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A neuro-immune model of ME/CFS.

Discussion in 'Latest ME/CFS Research' started by asleep, Jun 22, 2012.

  1. Bob

    Bob

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    I think many of us following the HGRV research wanted to see it fully researched and fully resolved, but XMRV has now got to the situation where we have to continue to fully explore all other likely disease explanations if we are to move forward. Rituximab couldn't have come at a better time, in my opinion, and it helpfully builds on all of the existing immunology (and auto-immune-related) ME research that has been carried out for years.
    merylg, justy and George like this.
  2. Jenny

    Jenny Senior Member

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    Unfortunately, there are dozens of theories and models that attempt to explain ME!

    Jenny
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  3. Mula

    Mula Senior Member

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    There has never been another explanatory model published.
  4. Bob

    Bob

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    Are you sure about that Mula?
  5. Mula

    Mula Senior Member

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    I am in no doubt.
  6. jeffrez

    jeffrez Senior Member

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    Sure there has been, including Marty Pall's model of oxidative stress from nitric oxide radicals. His stuff came out almost a decade ago, I believe. We also have theoretical models involving HPAA dysregulation, immune involvement (post-viral syndrome, etc.), mitochondrial damage and/or dysfunction, and whether we like it or not, psychogenic models. Rich van K. on this forum has a fairly robust and detailed explanatory model involving glutathione depletion and the methylation cycle. I'm not aware that's published anywhere, but it probably wouldn't take much to have it typed up and submitted to med hypotheses.
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  7. jeffrez

    jeffrez Senior Member

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    E.g.:

    Ann N Y Acad Sci. 2001 Mar;933:323-9.
    Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and posttraumatic stress disorder.

    Pall ML, Satterlee JD.
    Source

    School of Molecular Biosciences, Washington State University, Pullman 99164-4660, USA. martin_pall@wsu.edu
    Abstract

    Various types of evidence implicate nitric oxide and an oxidant, possibly peroxynitrite, in MCS and chemical intolerance (CI). The positive feedback loops proposed earlier for CFS may explain the chronic nature of MCS (CI) as well as several of its other reported properties. These observations raise the possibility that this proposed elevated nitric oxide/peroxynitrite mechanism may be the mechanism of a new disease paradigm, answering the question raised by Miller earlier: "Are we on the threshold of a new theory of disease?"
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  8. Mula

    Mula Senior Member

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    Those are observations which are also raised in stress and don't explain the disease. There is no detailed explanation of how those levels are first elevated, and they don't deal with PEM, exercise intolerance, the remitting relapsing nature, autoimmunity, NK cells, CD69, TNF alpha. The paper from Pal is not near to reaching the status of a model.
  9. jeffrez

    jeffrez Senior Member

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    Well, that's merely your opinion (and a largely unfounded one, b/c peroxynitrite elevation and feedback loops are given as explanations for PEM, as well as mitochondrial energy studies using the ATP profile test). But your statement that there aren't other published models is simply false, as the med hypothesis paper shows. There are also published theoretical models dealing with HPAA dysregulation from Ben-Zvi et al.
  10. Sam Carter

    Sam Carter Guest

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    Med Hypotheses. 2011 Jul;77(1):77-83. Epub 2011 Apr 6.

    Chronic fatigue syndrome--a neuroimmunological model.

    Arnett SV, Alleva LM, Korossy-Horwood R, Clark IA.

    Abstract

    The aetiological and pathophysiological basis of chronic fatigue syndrome (CFS) remains a controversial field of inquiry in the research community. While CFS and similar disease conditions such as fibromyalgia (FM) and post-infectious encephalopathy have been the focus of intense scrutiny for the past 20 years, results of research were often contradictory and a cohesive pathological model has remained elusive. However, recent developments in understanding the unique immunophysiology of the brain may provide important clues for the development of a truly comprehensive explanation of the pathology of CFS. We argue that CFS pathogenesis lies in the influence of peripheral inflammatory events on the brain and the unique immunophysiology of the central nervous system. There is also evidence that CFS patients have a relative immunodeficiency that predisposes to poor early control of infection that leads to chronic inflammatory responses to infectious insults. The neurological and endocrine changes have been described in CFS patients support the view that CFS has an inflammatory pathogenesis when considered as a whole. An inflammatory model of disease also provides an explanation for the marked female sex bias associated with CFS. This review therefore posits the hypothesis that CFS as a disease of long-term inflammatory processes of the brain. We will also provide an investigative framework that could be used to justify the use of anti-TNF biological agents as a reliable and effective treatment approach to CFS, a syndrome that to date remains frustratingly difficult for both patients and health care professionals to manage.

