In response to Jen X' first blog on her recovery, I yesterday looked up if itaconate by chance was a JAK inhibitor (potentially providing a role to itaconate to dampen this loop)
[REF1]
title: "Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages"
definition: "itaconate (OI)"
"JAK1 activation was also inhibited by OI in response to IL-13, interferon-β, and interferon-γ in macrophages and in T helper 2 (Th2) cells. Importantly, JAK1 was directly modified by itaconate derivatives at multiple residues, including cysteines 715, 816, 943, and 1130. Itaconate and OI also inhibited JAK1 kinase activity."
In response to Jen X' second blog on her recovery, I looked up what could be important about her / some cases of ME/CFS, in particular her high IL2 levels.
[REF2]
title: "Disease-Modifying Treatments for Multiple Sclerosis Affect Measures of Cellular Immune Responses to EBNA-1 Peptides"
"EBNA-1 stimulation of whole blood samples produced higher levels of IFN-γ and IL-2 in pwMS compared with controls and PWE".
[CONCLUSION1]
=> Combining [REF1] and [REF2] lead to the plausible involvement of trained / acquired immunity of T-cells against EBNA-1, a latent Ebstein-Barr viral protein. I followed that as one of plausible trails.
[REF3]
academic.oup.com
title: "Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis"
[CONCLUSION2]
=> Title of [REF3] confirms cases of *addaptive* immunity of T-cells to EBNA-1 is a real, occuring and observed phenomen by research
[HYPOTHESIS1]
=> [REF2], [REF3] and [CONCLUSION2] could, in some EBV related case, cause a persistent upregulation of IFN-γ and IL-2, EBNA-1 (latent EBV nuclear antigen-1) specific antigen T-cells and a whole range of immune activations this EBNA-1 specific antigen triggers when it activates the specific T-cells. This would happen as EBNA-1 latent antigen is produced lifelong by EBV infected cells. Such constant stream of EBNA-1 antigen then has the potential to bind to these specific EBNA-1 antigen T-cells and trigger the clonal expansion of these EBNA-1 antigen T-cells, further increasing (amplifying) the strength of the sort of self-immune reaction and so on.
[HYPOTHESIS2]
=> [HYPOTHESIS1] has a major problem: it would *risk* leading to cause a cytokine / immune reaction storm that is rather destructive. Such strong storms can kill patients quickly, as is seen in Covid-19 as too strong immune response to the Covid19 virus is a leading cause of death in Covid19 disease. This hence could kill the patient, unless 'resolved, containt' by things like strong immuno represants or plain immune exhaustion. Itaconate happens to dampen (auto-)immune reactions too, Jen experienced a confirmed cytokine storm and it is fair to say (near?) all ME/CFS patients experience immune exhaustion. Such immune exhaustion could have a powerfull dampening effect on the (many chained elements of the) feedback loop, preventing it to further auto-escalate.
[REF4]
title: "Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis"
"Specific cytotoxic T cell responses can control EBV-infected GlialCAM-specific B cells"
[REF5]
pmc.ncbi.nlm.nih.gov
title: Serological diagnosis of Epstein-Barr virus infection: Problems and solutions
"As EBNA-3 is a target of CD8+ lymphocytes[7], latent cells are normally eliminated by cytotoxic T lymphocytes in immunocompetent patients[1], whereas the transformed cells can proliferate and cause various lymphoproliferative disorders in immunosuppressed patients[13]."
[HYPOTHESIS3]
=> [REF4] and [REF5] lead to the hypothesis that EBV infected B-cells that are masters in evading elimination by our own immune system, are tracked and targetted for destruction by recognising latent EBNA loads (ready for shedding) in these cells; in this specific research EBNA-3 is a main T-cell specific antigen (‘able to zoom in on cells loaded with EBNA-3’ in order to eliminate them).
=> This makes the production of EBNA antigen specific T-cells after (elaborate, meaning a large amount of infected cells) EBV infection not a mere random fluke but a likely and common result.
=> This also would explain why (EBV) post-viral problems are much more common in adult onset cases of EBV then infection at very young age: the infection at young age is typically a lot more mild. Older age first EBV infection hence would have a chance to infect a lot more cells due to the generally far stronger EBV infection associated disease at that age.
=> That would lead to two things amplifying the possible self-immune loop: first a higher production of EBNA proteins due to higher amount of EBV infected cells, second a higher chance (or higher amount) of the own immune system to form antibodies against EBNA due to a higher amount of 'problematic' EBV infected B-cells and higher EBNA amounts in plasma.
