Origin of M.E. disease process in the immune system.

The sudden onset of M.E. (myalgic encephalomyelitis, ME/CFS) 3 months ago occurred when I when I was experiencing a flare of psoriatic arthritis, an autoimmune disease. The virus infection caused an huge amount of inflammation. Everything suddenly changed virtually overnight… so I have a personal insight into the ME disease process that doctors and other patients may not have.

Internal radiation exposure causes damage to the JAK/STAT pathway.

The JAK-STAT signaling pathway transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. The JAK-STAT system is a major signaling alternative to the second messenger system.

The JAK-STAT system consists of three main components: (1) a receptor (2) Janus kinase (JAK) and (3) Signal Transducer and Activator of Transcription (STAT).[1]

Many JAK-STAT pathways are expressed in white blood cells, and are therefore involved in regulation of the immune system.

The receptor is activated by a signal from interferon, interleukin, growth factors, or other chemical messengers. This activates the kinase function of JAK, which autophosphorylates itself (phosphate groups act as “on” and “off” switches on proteins). The STAT protein then binds to the phosphorylated receptor, where STAT is phosphorylated by JAK.The phosphorylated STAT protein binds to another phosphorylated STAT protein (dimerizes) and translocates into the cell nucleus. In the nucleus, it binds to DNA and promotes transcription of genes responsive to STAT… (link)

The STAT protein (Signal Transducer and Activator of Transcription, or Signal Transduction And transcription) regulates many aspects of growth, survival and differentiation in cells. The transcription factors of this family are activated by Janus kinase (or ‘Just Another Kinase’, JAK) and dysregulation of this pathway is frequently observed in primary tumours and leads to increased angiogenesis, enhanced survival of tumours and immunosuppression. (link)

Specifically, radiation impairs the activity of STAT-1 protein, which is required for IFN-γ signalling. (link) IFN-γ is the hallmark Th1 cytokine, which is involved with cellular immunity.

We have recently characterized different mutations responsible for partial STAT1 functional deficiency. STAT1 is an essential protein for the signal transduction induced by IFNγ, under its homodimeric form (STAT1/STAT1, known as GAF) as well as its heterotrimeric form (STAT1/STAT2/p48, of ISGF3)… As a result, these observations prove that IFNγ-mediated anti-mycobacterial immunity depends on STAT1 and GAF. The characterization of patients with a STAT1 complete deficit and showing severe viral infections demonstrates that type I IFNs-mediated antiviral immunity is STAT1-dependent and ISGF3-dependent, at least for Herpes viruses. (link)

ME/CFS is usually linked to herpes viruses, Epstein-Barr viruses, or enteroviruses. Degradation of the STAT-1 pathway reduces immunity to these viruses. Herpes viruses hide in the immune system. They can become reactivated at any time. Everyone has these viruses latent in their systems since childhood. They are just waiting for a trigger to come back.

Smad7 is a protein, the expression of which is induced by STAT-1 and IFN-γ.

SMAD7 is a protein that, as its name describes, is a homolog of the Drosophila gene: “Mothers against decapentaplegic”. It belongs to the SMAD family of proteins, which belong to the TGFβ superfamily of ligands. Like many other TGFβ family members, SMAD7 is involved in cell signalling. It is a TGFβ type 1 receptor antagonist. It blocks TGFβ1 and activin associating with the receptor, blocking access to SMAD2. (link)

Here we present a basis for the integration of TGF-beta and IFN-gamma signals. IFN-gamma inhibits the TGF beta-induced phosphorylation of Smad3 and its attendant events, namely, the association of Smad3 with Smad4, the accumulation of Smad3 in the nucleus, and the activation of TGFbeta-responsive genes. Acting through Jak1 and Stat1, IFN-gamma induces the expression of Smad7, an antagonistic SMAD, which prevents the interaction of Smad3 with the TGF-beta receptor. (link)

So radiation damages the STAT-1 pathway, reducing IFN-γ, and reducing Smad7, which causes uncontrolled growth in TGF-β levels. This cytokine suppresses the immune system further, and causes the development of Treg cells, which regulate and suppress the immune system.

