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NEID Disease? Study Suggests Neuro, Endocrine and Immune Systems Work Together to Produce ME/CFS

Bruun Wyller continues to surprise. When last heard from this erstwhile cognitive behavioral therapy (CBT) proponent asserted that more research into Epstein-Barr virus in chronic fatigue syndrome (ME/CFS) was needed. Now he’s looking at the interaction between the immune and endocrine systems.

The Evolution of a Chronic Fatigue Syndrome (ME/CFS) Researcher? CBT Proponent Calls for More Herpesvirus Research

Transforming growth factor beta (TGF-β) in adolescent chronic fatigue syndrome Vegard Bruun Wyller1,2*, Chinh Bkrong Nguyen1, Judith Anita Ludviksen3,4 and Tom Eirik Mollnes. J Transl Med (2017) 15:245 https://doi.org/10.1186/s12967-017-1350-

Wyller begins his new study reporting that systemic inflammation is probably present and B-cell functioning is impaired (if modestly) in ME/CFS, but that the picture regarding cytokines is muddier. A meta-analysis of 38 ME/CFS cytokine studies examining 77 cytokines found only one standout – a cytokine called TGF-B. It was consistently elevated in 2/3rds of the studies.

cytokines chronic fatigue syndrome

Only one cytokine has more or less consistently shown up elevated in ME/CFS studies – TGF-B

Given its unusual and consistent appearance in cytokine study results, why TGF-B has gotten so little attention in ME/CFS is unclear. The fact that it’s kind of a weird cytokine probably doesn’t help. Secreted by macrophages and some other immune cells, TGF-B can function as both an anti and pro-inflammatory cytokine depending on the situation it’s in.

It’s three forms are involved in a multitude of regulatory processes involving inflammation and immunity.  It does more than participate in the immune system; TGF-B also affects or is affected by the two stress response systems in our bodies – the HPA axis and autonomic nervous system. All that makes TGF-B a complex character indeed.

Take our two stress response systems. During stressful situations increased TGF-B levels appear to be associated with increased levels of cortisol – the main stress hormone of the HPA axis.  An ME/CFS study examining the gene expression of immune cells found an abnormally high expression of genes that interact with the HPA axis and autonomic nervous system. That suggested that a significant immune-hormone component is present. Indeed, ME/CFS has long been characterized as a neuroendocrineimmune (NEID) – a disease that effects all three systems.

In this study Wyller, a Norwegian researcher, again used his own broad definition of ME/CFS to find patients, but this time he did post hoc analyses using the Fukuda and Canadian Consensus criteria to determine if different definitions of ME/CFS made a difference – they didn’t). As always, Wyller studied adolescents – a lot of them (n=120) and 68 controls to produce a very nice sized study. The data analysis took a long time; the data itself was collected from 2010-2012.

TGF-B actually comes in three forms ((TGF‑β1, TGF‑β2 and TGF‑β3). For the first time ever in ME/CFS Wyller tested for all three forms of TGF-B, as well as norepinephrine, epinephrine and cortisol (urine) and c-reactive protein (serum).   He also assessed heart rate variability, and in 29 patients examined their whole blood gene expression.  Questionnaires assessing fatigue, inflammatory symptoms, post-exertional malaise, sleep, mood and anxiety were also given.

Results

Wyller expected TGF-B levels to be higher in his adolescent ME/CFS patients, but to his surprise even using the CCC and Fukuda criterias, they were not. Nor was TGF-B associated with any clinical markers such as fatigue, PEM, sleep problems, etc.

cortisol

Wyller suggests an unusual neuroimmune connection involving TGF-beta and stress hormones such as cortisol (pictured) may be present

The study was looking like a bust until Wyller dug a little deeper. It turned out that TGF-B levels were associated with increased levels of the stress hormones cortisol, norepinephrine and epinephrine in the ME/CFS patients but not in the healthy controls.

An unusual immune-endocrine interaction was occurring in ME/CFS patients that was not found in the healthy controls. For some reason, TGF-B  levels rose in conjuction with stress hormones in the ME/CFS patients but not in the healthy controls.  All three TGF-B isoform displayed this association.

Plus that association also correlated with symptom severity. Wyller found that the TGF-B-cortisol-autonomic nervous system correlation was strongest in the most fatigued ME/CFS patients.  Less fatigued ME/CFS patients, on the other hand, had much less of this association.