=> Two factors in the feedback loop increasing has a very potent effect on increasing the chance that the feedback loop becomes ‘unstable’ (causes severe problems in this case).
=> Immune exhaustion is one of potential 'sort of solutions' to dampen this feedback loop that can be dangerous if out of control, similar to the own immune system being a big cause of death in Covid-19 infection. Increased interferon / itaconate production can dampen this feedback loop as well as itaconate canb dampen many auto-immune diseases too.
[HYPOTHESIS4]
=> partial / frequent EBV reactivation offers the paradoxial potential to dampen this potentially dangerous / deadly feedback loop.
EBNA-1 and EBNA-3 are only produced during latency of the EBV infected cells, not during their activation. If / when EBNA specific activated T-cells risk to become the dominant risk to the human body for survival, the body could 'decide' to 'break' the production (or better said dampen its production) of EBNA by... ...letting / provoking / enticing the EBV infected cells to (partly and periodically) reactivate.
=> This may seem absurd at first glance, but if an overactive feedback loop risks permanent or even life-threathening risk, it would not be that unreasonable to do so *especially* if it could do so controlled.
=> As a matter of fact, many patients report frequent EBV reactivations and science ([REF6] below) is a strong indication that happens.
=> In this hypothesis, a 'partial' EBV reactivation of an EBV infected cell would halt and interrupt the production of all EBNA proteins inside that cell. Even a short EBV reactivation would trigger a new and significant delay before resuming EBNA production because the EBV infected cells would need time to go to the correct latency phase to restart producing the specific EBNAs. That should either significantly temporarily dampen EBNA production (in a cyclic fashion) or reduce the average *body wide* EBNA production if partial EBV reactivation did not always occured simultaneously in the body (e.g. different parts of the body experience EBV reactivation at different times). That in turn would significantly temporarilly (enough to take back part of the previous escalation of the feedback loop in the case of a cyclic event) or on average (if EBV reactivation was happening at different times in different places of the body) reduce the strength of the potentially dangerous EBNA - EBNA specific T-cell activation feedback loop. Potentially a partial reactivation of a modest percentage of EBV infected cells *might* be enough to signal *non-activating* EBV cells to temporarilly halt or reduce EBNA production as well, but this part is speculative.
[REF5]
pmc.ncbi.nlm.nih.gov
title: Stress-Induced Epstein-Barr Virus Reactivation
"Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is another disease associated with EBV reactivation [151]."
"Lastly, the authors showed that hypoxia-induced EBV reactivation"
[REF6] (from [151] above)
pubmed.ncbi.nlm.nih.gov
title: "Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome"
"In ME/CFS plasma samples, EBV DNA was found in 24.1%, CMV DNA in 3.4%, and HHV-6 DNA in 1.7% of samples."
[HYPOTHESIS5]
=> From [REF5]: Reduced blood volumes and blood flow, as often seen in ME/CFS, could lead to sufficient episodes of (enough) hypoxia to partly reactivate EBV infected cells.
=> Since such potential hypoxia would be condition dependent (gravitational location toward the heart, quality of blood flow to that organ, recent exertion of that or other organs], it would affect specific and (in time) different *parts* of the body, giving a good clue of how 'partial' (as in only part of the body) and 'time shifted smaller but more frequent spikes' of EBV reactivation could occur (leaving many of those episodes just below the clinical threshold quantifying for 'real' EBV reactivation).
[REF6]
www.nature.com
title: "Latency and lytic replication in Epstein–Barr virus-associated oncogenesis"
[REF7] from references from [REF6]
pmc.ncbi.nlm.nih.gov
title: "An Epstein-Barr Virus (EBV) mutant with enhanced BZLF1 expression causes lymphomas with abortive lytic EBV infection in a humanized mouse model "
"The SL mutant establishes an abortive form of lytic EBV infection in lymphoma cells."
"Furthermore, our results show that Z-expressing lymphoma cells in this mouse model contain an abortively lytic form of viral infection that does not appear to inhibit lymphoma cell growth"
[HYPOTHESIS6]
=> From [REF7]: In some cases, EBV reactivation *within* a single cell *could* be partial too, meaning that the activated cell does not follow the 'usual' path of quick viral production and lysis ('rupture') leading to the release of a large viral EBV load and the infected cell's death but to a 'recoverable' state where the infected cell increases EBV virus production more modest, the infected cell does not go into lysis (does not 'burst') and viral shedding from that cell is a lot more modest (again helping EBV reactivation easier to stay under clinical detection levels). The downside would be that the infected cell would survive, recover, go into latency again, produce EBNA again, reactivate again... ...and so on but in a modest 'slow motion' way rather then be eliminated by death through lysis.
