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.