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Dr Mady Hornig's Presentation at the P2P. Transcript from the video.

Discussion in 'General ME/CFS News' started by aimossy, Dec 20, 2014.

  1. aimossy

    aimossy Senior Member

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    Transcription of ‘The Role of the Immune System in ME/CFS’: a presentation given by Dr. Mady Hornig at the NIH Pathways to Prevention workshop, ‘Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome’, on December 9, 2014.

    I’ll speak about immune factors in chronic fatigue syndrome.

    We have been thinking about immune-mediated brain disorders as a wide range of disorders that are due to interaction between the brain and the immune system.

    We're very interested in the microbiome in this story and [we’re] thinking about the intestinal microbes that condition the immune system and create metabolites that are neuroactive and that may play an important role in the development of chronic fatigue syndrome.

    We have an enormous number of neuropsychiatric disorders that we consider to be due to brain-immune interactions, at least in a subset, ranging from autism to depression and schizophrenia as well as ME/CFS.

    There is a wide range of infectious factors we have thought of as triggers for this process.

    And so not only gut microbes but also implicated are herpes viruses, including Epstein Barr virus, HHV-6 and a wide range of other viruses.

    Microbes of course are important for normal brain function as well. We know that germ-free mice have abnormal cognition. They don't have normal anxiety responses.

    And so microbes are really critical, so we don’t only think of them as offending agents, but in the context of the symptom complex that we see in chronic fatigue syndrome, we're trying to understand what goes awry.

    The brain-gut axis has many aspects in which it interacts. If I were able to show you my slides, I would be able to show you how dietary products are acted upon by bacteria that are in the gut, and these can create tryptophan, which is the building block for the neurotransmitter serotonin, which is so important in a variety of key functions including sleep, sex drive, your vigilance factors and your ability to maintain your emotional tone.

    Tryptophan can be also broken down further by a variety of agents, including immune factors like interferon gamma. And so tryptophan — which normally will be a building block for serotonin synthesis and also for the circadian rhythm regulator melatonin — tryptophan can be degraded by activation of the immune system or by activation of the stress-response system in the hypothalamic-pituitary-adrenal axis like glucocorticoids.

    And that takes tryptophan down a pathway that has neuroactive and sometimes neurotoxic compounds that are regulating mood, regulating thought processes as well as regulating memory, and we believe that the tryptophan degradation that is activated by both stress factors — glucocorticoid stress hormones — but also by immune factors and pro-inflammatory cytokines may play a very important role in the activation of the biochemical changes that we see in ME/CFS.

    The lining of the intestines is flooded and studded with bacteria that condition our immune system.

    In animal models we know there are certain bacteria, called segmented filamentous bacteria or SFB bacteria, that are pro-inflammatory and increase cells called TH-17 cells that are involved in autoimmune and inflammatory disorders like rheumatoid arthritis as well as other...and probably implicated in other pain syndromes such as fibromyalgia, which of course we know overlaps with chronic fatigue syndrome.

    Similarly, other bacteria — the absence of these bacteria — seems to allow the increase of the types of t-cells that quiet down the inflammatory process, the t-regulatory cells that are beneficial and are able to reduce autoimmune and inflammatory responses.

    So here [indicates slide] we are able to see the segmented filamentous bacteria that increase the TH-17 cells, increase IL-17 production.

    So we have been thinking about a model wherein the microbes condition a wide range of factors that include oxidative stress factors, cystine production that is related to your mitochondrial pathways. In these pathways, one alters the redox status. If you have a severe shift in redox status you will cause oxidative stress.

    And this will alter your genetic regulation, turn certain genes on and off and lead to the production of inflammatory molecules and reduce t-reg cells that may lead to the alteration in the production of autoantibodies.

    Some of these autoantibodies, when we're looking at this process in the intestine, the autoantibodies that are produced may be to receptors that are present in the intestine that are there for your absorption of dietary products such as folate, as well as vitamin D receptors.

    We know that auto-immunity is altered by intestinal microbes in association with genetic factors, and these can be both beneficial in protection against autoimmune disease, such as in the SJL mouse in the EAE models — encephalomyelitis model — as well as causing suppression in autoimmune disease models with use of a particular probiotic agent.

    We also know that microbes may play a different role in the induction of autoantibodies that may mimic brain proteins, and there are many studies now that have suggested there may be an autoimmune process that contributes at least to a subset of ME/CFS.

    An example would be with H1N1 haemoglutenin; one sees that there are conserved parts in the sequence of the virus itself that are shared by certain brain proteins, and so this is a model for the possible production of autoantibodies that may be involved in regulation of fatigue, particularly mental fatigue and cognitive processes.