TGF-beta and CD4+CD25+ regulatory T cells (Treg) both play an important role in the control of immune responses and the maintenance of immune homeostasis. The mechanism of suppression induced by Treg and the factors which regulate Treg function and number, have only begun to be elucidated. TGF-beta seems to act as an effector cytokine involved in the immunosuppressive function of Treg in vitro and in vivo, although its origin and mechanism of action remains to be defined. In addition, TGF-beta signaling in peripheral Treg seems to be essential for the regulation of peripheral Treg numbers and for their immunosuppressive function in vivo. This review will focus on the role of TGF-beta for the generation and expansion of CD4+CD25+ Treg, as well as for their immunosuppressive function in vitro and in vivo. (link)

IL-22 (interleukin-22) is a cytokine that is produced by Th17 and Th22 cells. TGF-β counteracts IL-22 and reduces the differentiation of Th22 cells.

IL-22 a member of a group of cytokines called the IL-10 family or IL-10 superfamily (including IL-19, IL-20, IL-24, and IL-26),[4] a class of potent mediators of cellular inflammatory responses… IL-22 is produced by activated DC and T cells and initiates innate immune responses against bacterial pathogens especially in epithelial cells such as respiratory and gut epithelial cells. IL-22 along with IL-17 is rapidly produced by splenic LTi-like cells [6] and can be also produced by Th17 cells and likely plays a role in the coordinated response of both adaptive and innate immune systems. (link)

IL-22 is an important part of immune protection against enteropathogens. Depletion of Th22 cells depletes IL-22.

Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria…

Interleukin-22 (IL-22) is central to host protection against bacterial infections at barrier sites. Both innate lymphoid cells (ILCs) and T cells produce IL-22. However, the specific contributions of CD4(+) T cells and their developmental origins are unclear. We found that the enteric pathogen Citrobacter rodentium induced sequential waves of IL-22-producing ILCs and CD4(+) T cells that were each critical to host defense during a primary infection. Whereas IL-22 production by ILCs was strictly IL-23 dependent, development of IL-22-producing CD4(+) T cells occurred via an IL-6-dependent mechanism that was augmented by, but not dependent on, IL-23 and was dependent on both transcription factors T-bet and AhR. Transfer of CD4(+) T cells differentiated with IL-6 in the absence of TGF-β (“Th22” cells) conferred complete protection of infected IL-22-deficient mice whereas transferred Th17 cells did not. These findings establish Th22 cells as an important component of mucosal antimicrobial host defense. (link)

IL-22 suppresses bacterial translocation in the intestines, and promotes regeneration in the cells of the epithelial wall. It also activates STAT-3. IL-22 deficiency counteracts all this.

Intestinal mucus functions as a lubricant and a physiological barrier between luminal contents and mucosal surface (59). Mucin (Muc) 1, which is a heavily O-glycosylated membrane-bound mucin, represents one of the major components in the intestinal mucus (59)… Interestingly, a recent study proposes the ability of Muc1 to suppress the expansion of both Th17 cells and IL-17-producing ILCs presumably by blocking the translocation of bacterial products from intestinal lumen into intestinal lamina propria (62)… Interestingly, the ability of IL-22 to promote the production of functional Muc1 through activation of STAT3, but not STAT1, has been demonstrated using human colonic cancer cell lines (T84 and HT29) and primary colonic epithelial cells from mice (9,67)… IL-22 has been demonstrated to promote the epithelial cell regeneration with goblet cell restitution under intestinal inflammatory condition, but it may play no obvious role innormal colonic epithelial homeostasis in the healthy state (9,21). (link)

Cinnabarinic acid is a product of tryptophan metabolism, activates the aryl hydrocarbon receptor (AHR), and is an important source of IL-22.

