Severe ME Day of Understanding and Remembrance: Aug. 8, 2017
Determined to paper the Internet with articles about ME, Jody Smith brings some additional focus to Severe Myalgic Encephalomyelitis Day of Understanding and Remembrance on Aug. 8, 2017 ...
Discuss the article on the Forums.

Dysregulation of cytokine pathways in CFS and MS

Discussion in 'Latest ME/CFS Research' started by Sea, Jun 7, 2017.

  1. Sea

    Sea Senior Member

    Messages:
    1,270
    Likes:
    2,652
    NSW Australia
  2. AdamS

    AdamS Senior Member

    Messages:
    263
    Likes:
    766
    Full text is behind a paywall. Would be interesting to know a bit more about the model & specific cytokines. I wonder how this compares to other studies on cytokines in ME.
     
  3. voner

    voner Senior Member

    Messages:
    547
    Likes:
    857
    @AdamS, the full paper can be downloaded from http://sci-hub.ac

    enter the doi citation....often just the title works
     
    AdamS likes this.
  4. ljimbo423

    ljimbo423 Senior Member

    Messages:
    535
    Likes:
    827
    United States, New Hampshire
  5. Murph

    Murph :)

    Messages:
    533
    Likes:
    2,711
    Here are some of the graphics from the paper, showing network associations after stimulation with
    phytohaemagglutinin (PHA) and phorbol-12-myristate- 13-acetate (PMA)

    It is, obviously, very obvious what these pictures clearly imply. [sarcasm over].
    Screen Shot 2017-06-08 at 10.52.42 AM.png Screen Shot 2017-06-08 at 10.52.31 AM.png Screen Shot 2017-06-08 at 10.52.20 AM.png

    Here's what Jason and his crew say:

    ... a two-factor neighborhood model for CFS subjects suggests a more defined cytokine relationship and a stronger association among cytokines. It is interesting to note that PBMC cytokine production from CFS subjects is strongly characterized as a Th2 phenotype as well as a pro-inflammatory phenotype. The pro-inflammatory pheno- type is connected with IL10 in an attempt to reduce the inflammatory phenotype. IFN and IL12 are connected normally and a Th1 pathway is apparently unaffected by the disease. The IL4, IL5, and IL13 connective phenotype is consistent with the Th2 phenotype and this association is also unaffected by the disease. Alternatively, this Th2 phenotype may serve to counteract Th1 cytokines consistent with an anti-inflammatory phenotype augmented by increased production of cellular growth factors and a neurotrophic protein (BDNF).


    These findings imply that CFS is characterized by a pattern of global immunologic acti- vation in a differential pattern than seen in MS or healthy control subjects. The connec- tivity between IFN and IL12 is as expected, while there is also connectivity between IL4, IL5, and IL13 in a manner consistent with either a Th2 or alternatively an anti-inflammatory response.

    While a finding of a pro- and anti-inflammatory cytokine grouping would not be unexpected, finding such associations within one neighborhood implies an ineffective compensatory response. That is, the anti-inflammatory protein production is increasedin an attempt to mitigate pro-inflammatory production, but the attempt appears ineffec- tive. This pattern of cytokine production provides evidence for a unique immunologic response in those with CFS, with the differential neighborhood association highlighting dissimilarity between MS and CFS.
     
    Last edited: Jun 7, 2017
    rosie26, ukxmrv, Sancar and 7 others like this.
  6. Murph

    Murph :)

    Messages:
    533
    Likes:
    2,711
    It occurs to me that it matters whether the PMBCs were tested in or out of the patients' serum.

    I've read the methods section and I can't tell but maybe someone can:

    Peripheral blood was drawn into lithium citrate tubes and processed within six to eight hours of sample procurement. All samples were collected and processed by the same clini- cal laboratory. Plasma samples were obtained from blood collection tubes which were spun for 20 minutes at 1000×g, and plasma aliquots were pipetted directly from each tube with phosphate buffered saline used for volume replacement. Afterward, heparinized peripheral blood was overlaid onto Ficoll/Hypaque and then centrifuged at 1000×g for 20 min. Cells at the interface were washed with Hank’s Balanced Salt Solution (HBSS) and enumerated with a standard hemocytometer.