    We know that certain microbes are producers of short-chain fatty acids that are anti-inflammatory like the butyrate producers here [indicates slide], and when you have a reduction in butyrate producers one often will see classical autoimmune diseases being increased, like Type 1 diabetes, whereas you have an autoimmune scenario that may be induced by other short-chain fatty acids such as acetate and propionate that lead to a leaky gut and a greater production of TH-17 cells and autoimmune phenomena.

    Probiotics can influence this scenario; we have seen it in animal models, where giving Lactobacillus johnsonii will increase tryptophan production both in the intestine and the ileum — the small intestine — as well as in the peripheral blood and the serum.

    And one can also see this even in human studies where probiotics can prevent encephalopathic reactions in individuals with cirrhosis, and you can reduce the probability of development of this brain dysfunction by the use of probiotics that alter the commensal bacteria and alter the serotinergic and tryptophan metabolites in the blood.

    Our studies have been wide-ranging. We have many collaborators in the audience here today, working with the Chronic Fatigue Initiative, which is five centers of excellence for chronic-fatigue care with 200 cases, 200 controls with a follow-up study that has just been completed in sample collection with some microbiome samples as well as plasma and PBMC samples for a variety of gene expression studies as well as longitudinal immune studies in 50 cases and 50 controls who had participated in the initial cohort study.

    The earlier NIH study — 150 cases and controls — we are currently planning a follow-up and hoping to follow up and we have other studies that we have been doing, including a spinal fluid study, an immune analysis which I will show you some data for.

    Our approach has been to take a wide look at all of the triggers of immune dysfunction through a staged strategy that includes molecular analyses, looking at the bacterium as well as doing classical pathogen-discovery with high-throughput sequencing but also screening results.

    We also look carefully at host responses and try to integrate what pathogens we might find, and looking at immune markers, doing RNA seq and gene expression, also looking at autoantibodies that may tell us something about autoimmune diseases that may be triggered by shared conserved sequences, as I showed with the H1N1 scenario; also anti-pathogen antibodies as well as proteomics and metabalomics.

    Our studies for looking for pathogens that may be a trigger started with those agents that clinicians in our working group for ME/CFS had identified as being ones that may be involved, and so we created multi-presentation techniques looking at these agents, and we found very little in serum but it may be that these agents are cell-associated.

    So we are now looking at peripheral blood mononuclear cells but here we see that there area only two free in serum: two HHV-6 and one parvovirus B19.

    Similarly, in a study using Dr. Jose Montoya’s samples, we found very little to suggest that there’s a specific pathogen involved in chronic fatigue syndrome, although we did find some increase in annelloviruses, which are very small and very ubiquitous viruses but you can see it was actually a much higher rate in controls than in cases.

    Again, sort of like the commensal bacteria which may play an important role in calming down our immune systems, perhaps certain viruses are important as commensal agents that are controlling the immune response and that perhaps their presence is a healthy presence, keeping other pathogens from leading to a strong inflammatory response.

    Also, we're also pursuing HHV-6 studies using peripheral blood mononuclear cells.

    What we have really been seeking, though, are aspects of host response that may be more generic and more general, that may be independent of a specific infectious trigger or may occur with certain classes of triggers, and we are looking at a wide range of cytokines and chemokines that we know have a role in brain function and that interact with our stress response — the hypothalamic-pituitary-adrenal axis.

    ...[have removed reference to results that have been submitted for publication]

    So we're trying to understand the nature of these differences, and the central nervous system and the peripheral regulation.

    -------------------------------------------------------------------------

    Here is the video. Dr Hornig's presentation starts at 146 minutes into the video.
    http://videocast.nih.gov/summary.asp?Live=14727&bhcp=1
     
    Last edited: Dec 22, 2014
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  2. duncan

    duncan Senior Member

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    Did she just characterize ME/CFS as a neuropsychiatric disorder?

    She prefaced the majority of her presentation with a statement that clear as day lumps ME/CFS with schizophrenia and DEPRESSION.

    Everything else she had to say was background noise. That characterization will have colored everything else she addressed.
     
    Last edited: Dec 20, 2014
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  3. aimossy

    aimossy Senior Member

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  4. duncan

    duncan Senior Member

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    Neuropsychiatry in part combines neurology and psychiatry. It is the integrated study of neurologic and psychiatric disorders. The last thing we need at a critical gathering such is this is to associate ME/CFS with psychiatric disorders. She does precisely that with the neuropsychiatric label, and she does it when she groups us with schizophrenia and depression.
     