The aryl hydrocarbon receptor (AHR) binds to environmental toxicants including synthetic halogenated aromatic hydrocarbons and is involved in a diverse array of biological processes. Recently, the AHR was shown to control host immunity by affecting the balance between inflammatory T cells that produce IL-17 (Th17) and IL-22 versus regulatory T cells (Treg) involved in tolerance. While environmental AHR ligands can mediate this effect, endogenous ligands are likely to be more relevant in host immune responses. We investigated downstream metabolites of tryptophan as potential AHR ligands because (1) tryptophan metabolites have been implicated in regulating the balance between Th17 and Treg cells and (2) many of the AHR ligands identified thus far are derivatives of tryptophan. We characterized the ability of tryptophan metabolites to bind and activate the AHR and to increase IL-22 production in human T cells. We report that the tryptophan metabolite, cinnabarinic acid (CA), is an AHR ligand that stimulates the differentiation of human and mouse T cells producing IL-22…

Although the AHR was initially proposed to affect Treg and Th17 development, a Th17-associated cytokine, IL-22, is even more specifically dependent upon AHR activation [13]. Ahr -/- mice retain the ability to generate some Th17 cells but are compromised in terms of IL-22 production [13,17]. Human T cell differentiation also exhibits distinct requirements for the AHR: activation of the AHR in stimulated human T cells was found to inhibit Th17 differentiation and to promote the differentiation of CD4+ T cells that produce IL-22 [18]…

Potential enzymatic modulators that can regulate the generation of CA from 3-HAA would predictably affect the resolution of inflammation. Such enzymes include ceruloplasmin [39], super-oxide dismutase [33], catalase [33], and the fungal virulence factor, laccase [39]…

We have shown previously that tryptophan catabolism can result in a loss of Th17 cells in the context of HIV disease through generation of 3-HAA [30]. We hypothesize that this loss, particularly within the gut mucosa, allows for ongoing inflammation due to continued microbial translocation. Conversion of 3-HAA into CA could reverse the effects of 3-HAA within immune cells, and thereby restore IL-22-producing cells in the context of increased IDO activity. This would allow for the resolution of the inflammatory signaling cascade by strengthening the mucosal barrier, thus stopping a vicious cycle that might otherwise drive disease progression [30]. Although IL-22 was initially linked to IL-17 as a pro-inflammatory cytokine, recent evidence suggests that it probably plays an independent immunoregulatory role in the context of non-hematopoietic cells, maintaining epithelial cell homeostasis in the mucosal tissues [50,57,58]. If so, the pathways that lead to the generation of CA may operate in tandem with the immunosuppressive mechanisms linked to tryptophan metabolism to generate a population of IL-22 producing cells that plays a specific role in tissue repair following inflammation [58]. (link)

So the initial insult of the disease that triggers ME causes massive inflammation, but the lack of IL-22 causes the damage from this inflammation to not be healed, which results in bacterial and viral translocation from the gut. Consequently, the patient is repeatedly re-infected with these pathogens. The lack of IFN-γ and IL-22 reduces innate and adaptive immunity to these pathogens. Tryptophan metabolism is also affected, and its normal function in healing of the gut is abrogated by excessive amounts of TGF-β.

This immune process begins a dysfunctional process that affects the entire body. But it begins with STAT-1 impairment. An effective treatment for M.E. would target the source. Everything else has to do with reducing symptoms.

22 thoughts on “Origin of M.E. disease process in the immune system.

  1. Systemic Mastocytosis/Mast Cell Activation Disorders/Histamine Intolerance Tryptase Serum Diagnostic Test 🙂 CFS/Fibro/Lyme disease…

  2. Another very good article. This implies that increasing levels of IL-12 or IL-23 will increase both IFN-γ and IL-22. TGF-β, on the other hand, wipes IL-22 out. You need just a teeny bit of TGF-β, though, together with the IL-12.

