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Biomarkers in CFS: Natural Killer function (Fletcher/Klimas 2010)

Discussion in 'Latest ME/CFS Research' started by oceanblue, Jun 22, 2011.

  1. oceanblue

    oceanblue Senior Member

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    This appears to be the most robust evidence to date of a biological abnormality in CFS. The findings have been mentioned on several threads I thought but the research itself deserved discussion on its own thread.

    Biomarkers in Chronic Fatigue Syndrome: Evaluation of Natural Killer Cell Function and Dipeptidyl Peptidase IV/CD26

    Bottom line: this very large study (n=176 patients) shows a clear biological difference between CFS patients and controls. Natural Killer Cells of CFS patients, on average, show a very marked reduction in the ability to kill target cells compared with controls: only 12% of target cells were killed by CFS patients NK cells compared with 28% for controls. This confirms earlier, smaller studies by the same authors and has since been independently confirmed by another group in 2011.
  2. oceanblue

    oceanblue Senior Member

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    Abstract (Full abstract, bit heavy going in places)

    Background
    Chronic Fatigue Syndrome (CFS) studies from our laboratory and others described decreased natural killer cell cytotoxicity (NKCC) and elevated proportion of lymphocytes expressing the activation marker, dipeptidyl peptidase IV (DPPIV) also known as CD26. However, neither these assays nor other laboratory tests are widely accepted for the diagnosis or prognosis of CFS. This study sought to determine if NKCC or DPPIV/CD26 have diagnostic accuracy for CFS.

    Methods/Results
    Subjects included female and male CFS cases and healthy controls. NK cell function was measured with a bioassay... Analysis by receiver operating characteristic (ROC) curve assessed biomarker potential. Cytotoxic function of NK cells for 176 CFS subjects was significantly lower than in the 230 controls. According to ROC analysis, NKCC was a good predictor of CFS status... Analyses by ROC curves indicated that all three measurements of DPPIV/CD26 demonstrated potential as biomarkers for CFS. None of the DPPIV/C26 assays were significantly correlated with NKCC.

    Conclusions
    By ROC analysis, NKCC and three methods of measuring DPPIV/C26 examined in this study had potential as biomarkers for CFS... Abnormalities in DPPIV/CD26 and in NK cell function have particular relevance to the possible role of infection in the initiation and/or the persistence of CFS.

    Cort has written a short review of the study (see "Natural Killer Cells and a Biomarker?" heading)
  3. oceanblue

    oceanblue Senior Member

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    For me the key findings are the reduction in Natural Killer Cell Cytotoxicity (NKCC) rather than the weaker findings about DPIV/CD26. The difference in NKCC levels is large: 28% for controls vs only 12% for CFS patients, and highly significant with a stated "p=0.000" (which I assume means p<0.0005).

    However, its not, unfortunately, as simple as All CFS patients have much lower NKCC than controls. What complicates things is that theres a lot of variation in the NKCC levels of both controls and patients, with a substantial overlap between the two. (For instance, although patients on average have much lower NKCC levels, a quarter of them scored above 21% while a quarter of controls had NKCC below the same level)

    Not really a biomarker
    Unfortunately the data in their paper suggests NKCC would not be a clinically useful biomarker. According to Leonard Jason a test needs an AUC threshold of between 90-100% to have diagnostic meaning, and 95% or above to be considered a good diagnostic tool. The NK Cell Cytotoxicity test had an AUC of 0.776 (77.6%) so on this basis would not make a good diagnostic tool. This isnt surprising given the overlap in NKCC levels between patients and controls discussed above.

    One slight cause for concern is that none of the assays for DPPIV/C26 (the other proposed biomarker, see next post) were significantly correlated with NKCC. If both NKCC and DPPIV/CD26 were really measuring underlying CFS-ness you would expect there to be a strong correlation between the two. This suggests that at least one of the two is not really measuring CFS-ness.