Once again, context appeared to be king in the ME/CFS patients. The levels of TGF-B didn’t matter but the network they were embedded in did. A similar scenario showed up in the huge cytokine study conducted by Dr. Montoya and Mark Davis of Stanford. That study, like Wyller’s, didn’t find high levels of cytokines, but it did find that even normal cytokine levels affected symptoms. That suggested some sort of immune hypersensitivity, perhaps associated with some unusual network functioning, was present.

Now Wyller apparently finds an immune and autonomic nervous sensitivity to TGF-B. It’s not the cytokine levels themselves but the effect they have on stress hormones.  Indeed, Wyller suggested that the primary disease mechanism in ME/CFS is not altered immune production but altered immune control. Somehow the immune system is affecting other systems in unusual ways.

That’s an intriguing idea given what we’ll shortly see from Dr. Klimas, whose intense testing during exercise suggests that exercise induced immune activity trips off autonomic nervous system problems in ME/CFS. Gordon Broderick’s network studies suggest that cytokine levels don’t need to be high to have untoward effects on ME/CFS patients – they simply have to be embedded in an unusual immune network.

Wyller - neuro-endocrine-immune disease

Wyller believes a complex neuro-endocrine-immune interaction may be contributing to the fatigue and possibly the EBV issues in ME/CFS.

Dr. Klimas will be trying in a series of small studies to move those systems back to normal this year. (More on that later.)

Wyller’s findings suggest that his “sustained arousal” hypothesis may be correct and that the “sustained arousal” he believes is present in ME/CFS is being triggered by the immune system. His small gene expression study possibly bares this out. Wyller warned about reading too much into the gene expression analysis because of the small sample size (n=29). The analysis found, though, that the TGF-B3 isoform was negatively associated with reduced expression of two B-cell genes (TNFRSF13C and CXCR5).

Wyller suggested that TGF-B3 may be altering the effect that cortisol – the master immune regulator – has on B-cell genes in ME/CFS.  If TGF-B and cortisol combine to smack B-cell genes in ME/CFS, Wyller suggests that could translate into problems reining in Epstein-Barr virus (EBV) – a common trigger in ME/CFS.  Wyller’s earlier gene expression study, in fact, suggested that B-cell problems could be the key to the EBV problems seen in ME/CFS. Now Wyller suggests that these B-cell problems could result from a complex interaction between TGF-B and cortisol.

Wyller’s going to check out that interaction in a study which will determine how effectively the B-cells in ME/CFS patients respond to EBV in the presence of neuroendocrine hormones. If cortisol or other neuroendocrine hormones impair the ability of B-cells to whack EBV in ME/CFS, Wyller may have uncovered one reason why mononucleosis is such a common trigger for ME/CFS.

Mold Connection?

Wyller’s focus on the research literature apparently precluded him from exploring another TGF-B angle. Mold has become a hot if little studied topic in ME/CFS. For over a decade, mold doctor Ritchie Shoemaker has asserted that elevated TGF-B levels play a major role in mold related illnesses.  Instead of B-cells, though, Shoemaker ties TGF-B issues to T cell problems and reduced blood flow in the capillaries, which translate into reduced oxygen uptake and problems with producing energy in the mitochondria – a key theme in ME/CFS.

Shoemaker, interestingly, asserts those blood flow and immune problems mirror what is happening in sepsis. In fact, Shoemaker believes that the chronic inflammatory response syndrome (CIRS) he sees in his patients is a chronic form of sepsis. Over ten years ago ME/CFS specialist Dr. David Bell proposed a chronic form of sepsis exists in ME/CFS as well.

Could Chronic Fatigue Syndrome (ME/CFS) Be a Chronic Form of Sepsis?

 

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25 Comments

  • Issie

    January 26, 2018 at 7:48 pm - Reply

    I’m glad you referenced the article we had discussion on with connection to sepsis and CIRS. Valuable info there. I LOVE it when puzzle pieces come together!
    Issie

  • Patricia D

    January 26, 2018 at 7:50 pm - Reply

    I was Dx w/ CFS in 2001 after a severe EBV infection (actually had EBV meningitis) left me feeling awful, in pain and absolutely exhausted all the time. Over the years I have had multiple EBV infections proven by titers, including pneumonia, hepatitis and pancreatitis. I also have hypopituitary and must take thyroid hormones and hydrocortisone. Once this was diagnosed and treated a lot of things improved but the CFS has continued to worsen. I’m not quite homebound but can no longer even make a 2 hour trip.