    The inflammatory IL-17 pathway is completely separate.

    So look for foods, herbs, supplements, medications that increase IL-22, IL-12, IL-23, or IFN-γ. And those that decrease TGF-β.


    To address this hypothesis, we systematically tested the role of single cytokines promoting Th1 and/or Th17 differentiation in the induction of IL-22 and IL-17 by naive CD4 T cells. We found that individual inflammatory cytokines (IL-1β, IL-6, TNF) and TGF-β did not induce IL-22 (Figure 2A) or IL-17 production (Figure 2B). On the contrary, naive T cells cultured in the presence of IL-12 (Th1 condition) or IL-23 produced high levels of IL-22 but not IL-17 (Figure 2B). This indicated that IL-23 and IL-12 are 2 underlying factors explaining the differential regulation of IL-17 and IL-22 revealed by statistical methods. These findings are consistent with previous results reporting a role for IL-23 in dermal inflammation and acanthosis in a psoriasis mouse model.8 The importance of IL-12 in inducing IL-22 is supported by a previous study showing a reduced IL-22 secretion by T cells purified from IL-12- and IL-12 receptor-mutated patients.23 This also suggests that IL-22/IFN-γ coproduction could play an important role in Th1-associated diseases.


    • ME involves a Th2 shift, away from Th1, due to decreases in IL-22 and IFN-γ. Diseases that do not feature this Th2 shift in the early stages are not ME. They might be CFS, though.

    • ME is primarily an immune deficiency disease. There is an uptick in allergic responses due to the Th2 shift. But cellular immunity is compromised, and the patient is more vulnerable to viruses and bacterial infections.

    • ME is not an autoimmune disease. But in later stages, after years, Th1 activity comes back somewhat, and Th17 inflammation rises. The same thing happens in lupus (SLE).

    • The probiotic Lactobacillus rhamnosus jb-1 increases levels of IL-22.

      http://nk2012.files.wordpress.com/2012/04/nk2012-abstracts-posters.pdf (p.72)

      Belly bacteria boss the brain

      Mice fed broth fortified with a type of friendly intestinal bacteria called Lactobacillus rhamnosus behaved less anxiously than mice fed broth without bacteria. Those behavior changes were accompanied by differences in levels of a brain-chemical sensor and stress hormones…

      The research team — led by John Bienenstock of McMaster University in Hamilton, Canada, and John Cryan of the University College Cork in Ireland — looked at the mice’s brains to examine levels of the GABA receptor, a protein that senses and responds to an important brain chemical messenger called GABA. Alterations in the way GABA and other brain chemical systems work influence behavior. Mice fed bacteria-containing broth had higher levels of the receptor protein in some parts of the brain and lower levels in other parts than did mice fed sterile broth.

      Mice usually stay close to walls, but ones that consumed the bacterium spent more time in open spaces in a special maze — a measure that tells scientists the mice are less anxious than usual. The researchers also gave the mice a stress test by forcing the animals to swim in a water tank. Stressed mice that had eaten Lactobacillus rhamnosus had lower levels of stress hormones than did mice that ate broth alone.


      *** It has to have something to do with mGluR4 activation. That must be the connection between IL-22 and GABA. ***

      • The lack of IL-22 has caused all sorts of leftover crap from the illness to leak out of my gut. This whole thing starts in the gut.

      • Bobby1, this is a groundbreaking study. What it means is that eating sterile foods, such as pasteurized cheese (as opposed to raw cheese), is actually unhealthy.

    • Natural killer (NK) cells are classically viewed as lymphocytes that provide innate surveillance against virally infected cells and tumour cells through the release of cytolytic mediators and interferon (IFN)-γ…

      Here we report the characterization of a human NK cell subset located in mucosa-associated lymphoid tissues, such as tonsils and Peyer’s patches, which is hard-wired to secrete interleukin (IL)-22, IL-26 and leukaemia inhibitory factor. These NK cells, which we refer to as NK-22 cells, are triggered by acute exposure to IL-23… NK-22 cells are also found in mouse mucosa-associated lymphoid tissues and appear in the small intestine lamina propria during bacterial infection, suggesting that NK-22 cells provide an innate source of IL-22 that may help constrain inflammation and protect mucosal sites.