=> Things like increased potentially interferon / itaconate within these cells plus reduced production / supply of ATP which is consumed at high rate during viral replication might 'better allow' for such hypothesized partial / slow *within cell* EBV activation rather then full activation and lysis. It sort of would be a 'Dauer within the infected cell'.
[HYPOTHESIS7]
=> CMV, another virus popping up frequently in ME/CFS discussion, is a latent / reactivation virus too and hence could trigger similar problems.
[REF8]
title: "Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis"
"One study demonstrated cross-reactivity between EBNA1 amino acids 394 to 399 and GlialCAM (18), and we have previously demonstrated the same for EBNA1 amino acids 431 to 440 with ANO2 (17). In addition, EBNA1 amino acids 411 to 426 and myelin basic protein cross-reactivity has been demonstrated in experimental autoimmune encephalomyelitis (EAE) (36), and EBNA1-specific T cells have been shown to react to a mixed myelin antigen pool (33)."
[NOTE1]
ANO2
"ANO2 include Von Willebrand Disease, Type 3 and Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2L.Among its related pathways are Infectious disease and SARS-CoV-2 Infection."
pubmed.ncbi.nlm.nih.gov
title: "TMEM16B regulates anxiety-related behavior and GABAergic neuronal signaling in the central lateral amygdala "
"TMEM16B (ANO2) is the Ca 2+-activated chloride channel expressed in multiple brain regions, including the amygdala.Here we report that Ano2 knockout mice exhibit impaired anxiety-related behaviors and context-independent fear memory, thus implicating TMEM16B in anxiety modulation."
pmc.ncbi.nlm.nih.gov
title: "Cellular functions of TMEM16/anoctamin"
"ANO1 is known to mediate Cl− secretion in secretory epithelia such as airways, salivary glands, intestines, renal tubules, and sweat glands. ANO1 is a heat sensor activated by noxious heat in somatosensory neurons and mediates acute pain sensation as well as chronic pain. ANO1 is also observed in vascular as well as airway smooth muscles, controlling vascular tone as well as airway hypersensitivity. ANO1 is upregulated in numerous types of cancers and thus thought to be involved in tumorigenesis."
=> ANO1 affects mucus quality, a published (need reference) suspect in ME/CFS
=> Also controlling blood flow (vascular tone), chronic pain, involved in types of cancer...
GlailCAM
pubmed.ncbi.nlm.nih.gov
title: "GlialCAM, a glial cell adhesion molecule implicated in neurological disease"
"In epithelial cell lines, overexpression of GlialCAM increases cell adhesion and motility but also inhibits cell growth in tumor cell lines, leading to senescence."
=> Another relation to chloride channels (mucus) and cancer (inhibition or lack of inhibition of tumor cells depending on expression)
meylin
=> Well known to be the component attacked by the own immune system in the auto-immune disease MS.
[REF9]
pmc.ncbi.nlm.nih.gov
title: "Epstein-Barr Virus in Systemic Lupus Erythematosus, Rheumatoid Arthritis and Multiple Sclerosis—Association and Causation"
"Sequence or structural similarities between microbial and self-antigens are believed to cause cross-reactivity of T-cells, B-cells and antibodies. It has been shown that cross-reactive antibodies are involved in the pathogenesis of Sydenham chorea, Guillain-Barré syndrome and HTLV-1 associated myelopathy."
"In SLE, autoantibodies against epitopes on SmB’ and SmD1 have been shown to cross-react with different domains of EBNA-1"
[NOTE2]
For completion, with [REF9]:
"In contrast, although there is strong circumstantial evidence [170,171] and the mechanism is shown to be relevant in animal models of autoimmune diseases [172], cross-reactive T-cells have so far not been shown to mediate human disease."
=> Maybe the circumstantial evidence is not wrong, and further research could show it can and does mediate human disease?
[NOTE3]
From Wikipedia (good enough reference for general disease discription for now): "Sydenham's chorea, also known as rheumatic chorea, is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet."
From Wikipedia too: "Guillain–Barré syndrome is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain often in the back along with muscle weakness, beginning in the feet and hands, often spreading to the arms and upper body."