    • Rita

      March 17, 2018 at 6:43 pm - Reply

      Patricia,
      I also have all the same illnesses you wrote? Is it a coincidence? I don’t think so..
      I also have hypopituitism
      The fatigue in my mind and muscles is paralyzing my life.
      I’m taking adderal 2x day and even with this boost of energy I’m lucky to get out of my house once or twice a month.
      I don’t even go to the dr’s anymore. I try. I make the appointments but I just can’t sum up the energy to put one foot in front of the other. This makes me miss needed health care. and I have no self esteem.
      I know I have a serious illness but I get so down on myself. Life is passing me by and I’m Not really participating anymore.
      Its like I just viewing from the sidelines. It can be so depressing.
      I see people walking outside laughing, really enjoying themselves, and I feel like I’ve lost that. Now I feel like I’m on the outside of life looking in.
      This illness is horrible. What it does to working, happy, healthly proproactive adults is a crime.
      It robs us of our whole life’s, takes away our choices, and isolates us from living by robbing our bodies of energy.
      I used to go dancing 3 times a week. I love to dance. I thought it was healthy to do with this condition. But within a few months I was bedridden..my hgh = human growth hormone was down to 37?
      So now I don’t dance anymore, another thing robbed by this desease.
      I try to find peace with doing small things like visiting my grandsons, I do enjoy them. But when their mom wants to take them to park or movies I have to pass. It’s like I’m in this body but I’m not in controll of it.
      My personality is not pne to be idle. So I try, but when I get a ebv flare up or a infection from living a little. I pay the price.
      If I could remove my self into a super realistic robot? Lol I would in a 2nd.
      Then I could control it and live as I’d like to live.
      Sorry, I don’t mean to be so negative. Its St. Patty’S day.
      Which I love. My family have cooked dinner and are waiting for me, yet I don’t feel up to it physically..but I will push through just to see them..
      I wondered as you have almost same health issues as me, how do you feel? Physically? Mentally? Could you send me a email please and share with me?
      Its such a isolating illness.
      I have no one who understands it at all.
      Be my friend?
      Rita @ Ritashaw8588@gmail.com

  • Emer

    January 26, 2018 at 7:57 pm - Reply

    I just can’t wait to read about Nancy Klimas’s work, sounds like she is trying to fix us..no pressure Cort regarding that update!!

    • Gail Williamson

      January 27, 2018 at 6:51 pm - Reply

      Emer,

      Did you see this video of Dr. Klimas? If not, it’s really worth watching. If she’s able to knock the system of GWI vets back to where they should be, maybe it can be done for us too! I’m so excited to see the results of her GWI trial. https://www.youtube.com/watch?v=9TizGFYJyLo&t=5s

      • Cort Johnson

        January 28, 2018 at 5:35 pm - Reply

        Thanks for the tip 🙂

  • Erik Johnson

    January 26, 2018 at 9:48 pm - Reply

    Cort. You were standing next to me as I told the story of “Mold at Ground Zero for CFS” to Dr. Unger, and offered her the chance to “step up” and perform the ultimate irony of having the CDC beat CFS researchers to “responding like real researchers” to the incident that started the syndrome. And explained to Dr. Unger that such a wild turn of events could help redeem the CDC’s shattered credibility.

    It’s a darn shame that Dr. Unger didn’t take my up on my offer.
    However, now that this is all out in the open, there is nothing stopping us from saying to the CDC, “You know the facts of the matter. Failure to respond is a disqualification to even BE a CFS researcher”

    (Deliberate subversion of relevant evidence is “science fraud”)

    In the meantime, if there happen to be any “real researchers” out there who want to know the hidden backstory of biotoxins as a factor in the creation of the CFS syndrome, there is absolutely nothing stopping them from contacting me.

    Nothing, that is…. except their own elitist-authoritarian desire that nothing worth knowing should ever come from a mere patient.

    https://cfsuntied.net/2016/09/13/how-to-make-sure-an-invisible-disease-stays-that-way/

    • Cort Johnson

      January 27, 2018 at 6:14 pm - Reply

      I totally agree Eric – we need more research on mold. In fact we need SOME research on mold in ME/CFS. I can think of only one study so far….