  3. I submitted a copy of this post to the Agency for Healthcare Research and Quality.


    Dear Scientific Information Packet submitter:

    Thank you for submitting scientific information on the topic, Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We greatly appreciate the time you have dedicated to improving Effective Health Care Program research and reports.

    The scientific information packet you submitted will be reviewed and may be incorporated as appropriate into the report; however, we cannot guarantee that all information submitted will be included. Additionally, the Effective Health Care Program may use the scientific information packet you submitted to guide future research. We may contact you at this e-mail address, if we have questions about your submission.

    • I don’t know anything about this particular institution, but as a general recommendation, submitting ground-breaking conclusions that threaten to shake up the status quo to the establishment is a very god way of getting oneself into trouble. Lucky you don’t need a licence to practice medicine (on yourself), they would take it away from you for having an opinion. Look what happened to Dr. Burzynski in Texas and Dr. Simoncini in Italy, and countless others. How dare they look for the truth, how dare they find a cure for cancer (that threatens a multi-TRILLION Dollar industry)! Same thing with the American Dental Ass. Try telling them that mercury fillings are EXTREMELY toxic to the brain, the CNS and the body; the science is irrefutable and yet good luck with that. Medicine is a business without ethical boundaries.

  4. Finally found it… the link between tryptophan and STAT-1. Helps with cancer, too.

    The missing piece of the jigsaw puzzle.

    “Indoleamine 2,3-dioxygenase-1 (IDO1;
    IDO) mediates oxidative cleavage of tryp-
    tophan, an amino acid essential for cell
    proliferation and survival. IDO1 inhibition
    is proposed to have therapeutic potential
    in immunodeficiency-associated abnor-
    malities, including cancer. .. Analysis of plasma kynurenine/
    tryptophan levels in patients with cancer
    affirms that the IDO pathway is activated in
    multiple tumor types. Collectively, the data
    suggest that selective inhibition of IDO1
    may represent an attractive cancer therapeu-
    tic strategy via up-regulation of cellular im-


  5. there are many such citations, brain and nervous system quite vulnerable to damage from nuclear, man-made radioisotopes.. pgs 115-116
    “Among the consequences of the damage
    to the nervous system caused by the Chernobyl
    catastrophe are cognitive, emotional,
    and behavioral disorders. Adverse effects
    also include neurophysiological abnormalities
    in the prenatally exposed and neurophysiological,
    neuropsychological, and neuroimaging
    abnormalities in liquidators, manifested
    as left frontotemporal limbic dysfunction,
    schizophreniform syndrome, chronic fatigue
    syndrome, and, combined with psychological
    stress, indications of schizophrenia and related
    116 Annals of the New York Academy of Sciences
    Only after 2000 did medical authorities begin
    to recognize the radiogenic origin of a universal
    increase in cataracts among liquidators
    and evacuees from the Chernobyl territories.
    Official recognition occurred 10 years (!) after
    doctors began to sound the alarm and 13 years
    after the problem was first registered.”