    PBMCs (1 × 106) were cultured in RPMI 1640 plus 10% fetal bovine serum (sup- plemented with glutamine, penicillin, streptomycin), with (stimulated) and without (constitutive) a mixture of phytohaemagglutinin (PHA) and phorbol-12-myristate- 13-acetate (PMA) (PMA @ 20 ng/well; PHA @ 0.05%/well) in 24 well plates for 48 hours at 370°C. After 48 hours, aliquots of supernatant fluid were collected and stored (–70°C) until analyzed. The following cytokines were evaluated using a mul- tiple analyte platform (BioPlex) and commercially available kits from BioRad (Bio- Plex Human Cytokine 17-plex): G-CSF, GM-CSF, IFN-γ, IL1β, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12 (p70), IL13, IL17, MCP-1(MCAF), MIP-1β, and TNF-α. BDNF levels were determined using commercially available kits purchased from R&D Systems (Minneapolis, MN).
     
    merylg, Sancar and AdamS like this.
  7. ash0787

    ash0787 Senior Member

    Messages:
    301
    Likes:
    580
    looks convincing to me, " characterized by a pattern of global immunologic activation " thats what I've been saying, there seems to be no other explanation for the sudden feelings of heat, rituximab responders, disproportionate instability in the system introduced by pathogens / allergens and localized muscle and joint problems ? why can I drift a car with no problems and then a week later get acute muscle inflammation that feels like an ankle sprain within about half an hour of driving casually ?

    I think maybe severe patients never leave this heightened immune state, but I think theres something else at play which is also contributing, but I can't put my finger on it ... there was a certain point though last year where my muscles worked normally and then a month later everytime I try to walk I only get like 50 metres before the lactic acid becomes overwhelming, irrespective of how much energy I have / lack of symptoms.
     
    merylg, ukxmrv and ljimbo423 like this.
  8. Hutan

    Hutan Senior Member

    Messages:
    1,069
    Likes:
    6,431
    New Zealand
    The authors are clear that this is a pilot study; they know the CFS sample size is small.

    I don't understand the various treatments/stimulation. Hopefully that all makes sense to someone who knows about cytokines.

    I haven't seen any paper that evaluates CFS samples against the idea proposed by Lipkin and Hornig, that cytokines vary with the length of the CFS disease i.e. that the immune response initially fires and then burns itself out after maybe three years. This paper doesn't either (although perhaps the already small size made any further subdivision impossible).

    But why has no one supported or negated that theory? If it was my data, I'd certainly be dividing the samples into short and long duration CFS and seeing if I could see a similar pattern. If there really is a major change over time, it would mean that any cytokine patterns found in a sample of mixed disease length would mean nothing.
     
    ljimbo423, ScottTriGuy and Murph like this.
  9. AdamS

    AdamS Senior Member

    Messages:
    263
    Likes:
    766
    One very high level observation is that when compared to stimulated/unstimulated controls, the strength of cytokine relationships and number of positive relationships seems to be much increased in CFS/ME patients. You can see this from the thickness/colour of the connecting lines in the images.

    I'm reading this as chronic (global?) immune activation and I think that the authors are trying to say that the illness may not be tied to one protein but rather could be mediated by immune pathway dysregulation.

    I wonder if this is the cause of the energy problem or if it is being caused by something else? I also wonder what would happen if we blasted/inhibited some of these cytokines/receptors such as IL-6/IL-8. We need more treatment studies ASAP!

    IMG_1525.JPG
     
    ukxmrv, Sancar, Cheesus and 5 others like this.
  10. AdamS

    AdamS Senior Member

    Messages:
    263
    Likes:
    766
    Also...

    It's clear that some cytokines have many more lines/connections in ME/CFS than in controls.

    For example:

    IL- 6 has 2 lines in unstimulated controls.

    But it has 9 correlative lines in unstimulated ME/CFS patients. These lines are also quite wide indicating high strength correlation.

    Perhaps this is why we have an anecdotal report of tocilizumab helping someone on PR here.

    Tagging @Jesse2233 as this may be of interest.
     
