Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
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New review in Brain, Behavior and Immunity

Discussion in 'Latest ME/CFS Research' started by kaffiend, Dec 15, 2011.

  1. kaffiend

    kaffiend Senior Member

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    This is a not yet hot off the press (Jan 2012) review to appear in the journal Brain, Behavior and Immunity. It might be the best review on ME/CFS I've seen. I've pasted the abstract and conclusion/summary below. You'll note that the paper uses the term CFS and not ME. The distinction is important and your anger is shared but let's talk about something else. :D


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    Chronic fatigue syndrome, the immune system and viral infection
    A.S. Bansala, A.S. Bradleya, K.N. Bishopb, S. Kiani-Alikhanc, B. Forda

    a Dept. of Immunology, Epsom and St. Helier University Hospitals NHS Trust, Carshalton, Surrey, SM5 1AA and Chronic Illness Research Team, Stratford Campus, University of East London, London E15 4LZ, UK
    b Division of Virology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK
    c Dept. of Immunology, Kings College Hospital, Denmark Hill London, UK
    Received 8 April 2011; revised 14 June 2011; Accepted 28 June 2011. Available online 2 July 2011.

    Abstract
    The chronic fatigue syndrome (CFS), as defined by recent criteria, is a heterogeneous disorder with a common set of symptoms that often either follows a viral infection or a period of stress. Despite many years of intense investigation there is little consensus on the presence, nature and degree of immune dysfunction in this condition. However, slightly increased parameters of inflammation and pro-inflammatory cytokines such as interleukin (IL) 1, IL6 and tumour necrosis factor (TNF) ? are likely present. Additionally, impaired natural killer cell function appears evident. Alterations in T cell numbers have been described by some and not others. While the prevalence of positive serology for the common herpes viruses appears no different from healthy controls, there is some evidence of viral persistence and inadequate containment of viral replication. The ability of certain herpes viruses to impair the development of T cell memory may explain this viral persistence and the continuation of symptoms. New therapies based on this understanding are more likely to produce benefit than current methods.


    Summary
    There are major challenges in the analysis of immune function in a condition as heterogenous as CFS where the cause is unknown. Add to this the marked variability in symptom severity from day to day and from hour to hour and there is bound to be variation in the levels of proteins such as cytokines that have short half lives. Further complications are evident in the analysis of immune cells which can vary in number depending on time of day and even mild exertion. Moreover, it is now established that stress and sleep disturbance, which are common in CFS, can alter immune function. Couple this with the fragile nature of most cytokines demanding immediate blood separation and the marked variation in assay sensitivity and reproducibility and it is easy to understand why there is little consensus in the literature on the exact immune dysfunction in CFS. Nevertheless the CFS literature taken as a whole suggests mildly raised circulating pro-inflammatory cytokines and a skewing towards impaired cellular immunity. More work is needed to take into account the level of stress and sleep disturbance amongst the study population and to correlate the immune function with the patients perception of how severe their symptoms were at the time of immune analysis. Most importantly of all more longitudinal studies investigating immune function with changes in the severity of CFS symptoms are urgently needed. It is likely that viral infection(s) and immune dysfunction in CFS interact in a manner which perpetuates the conditions necessary for maintaining symptoms. Fig. 1 summarises the interplay between the important variables. It is likely that an initial viral infection or stress acting singly or in combination leads to a state of impaired cellular immunity, immune memory dysfunction and disturbed NK cell activity. This promotes reactivation of previously acquired EBV or related virus infection and wide dissemination of the original viral infection. EBV and other viral proteins stimulate the release of pro-inflammatory cytokines which contribute to fatigue, low grade fever, aching, disturbance of sleep and inactivity. The severity and prolonged nature of these symptoms encourages further stress leading to continued immune paresis and production of immune dysregulating viral proteins. The latter then perpetuate the immune dysfunction with continuation of symptoms. In view of the significant interaction between each of these areas, treatments targeting several areas simultaneously are more likely to be successful than those used selectively in one area.
     
  2. merylg

    merylg Senior Member

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    Hi kaffiend,

    Quite impressive, considering...and except for the last waffley statement!!! (Spellchecker didn't like waffley or even waffly...maybe it's another one of our Australian idioms!) To the writers:
    Don't beat around the bush or give us bulldust! :cool:

    meryl
     
  3. kaffiend

    kaffiend Senior Member

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    This type of broad language is common for discussion/summaries at the end of journal articles. I take it to mean that the symptoms (caused by viral proteins and immune activation) promote inactivity and stress and a vicious cycle between the two. Treatments targeting only one area (inactivity and stress) will be less successful than those that also target the immune dysfunction. The paper details a treatment algorithm for patient subsets based on the type of immune dysfunction.
     