    “Chernobyl: Consequences of the Catastrophe for People and the Environment”
    by Alexey Yablokov, Vasily Nesterenko and Alexey Nesterenko
    NY Academy of Sciences, Volume 1181, 2009.
    5,000 Slavic language studies reviews, over 1,400 cited.
    hard copy now available at Greko Printing P:734.453.0341;

  6. Yes, Chernobyl was a warning shot. Fuku had the same design flaws, and there are more of these nuclear plants waiting to melt down. France alone has enough of these to anhiliate all of Europe. It doesn’t take an earthquake, either. All it takes is time.
    Speaking of which:
    >Official recognition occurred 10 years (!)
    This is actually a breath-taking world record. _Only_ mere 10 years. Usually it takes longer, until the perpetrators are safely retired and a new generation takes the reigns. But look at fluoride in drinking water, it’s been 50+ yrs and institutionalized genocide by poisonous byproducts of the ever-so-selfless aluminium industry defies all science. Or look at “silver” fillings and their contribution to the misery of hundreds of millons people (from thyroid disorders, schizophrenia, autism, through infertility, MS, arthritis, fibro, Parkinson’s to cancer): it’s been over one hundred yrs of denial. Dentists must treat mercury filling material as an environmental hazard before placing it in your mouth as well as after pulling a tooth, but while it is in your mouth, it miraculously turns healthy, it miraculously quits releasing mercury vapors and leaking lead and arsenic into your bloodstream. Mercury is also “safe enough” to inject into babies with childhood vaccines and into pregnant women with flu vaccines – yes, Glaxo Smith Kline admits to using it this way, even though the EPA lists mercury as one of the most dangerous environmental poisons known to mankind. Ever. You can only beat the toxicity of mercury by making it radioactive, oh wait, we’ve done that, too!


    • Thanks, Fred. I believe that ME and CFS are distinct diseases. An overexpression of SOCS1 in ME would cause the disease process in the way that I have described here. Though I am not sure that this is the problem… it might be physical destruction of group 1 innate lymphoid cells.

      CFS is an autoimmune disease and would be associated with SOCS3, like you said.

      • The only T-cells which are increased in ME are Tregs. Th2 allergic reactions are upregulated, but that is because Th1 suddenly goes away, not because of an increase in Th2. But the increased Th2 activity causes more B cell activity. It appears to be an autoimmune disease, but it’s an illusion. The immune system is actually overregulated. It’s a deficiency of Th1 cellular immunity.

  8. Nice article. Do you think rhematoid arthritis lies on opposite end from CFS or ME? I ask this because one of the treatments available for RA is inhibiting JAK 1/3 pathways. This sounds like thr opposite of what you discussed.

    One concern I have is hair loss and I also have CFS. I react very negatively to many supplements like iodine, methyl b12, immune boosters such as IP 6, beta glucan, and lactoferrin, as my body very sensitive.

    Recently it was proven that JAK inhibitors can result in full hair growth for RA patients. It seems like I am suffering from two opposite ends. What is your opinion on this?

    • Yes… I had psoriatic arthritis… my joint were painful and stiff. I had a hard time moving my wrists, they were so stiff. Now since I got ME, my wrists are flopping around like Raggedy Ann dolls. And I had bad to severe muscle pain instead of joint pain.

      The skin disease is still there, but it is no longer psoriasis… it morphed into dermatitis, and dermatomyositiis is now showing.

      I wrote this in July 2014, this was very early, but it was obvious right away that interferon-gamma was being targeted for removal by the disease. This has enabled the enterovirus infection to persist. The eczema and dermatitis are caused by Th2 cytokines, and the dermatomyositis come from Type I interferons. Both of these sets of cytokines suppress Th1, and specifically IFN-gamma.

      It appears the body is suppressing Th1 to counter neuroinflammation. Both interferon-beta and TGF-beta, which seem to be excessive, suppress neuroinflammation. If anything, I have excessive neurogenesis, with spindly neurons out of sync with each other. This is anti-multiple sclerosis.

      I don’t know about CFS, my disease has very little in common with it, but I also react negatively to most things. I have excessive excitotoxicity, the neurons are abnormally stimulated. I take phenibut for this… I am looking for R-phenibut (purified phenibut) and fenobam. I think this could be a long-term treatment. Just taking phenibut will de-sensitize the GABA-B receptors, rendering it ineffective. At that point, not only would I be bedbound, but at my age (going on 61) it would be life-threatening.

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