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  5. Bob

    Bob

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    I think that Dr Hornig specialises in investigating organic illnesses and conditions in the field that she calls "neuropsychiatry". For example, she studies the biomedical causes of autism and PANDAS both of which I think she classifies as neuropsychiatric. She doesn't use the term to suggest that any of these illnesses or conditions have a psychological cause, but she investigates their biomedical underpinnings. I guess she sees ME/CFS as having a similar biomedical basis as autism and PANDAS. i.e. it's an immune-related illness that has a neurological impact.
     
    Last edited: Dec 21, 2014
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  6. duncan

    duncan Senior Member

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    With all due respect, Bob, I admire your insights, but here I fear you are splitting hairs, or being too kind. I think anyone within earshot will take away the same connotations - if not denotations - I did.

    They will hear psychiatric and depression and schizophrenia, and that connection will be made in their brains, and it will impact their interpretation of what ME/CFS is. THAT is what matters - not whether she tries to reveal their biological underpinnings. Does she try to reveal the biological underpinnings of brain cancer? No. She explores those underpinnings as they relate back to psychiatric disorders. Some will in all likelihood interpret her as saying ME/CFS is a psychiatric disorder, and she is busy sleuthing away to figure out its organic nature. Good for her; not so good for us.
     
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  7. Bob

    Bob

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    I'm not defending her terminology. I'm just attempting to give some background or context to it. Perhaps you could write to her with your concerns about her categorisation of ME/CFS. You might find her receptive. Judging from her research program and presentations, I'm pretty sure that Dr Hornig believes that ME is an immunological illness, with neurological effects. I believe that she really is on our side, and doing some serious heavy-duty immunological research.
     
    Last edited: Dec 20, 2014
  8. aimossy

    aimossy Senior Member

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    'Neuropsychiatric' is a broad brush terminology that covers many illnesses in the field of brain pathophysiology. I would rather these researchers be working on our case than be splitting hairs over this terminology even if it is unfortunate archaic medical terminology. They are doing great scientific work on our illness which they believe is Neuroimmune and biomedical. Show some respect to people with Schizophrenia and Depression and illnesses like PANDAS, Autism, MS, Brain Injury - acquired and traumatic, Alzheimer's and Dementia etc who all get lumped under the Neuropsychiatric umbrella.
     
    Last edited: Dec 20, 2014
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  9. duncan

    duncan Senior Member

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    aimossy, please do not presume to know who I have, or do not have, respect for.

    It is not the point anyway, is it?

    The point is whether Mady Horning just characterized ME/CFS as a psychiatric disorder to the audience at the P2P. If she did, then I personally believe this may have colored the perception of what constitutes ME/CFS in an inaccurate manner - and at a time and place where definitional precision is being scrutinized. That is bad.

    We are fighting - every day - for recognition, for acknowledgement of the physical nature of our disease, of its neurological and immunological origins. Every inch of progress we claim is hard fought. We've been engaged in this struggle for decades. It is not getting any easier.

    If one of our "champions" creates a soundbite that the pyschobabblers can carry like a torch to the Olympics, our cause potentially gets blindsided, and our struggle could grow only more difficult.
     
    Last edited: Dec 21, 2014
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  10. Snow Leopard

    Snow Leopard Hibernating

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    I agree, it is guilt by association, without having compelling evidence. I strongly respect the work that Dr Hornig is doing, but this kind of language is unfortunate.
     
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  11. biophile

    biophile Places I'd rather be.

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    "Psychiatry is the medical specialty devoted to the study, diagnosis, treatment, and prevention of mental disorders. These include various affective, behavioural, cognitive and perceptual abnormalities." (http://en.wikipedia.org/wiki/Psychiatry) "Neuropsychiatry is a branch of medicine that deals with mental disorders attributable to diseases of the nervous system." (http://en.wikipedia.org/wiki/Neuropsychiatry)

    Schizophrenia and depression primarily affect the functional aspect of our brain which we label the "mind". Can we say the same for ME/CFS? Obviously any dichotomy between mind and brain can be problematic and bring up complicated issues, but the above is simply not said for classic neurological diseases which affect nerve function. We do not say Parkinson's disease and multiple sclerosis primarily affect what we label the mind. CBT/GET psychobabble aside, is ME/CFS really mostly about "affective, behavioural, cognitive and perceptual abnormalities"?

    I don't have a problem with the term "neuropsychiatry" for specific symptoms if the nature of those symptoms and the underlying pathology suggest it, but I'm not convinced it should be used to generalize ME/CFS. What is "neuropsychiatric" about orthostatic intolerance and post-exertional symptoms, for example? After looking at the range of symptoms and pathophysiology presented in the ICC, should we accept that these symptoms are a "mental disorder", albeit "attributable to diseases of the nervous system"? I doubt it. It starts getting complicated when trying to assess exactly where in the hierarchy of the nervous system and supporting biological systems the pathology of ME/CFS is most relevant. Do we know enough about the pathophysiology of ME/CFS to make such an assessment?