  4. alex3619

    alex3619 Senior Member

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    This paper (and I have only read the abstract) summarizes the cytokine issues as an elevated background rate of cytokines. This misses the point. CCC CFS has a mild background rate, yes, but typically has massive cytokine and immune spikes (cytokine storms) - not slight elevation, but massive. This is associated with PENE. Research that does not take this into account is flawed. They might have discussed this in the main article, but I have not read it yet. Bye, Alex
     
    ahimsa likes this.
  5. kaffiend

    kaffiend Senior Member

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    I don't think the cytokine storm evidence exists in the literature. This might be due to flawed studies or varying methods for immunoassay but a review can only review the existing literature. Off the top of my head, I don't think the Light study showed dramatic increases in inflammatory cytokines, but rather alpha and beta adrenoreceptors. Measuring blood (rather than CSF) might miss it, or perhaps the CNS is overly sensitized to normal peripheral inflammatory signals, producing an exaggerated cascade in the brain. I can send the paper as a message if you'd like.
     
    Tony Mach likes this.
  6. Tony Mach

    Tony Mach Show me the evidence.

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    Upper Palatinate, Bavaria
  7. alex3619

    alex3619 Senior Member

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    Hi, I have gone back and done a little more research on this, this is info I keep forgetting:


    http://www.co-cure.org/Light.pdf

    Please look at figure 4.

    This is a substantive increase in specific cytokines. Many other cytokines were not tracked. I expect to see other differences appear over time as more cytokines are tracked. This is also only in 1. mild patients and 2. moderate exercise stress.

    However, I do take the point that the UK researchers may not consider the increases sufficient to be interesting - its only about two fold here. On the other hand, they do need to be aware that its post exercise increases that are more interesting than background levels.

    It is also unclear what patients were selected in the UK study. If they use Oxford, and don't further categorize in separate groups ICC ME or CCC CFS, the study has limited relevance. I will say more when I have read the paper.

    You might also like to see this:

    http://www.ncbi.nlm.nih.gov/pubmed/20230500


    Also this:

    http://www.ncbi.nlm.nih.gov/pubmed/22110941

    The free pdf for this is at:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200121/pdf/PRT2012-427869.pdf

    The coloured figure in this last is very intersting, its a composite of all the markers they are tracking. The adrenergic beta-1 shows the highest increase, but the green bars are the immune markers. After the beta-1 starts declining, alpha-2a is still increasing out to two days.

    It is worth noting that MS has a similar profile. The FMS and comorbid CFS show bigger immune increases than CFS alone.

    In my view it is absolutely critical in cytokine research in ME to be looking at post exercise cytokines.

    I am about to read the full Bansal et. al. paper, I may have more to say later.

    Bye
    Alex
     
  8. alex3619

    alex3619 Senior Member

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    This paper seems to be putting forward a model of CFS in which non-activity is included as a driving stressor, but not exercise.It is a nice source of much of the cytokine research but none of the Light papers are mentioned.

    It was received April 2011. Some of the Lights research was published several years prior.

    On the plus side they are careful to use research from CCC and Fukuda papers, which is good. Their model also attempts to link the NK dysfunction to other factors, another plus. They also pay a lot of attention to viruses.

    There is also a section on immune and viral therapy, which is nice to see.

    However there is a clear biopsychosocial link here ... and again I note the post exercise cytokine research is conspicously absent. Please note I am not trying to say they are biased - instead I suspect editing, reviewing and funding bias might be driving them this way, not necessarily from the journal in question, but overall as they tried to get funding and publish. It would be nice to find out what the history of funding and publication advice was.

    An alternative is of course that they are trying to create a greatest fit model. I disagree with the way they did this, but that is just my opinion. Their modelling certainly does fit a lot of the data together, which means its at least worth of consideration.

    I think if this paper were being developed in Australia or the USA it would be sufficiently different that I would really like the paper. The UK is very hostile to biomedical research on this topic.

    Bye
    Alex
     
  9. Nielk

    Nielk

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    I would be interested in that paper too, Kaffiend.
     
  10. kaffiend

    kaffiend Senior Member

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    That's a good point that I overlooked. The schematic should include physical and mental exertion and perhaps even say routine physical and mental exertion. I refrain from using the word exercise because I still appear to be an athletic person and many people just assumed I was overdoing it when I tried to explain the reactions I was having to normal levels physical activity.

    Hopefully this review will serve as a turning point. It's the first place I've seen Lerner's results cited and also any sort of treatment algorithm put forward that didn't highlight GET and CBT.
     
  11. Marco

    Marco Grrrrrrr!

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    Near Cognac, France

    If inactivity plays any role then it obviously plays no role in onset unless they are seperating the state of 'CFS' from a triggering or persistent infection. As a mainataining factor it can only apply to a sub-set as many of us have worked full or part time for many years and even now that I can't work I am still more physically active than when an office worker. I wonder do they believe we have a horde of carers to take care of the housework; shopping; paperwork; gardening etc. OK, it could be argued that 'inactivity' might apply to the 25% severely affected who are bed bound but its highly unlikely that the research reviewed included many who were unable to leave home to be tested.

    I suspect 'inactivity' is another assumption that may bear little resemblance to reality for the majority of patients. Again there is also the assumption that any 'fatigue' is largely physical whereas cognitive fatigue I would suggest is at least as important and unlikely to be subject to 'deconditioning'.

    I agree that the missing factor in their model is the abnormal intolerance for and reaction to often minimal cognitive or physical effort. This needs to be routinely built into any study of immune response.
     

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