    Z Med J. 2005 Dec 16;118(1227):U1780.

    Aetiology and pathogenesis of chronic fatigue syndrome: a review.

    Mihrshahi R, Beirman R.

    Abstract

    Chronic fatigue syndrome (CFS) is a debilitating disease of uncertain aetiology that is characterised by unexplained, severe fatigue associated with a number of typical symptoms. This paper reviews the scientific literature related to current theories about the aetiology and pathogenesis of CFS by focussing on what appear to be the four most significant aspects in the development and perpetuation of this disease: the role of infectious agents as well as immunological, neuroendocrine, and psychiatric factors. A multifactorial model for the aetiology of CFS, which includes and draws together these four aspects, is proposed; and suggestions are offered regarding approaches to the diagnosis and treatment of this disease.
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  11. Sam Carter

    Sam Carter Guest

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    J Affect Disord. 2012 Feb;136(3):933-9. Epub 2011 Oct 4.

    Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin.

    Maes M, Twisk FN, Kubera M, Ringel K.

    Maes Clinics @ TRIA, Bangkok, Thailand. dr.michaelmaes@hotmail.com
    Abstract

    BACKGROUND:

    There is evidence that inflammatory pathways and cell-mediated immunity (CMI) play an important role in the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Activation of inflammatory and CMI pathways, including increased levels of cytokines, is known to induce fatigue and somatic symptoms. Given the broad spectrum inflammatory state in ME/CFS, the aim of this study was to examine whether inflammatory and CMI biomarkers are increased in individuals with ME/CFS.
    METHODS:

    In this study we therefore measured plasma interleukin-(IL)1, tumor necrosis factor (TNF)α, and PMN-elastase, and serum neopterin and lysozyme in 107 patients with ME/CFS, 37 patients with chronic fatigue (CF), and 20 normal controls. The severity of ME/CFS was measured with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.
    RESULTS:

    Serum IL-1, TNFα, neopterin and lysozyme are significantly higher in patients with ME/CFS than in controls and CF patients. Plasma PMN-elastase is significantly higher in patients with ME/CFS than in controls and CF patients and higher in the latter than in controls. Increased IL-1 and TNFα are significantly correlated with fatigue, sadness, autonomic symptoms, and a flu-like malaise; neopterin is correlated with fatigue, autonomic symptoms, and a flu-like malaise; and increased PMN-elastase is correlated with concentration difficulties, failing memory and a subjective experience of infection.
    CONCLUSIONS:

    The findings show that ME/CFS is characterized by low-grade inflammation and activation of CMI. The results suggest that characteristic symptoms of ME/CFS, such as fatigue, autonomic symptoms and a flu-like malaise, may be caused by inflammatory mediators, e.g. IL-1 and TNFα.
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  12. Mula

    Mula Senior Member

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    It is not my opinion. Pal's paper and Ben-Zvi do not give an explanatory model of disease. A model would not explain in isolation one small part of a disease. There is no explanation for increased nitrosative and oxidative stress in those papers. They don't explain the symptoms using that observation.


    Arnett is also unable to explain PEM, excercise intolerance, mitochondrial dysfunction, raised proinflammatory cytokines, HPA axis hypoactivity and they only refer to purigenic receptors in the brain.

    Mihrshahi and Beirman is unable to explain mitochondrial dysfunction, HPA axis hypoactivity, excercise intolerance, autoimmunity, autonomic symptoms, pain. They also refers to psychiatric factors. It is a review of an existing theory but not a model of disease.

    The Maes, Twisk, Kubera, Ringel paper details chronic immune activation. It is unable to explain the symtoms or other various biomedical abnormalities.

