.1469-8986.2010.00978.x/

    As can be seen from study above^ , cytokine findings depend on WHEN sample was taken and heavily dependant upon SF (Symptom Flare).

    Test cytokines , especially iL-10, in subjects directly after excercice (which initiates symptom flare) and they will show to be quite clearly ELEVATED as this study shows.
     
  20. nandixon

    nandixon Senior Member

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    SOC likes this.

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