    Jesse2233, Sancar, ljimbo423 and 4 others like this.
  11. ash0787

    ash0787 Senior Member

    Messages:
    301
    Likes:
    580
    priority should be making sure there is nothing wrong with the muscle cells themselves as to cause such a response from the immune system, before going into a wild goose chase into the immune system which is known to be complicated. The debilitation is so severe in some cases while the immune activation not obvious that its hard to believe that it can all be coming solely from a misconfigured immune system, so I think its important to look for some sort of DNA methylation problem or mitochrondrial DNA mutation or what not ( though I think the OMF team has that aspect covered from what I understand ). I guess it depends on how good the rituximab trial results are though, which again is unknown as of yet.
     
  12. Janice Hargreaves

    Janice Hargreaves

    Messages:
    57
    Likes:
    172
    UK
     
    Murph likes this.
  13. ljimbo423

    ljimbo423 Senior Member

    Messages:
    535
    Likes:
    827
    United States, New Hampshire
    I've been struggling this this same question. Immune system activation can cause fatigue, brain fog, aches and pains etc, just like when someone has the flu or bronchitis. The research on mito dysfunction is also very convincing. I think the primary cause of symptoms are one or both of these things.

    I have been bouncing back and forth between the two. First thinking it's immune system dysfunction, then mito dysfunction. Now I'm starting to think it's both of them working together that causes most symptoms. I do think it's the immune system dysfunction though, that is causing the mito dysfunction, because the oxidative stress it causes.

    As @ash0787 says in his post above though, poor methylation could also be causing symptoms. Again, I think the impaired methylation though, is a downstream effect from the oxidative stress caused by a dysfunctional immune system.
     
    Manganus, GreyOwl, Sancar and 2 others like this.
  14. alicec

    alicec Senior Member

    Messages:
    1,422
    Likes:
    2,725
    Australia
    They were tested without patients' serum.

    The PBMCs were isolated from blood, washed then cultured in medium containing fetal bovine serum (a typical culture medium) with or without stimulants.

    They do describe collection of plasma samples from the patients but don't report using them in this study - perhaps they were collected for another study.
     
    ukxmrv, Hutan and Murph like this.
  15. Murph

    Murph :)

    Messages:
    533
    Likes:
    2,711
    This seems like bad news, if Davis' finding is true, that cells only misbehave in patient's serum.
     
    ukxmrv, Hutan and ljimbo423 like this.
  16. RogerBlack

    RogerBlack Senior Member

    Messages:
    891
    Likes:
    2,890
    It seems not that simple.
    There is research (forgive me, I'm blanking) on energy production differing in cells not in patients serum, in an almost opposite way, implying that it may be a compensatory mechanism gone wrong.

    A 'serum' paper would be great.
    Find a patient (or ten) with severe PEM at times. Do a battery of tests on them, and obtain samples of serum from when they're well, and when they're ~1h after exercise (when any hypothetical fatigue factor would be present), and when in PEM.

    Now, see what 'well', 'PEM', "post-exercise" serum do to the energy metabolism in cells from the patient and healthy controls.
     
    Janice Hargreaves and Murph like this.
  17. Silence

    Silence

    Messages:
    82
    Likes:
    75
    Northern CA
    I ran across this paper a few weeks ago and I think it might be related. I just can't be certain- My brain is basically mashed potatoes. For those interested, have a look:

    Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics
    Gerwyn Morris[​IMG]1,2 and Michael Maes2,3


    /https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847236/
     
  18. AdamS

    AdamS Senior Member

    Messages:
    263
    Likes:
    766
    I didn't realise ME was so closely related to MS (well at least according to this paper). Kinda scary...I wonder if MS treatments could be repurposed/would be helpful to us.
     
    Last edited: Jun 10, 2017
    Silence and Sancar like this.
  19. rosie26

    rosie26 Senior Member

    Messages:
    2,409
    Likes:
    5,145
    Priceless. Still chuckling when I think of it. No disrespect to this research just my own difficulty in understanding these diagrams.
     
    Murph likes this.
  20. wastwater

    wastwater Senior Member

    Messages:
    961
    Likes:
    657
    uk
    Can't we get in under MS other
     

See more popular forum discussions.

Share This Page