    The ICC describes ME as being a "Profound dysfunction/dysregulation of the neurological control system results in faulty communication and interaction between the CNS and major body systems, notably the immune and endocrine systems, dysfunction of cellular energy metabolism and ion transport, and cardiac impairments."
     
    Last edited: Dec 21, 2014
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  12. Sasha

    Sasha Fine, thank you

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    I'm no biomedical genius but the thing that caught my attention here was Dr H's references to tryptophan. I seem to remember being prescribed tryptophan as a supplement by an ME specialist about 20 years ago for sleep (?) and it not making any difference. I don't recall people on the forums talking about tryptophan - maybe it's out of fashion.

    I can't tell whether what Dr. Hornig is saying has implications for supplemental tryptophan as anything useful. Can anyone comment?
     
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  13. duncan

    duncan Senior Member

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    This is an intriguing discussion to have, and I think it would be interesting to engage in it. biophile, I think I agree with you in that ME/CFS - like Parkinson's and MS etc - could have neuropsychiatric symptoms or components, but that - like Parkinsons and MS- it is not a neuropsychiatric disorder (if I have understood you correctly).

    But, again, the merit of this topic as fodder for debate is not the issue, at least not for me. The issue as I see it is whether Mady Hornig left the impression ME/CFS is a psychiatric disorder at an important gathering that could weigh heavily on how ME/CFS is defined and perceived going forward. That was neither the time nor the place imo to run equivocal on such a profoundly important subject - although I don't really think she was equivocal; she sounded pretty sure of her wording to me.

    Everything she said after that little characterization gets drowned out for me due to the potential implications of that statement, as I fear it may for some of the P2P audience as well.
     
    Last edited: Dec 21, 2014
  14. Sasha

    Sasha Fine, thank you

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    Then why not do as Bob suggests, @duncan?

     
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  15. duncan

    duncan Senior Member

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    Hi Sasha. Because what I say to Mady Hornig in an email or phone conversation, and what she says to me, is done privately. It is not done at a public gathering. It is not done at a pivotal meeting whose convening is designed to qualify the future of ME/CFS. And it will not undo what she said to the audience.
     
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  16. ukxmrv

    ukxmrv Senior Member

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    It does seem to still come up in threads on neurotransmitters

    I think that there was a paper on tryptophan sometime this year. Maybe from the Netherlands? I'll have a look and see if I can find.

    http://www.biomedcentral.com/content/pdf/1756-0500-7-650.pdf
     
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  17. Sasha

    Sasha Fine, thank you

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    But if you object to her terminology, don't you want to put your view to her before her next public presentation when she might do it again? She does a lot for us and speaks at other conferences.

    If you were a scientist working hard doing your best possible biomedical research for a group of severely neglected patients, wouldn't you want to hear from them if they thought you were using terminology that wasn't helpful?

    I think you're missing a chance to do something constructive with your criticism.
     
  18. duncan

    duncan Senior Member

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    You mean she doesn't read this forum?

    I'm just messing with you. :)

    I exchange emails a lot with researchers. It only goes so far. I've sent some off to Columbia peeps in particular. You have no idea how many exchanges I have had with the NIH.

    Most of the time, I feel like a commercial - I am perceived as selling something and get tuned out. Worse, I get fed pablum.

    So, eh, I'm not eager to run that course again, thank you very much, especially with a neuropsych.
     
  19. Sasha

    Sasha Fine, thank you

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    Well I think I'll leave it there with you, Duncan. :)
     
  20. Bob

    Bob

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    I've recently come across some forum discussions about serotonin and tryptophan supplementation. As far as I recall no one said that they had seen any significant improvements in ME symptoms after taking tryptophan, but I think some people were using it to help mood and sleep issues.

    Yes, I got the feeling that she might be thinking along those lines, as something worth looking into, but I'm not hopeful that simple tryptophan supplementation will be at all helpful for ME, because it's easy to get hold of it online and I'm certain that we'd know about it by now if it were to have a significant impact on symptoms.

    I'm not aware of any published research re tryptophan metabolism in ME: There may perhaps be issues re tryptophan metabolism in ME, perhaps along with many other metabolic issues, but I think the remedy will have to be more sophisticated than supplementation with an off-the-shelf supplement.

    BTW, Mady Hornig is doing loads of research into ME, and the tryptophan metabolic pathway if just one aspect of it.
     
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