  • Deborah

    January 26, 2018 at 10:42 pm - Reply

    1991- Diagnosis Fibromyalgia with high ammount of inflammation of unknown origin

    Over the years, I have collected IBS, IC, Hypothyroidism, Sjorgens, Neuropathy of every ilk of unknown reason, Pelvic Floor Pain Syndrome,(my female region is Hiroshima, will only speak privately) they say it’s related to Neuropathy.. Anyways I can’t remember all the crap I have accumulated my thyroid got ate up with nodules, no one blinked though they didn’t know why. My kidneys began to fail but it was slow, like my sugar sensitivity so no worries. Still high inflammation but no one worries even though people with Fibro aren’t supposed to have inflammation. Well, my Neuropathy is all kinds of special neuropathy now and in Georgia because I have to drive barefoot so nearly nerve dead feet don’t get pedals mixed up, my dr gets to recommend me for a medical marijuana card. And I finally tested positive for a autoimmune disease hence the inflammation that’s now attacking my heart so the Dr’s are kinda shitting their britches. Cause according to initial test, I ain’t CFS, Lupus, RA, MS, or any of the regular thyroid bullies. And since we have no paternalistic real knowledge, they are going to DNA route to see if it’s an heredity thing. So, you may get to kick me out. I may have nothing, just a lot of symptoms I used to joke it just makes you feel like dying, (but I wasn’t joking) but you aren’t really. As of last Monday, the new serious outlook is 5 years till dialysis if my heart lets me. And they thought that was supposed to scare me. After all the things I have experienced in my life. I was a 20%er when I joined. Cort, the researchers, the articles, you guys, this is the first site that I learned things so brilliant and helpful that, I am living again, off opioids, up on vitamins again. I had given up. I was isolated. No one like wanted to fight because there was no sword but pills, pills, bed, pills. So, they aren’t going to kill me off with some unknown inflammation no one has cared about for years, because they still don’t know. Here’s a hint, I look radiantly healthy with great skin, laugh and don’t whine so I couldn’t have a thing wrong with me, and for so reason my chubby size 20 plus is losing weight I am a regular 16-18, lost about 40 pounds without trying. I have no desire to eat even if I would partake of something to stimulate eating. I feel great in all ways but nerve, muscles, back, regular drill.

    Thank you all for getting me out of my bed
    I am out of the house on my own 2-3 days a week now instead of out of bed 2 hours a day.

    • Rita

      March 17, 2018 at 7:12 pm - Reply

      Deborah, I know how you feel. I also have kidney desease. Funny They diagnosed it a year or so but never followed up more.
      When I read up on it ..I found out it causes inflammation..and something about it could bevmy body not able to fight infections off. Seeing as MRSA precluded this illness..I’m not surprised.I was also diagnosed peripheral neuropathy..emg confirmed. Cavus foot structure so both feet operated on..the pain was horridence, muscle craps, vibrations, tingling, swelling..but you are lucky..even with adnormal levels of lyme high elisa tests, rheumatoid 20, hig Vca IGG & Ebna IGG for ebv, hypopituitism, hypokelmia,CKD, Perineuropathy etc.. You are getting genetic testing.
      Good!! My dr’s labelled me fibro with M.E. and never tried to figure out the puzzle?
      Is my ckd genetic? Acquired? Why are my pituitary hormones and adrenal hormones so low?
      What is causing the Peri neuropathy? Is it aquired? Or inherited? High Possible CMT said foot surgeon.
      But my dr’s just brushed every question I asked away. Told me to go home grieve for my old self because that ones gone forever, and to accept my new self..nice huh..
      Its not because I’m in the smallest state it just seems to me by reading blogs alot of dr’s are patient managing only, not looking for answers just trying to mask the symtoms.
      I don’t have a primary anymore. I left that office after they told me to go home and grieve. and I did for 2 years.. I would get sick dehydrate but I would not go back. They took my hope away by not caring enough to look deeper.
      So I’m glad you have someone that will get you genetic testing, I’ve wanted that for along time even before I was sick because A couple of siblings andvmyself were born with birth defects of the spine, feet, arch, calf, clept lipand nose.
      Please let me know if your comfortable with sharing what they find. Especially with kidney. I hope beyond words they find your answers, no one deserves to suffer and not be able to live like they want because of this horrible illness..
      Best wishes, Rita @ Ritashaw8588@gmail.com

  • Forebearance

    January 26, 2018 at 11:04 pm - Reply

    This is all very interesting!
    Thank you for mentioning how Dr. Shoemaker’s ideas tie in to this.
    I also love it when the puzzle pieces start to come together.

    • Cort Johnson

      January 27, 2018 at 5:58 pm - Reply

      Let’s hope they are starting to. It would be great if some researchers would take up Shoemaker’s work.

  • Gijs

    January 27, 2018 at 10:48 am - Reply

    (…)TGF-β did not differ between patients and controls.
    https://www.ncbi.nlm.nih.gov/pubmed/29284500
    So, this theory of Wyller can be debunked.