[HYPOTHESIS8]
=> From [REF8] and [NOTE1], latent EBNA proteins and the trained immune response to them (as a means for cytotoxic T-cells to try and eliminate latent infected B-cells) could be at a crossroad between auto-immune disease MS, several other auto-immune diseases, several types of cancer and ME/CFS.
In other words: *in the case / subgroup of 'EBNA dominant ME/CFS'*, ME/CFS could be the (as proposed by dr Naviaux) 'Dauer' or inhibition in order to stave off risk of developping auto-immune diseases (MS and select others) or EBNA related cancers. In other words: 'Dauer' would not only be real but could 'hide, inhibit, shelter' against *actual modern day serious risks* rather then merely be an ancient genetic program we inherited from far ancestors.
=> That would also mean that 'without looking at EBV / EBNA status' or quality research 'breaking' this hypothetical 'EBNA Dauer' vicious circle *might* trigger an unknown (in size) risk to accelerate the alternative auto-immune and cancer routes. Care needs to be taken.
=> People infected at young age with EBV would be at far lower risk due to far less strong initial infection EBV disease strength, very strongly reducing the risk to create a self sustaining immune loop.
[REF10]
pubmed.ncbi.nlm.nih.gov
title: "Cytomegalovirus Latency and Reactivation: An Intricate Interplay With the Host Immune Response"
"Spontaneous reactivation induced by cellular aging/damage may explain why extensive expression of lytic genes has been observed in recent studies using highly sensitive transcriptome analyses of cells from latently infected individuals. Recent studies with animal models highlight the potential for harnessing the host immune response to blunt cellular injury induced by organ transplantation, and thus, prevent reactivation of CMV and its sequelae."
=> Indicates that 'EBV herpes family relative CMV' is *likely* able to partly reactivate even during latency
[HYPOTHESIS9]
=> From [REF10]: the body *might* indeed be capable to 'use' *well controlled!* reactivation of herpes type virusses in order to suppress (auto-)immune reactions (often occuring after organ transplantation). In the paper it involves herpes type CMV, but EBV is also a herpes type virus.
[NOTE4]
pmc.ncbi.nlm.nih.gov
title: "Epstein Barr Virus Reactivation during COVID-19 Hospitalization Significantly Increased Mortality/Death in SARS-CoV-2(+)/EBV(+) than SARS-CoV-2(+)/EBV(−) Patients: A Comparative Meta-Analysis"
=> Covid-19 infection seems to be quite able to reactivate EBV. EBV is a rather opportunisitic virus that tends to reactivate when patients are at their weakest. That reactivation (if not very well controlled) *could* significantly increase the number of EBV infected cells, significantly (and long lasting) increasing the amount of EBNA produced and the amount of EBNA specific T-cells and with it strongly increase the strength of the above mentioned EBNA - EBNA reactive T-cells immune loop (hence creating ME/CFS similar disease long-Covid)
[NOTE5]
(Prior) EBV infection is NOT needed to get struck with ME/CFS as a number of cases confirm. However few adults have zero latent herpes virus infections and other pathogens might pull similar tricks.
[HYPOTHESIS10]:
=> From many of above risks for different auto-immune diseases due to EBNA specific reactivity, many of the symptoms ME/CFS patients experience ‘could come from a fairly strong but incomplete suppressed auto immune-like reaction to EBNA’.
=> In other words: Many patients might show some amount of indications of a ‘grouped’ spectrum of auto-immune diseases but often (by a small or bigger margin) fail to qualify for a diagnose for any of these diseases.
=> In practice, many patients describe symptoms similar to *multiple* / a series of the above mentioned ‘alternative routes’ to EBNA reactivity (the list with EBNA related auto-immune diseases).
[REF1]
title: "Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages"
definition: "itaconate (OI)"
"JAK1 activation was also inhibited by OI in response to IL-13, interferon-β, and interferon-γ in macrophages and in T helper 2 (Th2) cells. Importantly, JAK1 was directly modified by itaconate derivatives at multiple residues, including cysteines 715, 816, 943, and 1130. Itaconate and OI also inhibited JAK1 kinase activity."
In response to Jen X' second blog on her recovery, I looked up what could be important about her / some cases of ME/CFS, in particular her high IL2 levels.