    A model would account mechanistically for all symptoms and biomedical abnormalities as the paper in Metabolic brain disease does.
    jace likes this.
  13. jeffrez

    jeffrez Senior Member

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    Martin Pall's theory in fact proposes multiple causative factors as initiators of the peroxynitrite loop:

    Dysregulated cortisol patterns and HPAA function has been proposed as a mechanism of many disorders, including CFS and even depression. Just because we might not know the exact cause of the dysregulation doesn't mean that those theories don't exist.

    Knock yourself out arguing if you want, but the basic fact is that there isn't really anything new in this latest paper. It looks like a good effort to link disparate processes into a comprehensive model, but the components really aren't all that new.
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  14. Enid

    Enid Senior Member

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    Thanks for your thoughts/input everyone - let's hope all the current research findings are taken into account in forming any "model". This looks good to me - no psycho mumbo at last, but then that is the point here. I may be wrong but think Prof Maes was also a psychiatrist firmly opposed in the light of pathology findings now to all their claptrap. (and over some years). Three cheers.
  15. justy

    justy Senior Member

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    Do we know when the full paper is to be published - will it be freely available?
    Really considering showing this paper to my GP - i've never shown him anything before, but feel this might be a good one to get on his desk.
    All the best, Justy
  16. Countrygirl

    Countrygirl Senior Member

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    Justy, the paper is available on the other main forum, if you belong to it, or on People with ME. I have a copy and could e-mail it to you, if you would like to give me your e-mail address.

    Warm wishes,

    C.G.
  17. justy

    justy Senior Member

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    Thanks CG - i will look for it there - if not will let you know my e mail:)
  18. George

    George waitin' fer rabbits

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    I think the main difference between this hypothesis paper and many of the ones that have come before it is a lack of "bias". I know that Gerwyn has researched every corner of this illness thoroughly. While his bias is or was towards the retroviral model because it fit every symptom beautifully; he knows far more than just that area of research. However, in co authoring this paper he left his bias behind. Rather, this paper looks at all the research over the last decade and pulls together the different pieces without prejudice in to a picture that fits the facts as a patient lives and experiences them.

    What so many former hypothesis paper have done is to promote a bias of one area of research over another. Instead of a true concurrent combination of all areas of research, most papers tend to promote the authors belief that if "everyone would just go down this road here" the answer would magically appear and the author would be vindicated, in his or her bias. (big grins) So in that respect alone this is one of the better hypothesis that has been written. It has some slight bias in that there are areas that need extended research while other areas have been more thoroughly studied and so have more papers to back that area over another.

    All in all I though it a nice win for the patients!
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  19. richvank

    richvank Senior Member

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    Hi, all.

    This sounds like a very interesting model, though I haven't seen the full paper yet. Sounds like they do include oxidative stress, and I'm glad to see that.

    As noted, my hypothesis has not yet been published, but those who are interested in finding out about it can view a fairly recent detailed discussion of it here in a Swedish seminar from last October (the slides are available by clicking on the blue print below the video):

    http://iaomt.media.fnf.nu/2/skovde_2011_me_kroniskt_trotthetssyndrom/${weburl}

    I do plan to submit it for publication in the future, after a few more loose ends are tied up.

    Since this Swedish seminar, I have added a couple of things. One is that some research in Korea last year quantitatively ties down the link between glutathione depletion and the functional B12 deficiency, so I think that cause and effect is more solid now. The other is that Marty Pall convinced me that the reason methylfolate drops in the blood, rather than rising, is that peroxynitrite catabolizes some of it. That removed the puzzle of why the methyl trap mechanism did not cause it to rise. At this point, I think it's a pretty tight cause and effect sequence, and I think it does account for the published research as well as patient experience with ME/CFS. Also, the treatment based on this model has provided benefit to many PWMEs. It remains to deal with the pathogens and toxins.

    As far as the autoimmune aspect goes, my view is that the presence of low levels of several autoimmune antibodies does not provide evidence that ME/CFS is an autoimmune disease. Rather, I suggest that the oxidative stress causes a lot of damage to cells, and the immune system is working to clean up the resulting debris. In the process, it produces some antibodies that have an autoimmune character.

    Best regards,

    Rich
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  20. Enid

    Enid Senior Member

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    Thanks Rich - I particularly like your observation "cause and effect". Precisely as one experiences as symptoms reveal themselves so to speak too.

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