    • Cort Johnson

      January 27, 2018 at 5:57 pm - Reply

      Not so fast, my friend. Yes, TGF-B levels were not increased – but they weren’t increased in this study either! When the analysis was done increased TGF-B levels in combination with neuroendocrine factors were associated with increased fatigue. This suggests that the levels of that factor don’t for some reason need to be high to have an effect. It’s only one study – it has not been validated – so it’s a preliminary finding.

      In general, though, TGF-B levels are increased in ME/CFS – just not in every study.

      A search was conducted on PubMed, Web of Science, Embase and PsycINFO, for CFS related-terms in combination with cytokine-related terms. Cases had to meet established criteria for CFS and be compared with healthy controls. Papers retrieved were assessed for both inclusionary criteria and quality. 38 papers met the inclusionary criteria. The quality of the studies varied. 77 serum or plasma cytokines were measured without immune stimulation.

      Cases of CFS had significantly elevated concentrations of transforming growth factor-beta (TGF-β) in five out of eight (63%) studies. No other cytokines were present in abnormal concentrations in the majority of studies, although insufficient data were available for some cytokines….The finding of elevated TGF-β concentration, at biologically relevant levels, needs further exploration, but circulating cytokines do not seem to explain the core characteristic of post-exertional fatigue.

      https://www.ncbi.nlm.nih.gov/pubmed/26148446

      • Wander

        January 27, 2018 at 7:02 pm - Reply

        Thanks for the Article! Very interesting. Shows again, how complicated this disease is and how careful the science needs to be done to get it right.

        But I have a problem understanding why in some studies TGF-B is elevated and in others there’s no significant difference compared to controls. I mean the the big cytokine study (Montoya, Davis) had nearly 200 CFS/ME patients and TGF-B was elevated with p = 0.005 — that can’t be a coincidence?

        I guess they all use the same standard statistic model for these calculations, so why the different results?
        Are the patient groups so unlike, because they were selected by different CFS definitions? I guess if TGF-B is really associated with fatigue severity, maybe in some studies the average severity was too low and thus no distinct elevation was seen?
        Though, reading the article, it seems to me that only the ‘TGF-B-cortisol-autonomic nervous system correlation’ increases with severity — not TGF-B levels themselves.

        And some days ago I was wondering if I’d pay to have my TGF-B levels checked, to have some evidence that it’s really CFS for me. I guess I can save that money ; )

        • Cort Johnson

          January 28, 2018 at 5:34 pm - Reply

          This is pretty much par for the course for cytokines. They tend to be all over the map. Despite it’s inconsistencies TGF-B is the standout. In this group – adolescents – TGF-B levels were not raised but TGF-B was with the other factors still associated with fatigue. Clearly we need more studies and Wyller’s next one – which will directly test his theory that TGF-B is having negative effects on fighting pathogens in the presence of neuroendocrine factors – will be the most direct test of TGF-B yet.

          I had forgotten about the Montoya study – thanks for mentioning that. That is significant since it was such a big study.

          • Gijs

            January 29, 2018 at 10:47 am -

            Thx Cort for your reply. Did Montoya use bloodsamples from Daniel Peterson? These samples are not representative for CFS/ME.

          • Cort Johnson

            January 31, 2018 at 12:57 pm -

            I think, but am not sure, that Montoya’s samples were from in house. Certainly most of them must have been.

      • Audrey Brimson

        January 28, 2018 at 12:26 am - Reply

        Thanks for my morning smile, isn’t it funny how 63% sounds so much more impressive than five eighths. 🙂

  • Audrey Brimson

    January 27, 2018 at 12:43 pm - Reply

    Thank you for your article. Having been in the ‘Allergic to the C20’ and ME/CFS scene for so long, 40 years, sometimes I wonder if anyone ever looks back on the past 40 years and realises how often the wheel appears to get reinvented. So many of the ideas, theories being put forward are reminiscent of the theories put forward in the 80s and 90s. Was there a song that went ‘Everything old is new again’. Don’t think this is a criticism, it is not, I just hope someone is listening and something meaningful eventuates as this particular cycle goes round. Keep up the good work Cort, the patient community is listening.

    • Cort Johnson

      January 27, 2018 at 5:49 pm - Reply

      Thanks Audrey,

      What I think is different now are the tools researchers have to assess what’s going on. If Wyller is right – and there’s a long way to go to tell if he is – then ME//CFS may indeed be the kind of NEID disease that was postulated so long ago. The HPA axis – which I thought was a kind of dead subject at one time – keeps coming back….

  • Sue

    January 28, 2018 at 11:51 pm - Reply

    Really, really hope it doesn’t get renamed NEID. I can see the headlines already: from ‘Me me me’ to ‘Needy’ syndrome…

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