    It's also worth noting that - as is the case in ANY study of biomarkers for CFS - the comparison with healthy controls isn't that helpful. Even an idiot like me could walk into a room of healthy controls and CFS patients and separate the CFS from the healthy with, I modestly suspect, pretty close to 100% accuracy using just a couple of questions. (The situation is different for something like HIV, where there may be no obvious signs of an illness.) What would be altogether more useful would be to distinguish between chronic fatigue of many different causes and ME/CFS itself and that would be an interesting next step, building on these findings.

    Biological significance of reduced NKCC levels in CFS patients
    Assuming the authors really have nailed a clear biological difference between CFS patients and controls, what does it mean? Is it just a helpful association or does this factor help explain the illness itself?

    A smaller study from 2006 indicated that patients with poor NKCC were more impaired, indicating the NKCC levels may be directly relevant to the illness rather than just being associated with it. This current study is continuting to collect data over 18 months which should throw more light on the situation.
    The authors also suggest that the reduced NKCC activity found in the current study indicates reduced innate immunity and a possilbe switch from Th1 to Th2-type, or humeral immunity.

    Although the precise significance of reduced NKCC levels is not yet clear, I think it is itself enormously important that the authors have pinned down a clear biological abnormality that has been reproduced both by their own group and others.
  4. oceanblue

    oceanblue Senior Member

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    Dipeptidyl Peptidase IV/CD26 findings

    The other finding of the study concerns Dipeptidyl Peptidase IV, also known as CD26, an enzyme expressed on the surface of many cell types that acts on many different types of molecules. Its physiological functions are largely unknown, though it has been implicated in immune regulation, signal transduction and apoptosis.

    The study measured CD26 levels in 3 different ways and all 3 correlated to some extent with CFS status. However, evaluated by ROC analysis, all 3 were found to be weaker biomarkers than NKCC, with AUC of between 0.65 and 0.75. This is rather modest. Note that this work was carried out on only a subset of patients (75/176) and controls (100/230).

    The only other study that has found CD26 differences between CFS and controls is one by the same authors 20 years previously, so these finding await independent replication.
  5. Dolphin

    Dolphin Senior Member

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  6. oceanblue

    oceanblue Senior Member

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    Sorry, don't know how I missed that. I did look quite hard to find any earlier threads but I've given up on the forum search as I find it misses so much usually, so do a site search on google instead (which did find several other PR threads mentioning this study) - clearly didn't work properly on this occasion!

    Nonetheless, there wasn't a lot of discussion on the original thread (which admittedly I must have ignored myself at the time) and I still feel this study deserves more attention than it has yet received.
  7. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    I think klimas is also working with bond uni in australia on their cfs nk function study where they are finding dysfunction in nk bright cells(which i think is the study in the links?). I heard a rumor recently that the bond uni people were going over to the USA to talk things over with dr dan peterson, maybe also klimas as well. I know the idea behind the australian cfs study is to design a test for cfs, maybe peterson could then use this test and treat these patients with ampligen. for every test they try to have a treatment i guess??????????????

    cheers!!!
  8. Dolphin

    Dolphin Senior Member

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    Ok. I found it using "dppiv"

    I like this sub-forum because of people like you and your serious analyses/critiques of papers having read the full paper. On some forums, papers that didn't come out in the very recent past might be considered old news but I certainly don't agree with that. Especially as probably nobody here (unless Ellen Goudsmit reads it?) read all the papers as they came out over the last 25 years; a lot of us are reading older papers and if you/we have something interesting to say, I want to hear it. So I have no problem with it being discussed now; just with more than one thread, it can get messy and people can feel they have to repeat themselves; also moderators/admins are too busy/whatever to merge threads these days I think.
  9. oceanblue

    oceanblue Senior Member

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    Exercise challenge testing underway too?

    I'd already pointed out that this study is continuting to collect data over 18 months which should throw more light on the situation:
    However, it appears that they are also doing exercise testing too, according to Mary Ann Fletcher's SOK presentation, covered by the Research1st website:

  10. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    oceanblue, are they also group the nk cells into bright and dim cells like the australian cfs study? It looks really interesting how they are also incorporating exercise testing as well.

    cheers!!!
  11. oceanblue

    oceanblue Senior Member

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    Not as far as I know.

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