[REF2]
title: "Disease-Modifying Treatments for Multiple Sclerosis Affect Measures of Cellular Immune Responses to EBNA-1 Peptides"
"EBNA-1 stimulation of whole blood samples produced higher levels of IFN-γ and IL-2 in pwMS compared with controls and PWE".
[CONCLUSION1]
=> Combining [REF1] and [REF2] lead to the plausible involvement of trained / acquired immunity of T-cells against EBNA-1, a latent Ebstein-Barr viral protein. I followed that as one of plausible trails.
[REF3]
Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis
Abstract. Epidemiological studies consistently demonstrate that patients with multiple sclerosis are almost universally infected with Epstein–Barr virus (E
academic.oup.com
[CONCLUSION2]
=> Title of [REF3] confirms cases of *addaptive* immunity of T-cells to EBNA-1 is a real, occuring and observed phenomen by research
[HYPOTHESIS1]
=> [REF2], [REF3] and [CONCLUSION2] could, in some EBV related case, cause a persistent upregulation of IFN-γ and IL-2, EBNA-1 (latent EBV nuclear antigen-1) specific antigen T-cells and a whole range of immune activations this EBNA-1 specific antigen triggers when it activates the specific T-cells. This would happen as EBNA-1 latent antigen is produced lifelong by EBV infected cells. Such constant stream of EBNA-1 antigen then has the potential to bind to these specific EBNA-1 antigen T-cells and trigger the clonal expansion of these EBNA-1 antigen T-cells, further increasing (amplifying) the strength of the sort of self-immune reaction and so on.
[HYPOTHESIS2]
=> [HYPOTHESIS1] has a major problem: it would *risk* leading to cause a cytokine / immune reaction storm that is rather destructive. Such strong storms can kill patients quickly, as is seen in Covid-19 as too strong immune response to the Covid19 virus is a leading cause of death in Covid19 disease. This hence could kill the patient, unless 'resolved, containt' by things like strong immuno represants or plain immune exhaustion. Itaconate happens to dampen (auto-)immune reactions too, Jen experienced a confirmed cytokine storm and it is fair to say (near?) all ME/CFS patients experience immune exhaustion. Such immune exhaustion could have a powerfull dampening effect on the (many chained elements of the) feedback loop, preventing it to further auto-escalate.
[REF4]
title: "Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis"
"Specific cytotoxic T cell responses can control EBV-infected GlialCAM-specific B cells"
[REF5]
Serological diagnosis of Epstein-Barr virus infection: Problems and solutions - PMC
Serological tests for antibodies specific for Epstein-Barr virus (EBV) antigens are frequently used to define infection status and for the differential diagnosis of other pathogens responsible for mononucleosis syndrome. Using only three parameters ...
pmc.ncbi.nlm.nih.gov
"As EBNA-3 is a target of CD8+ lymphocytes[7], latent cells are normally eliminated by cytotoxic T lymphocytes in immunocompetent patients[1], whereas the transformed cells can proliferate and cause various lymphoproliferative disorders in immunosuppressed patients[13]."
[HYPOTHESIS3]
=> [REF4] and [REF5] lead to the hypothesis that EBV infected B-cells that are masters in evading elimination by our own immune system, are tracked and targetted for destruction by recognising latent EBNA loads (ready for shedding) in these cells; in this specific research EBNA-3 is a main T-cell specific antigen (‘able to zoom in on cells loaded with EBNA-3’ in order to eliminate them).
=> This makes the production of EBNA antigen specific T-cells after (elaborate, meaning a large amount of infected cells) EBV infection not a mere random fluke but a likely and common result.
=> This also would explain why (EBV) post-viral problems are much more common in adult onset cases of EBV then infection at very young age: the infection at young age is typically a lot more mild. Older age first EBV infection hence would have a chance to infect a lot more cells due to the generally far stronger EBV infection associated disease at that age.
=> That would lead to two things amplifying the possible self-immune loop: first a higher production of EBNA proteins due to higher amount of EBV infected cells, second a higher chance (or higher amount) of the own immune system to form antibodies against EBNA due to a higher amount of 'problematic' EBV infected B-cells and higher EBNA amounts in plasma.
=> Two factors in the feedback loop increasing has a very potent effect on increasing the chance that the feedback loop becomes ‘unstable’ (causes severe problems in this case).
=> Immune exhaustion is one of potential 'sort of solutions' to dampen this feedback loop that can be dangerous if out of control, similar to the own immune system being a big cause of death in Covid-19 infection. Increased interferon / itaconate production can dampen this feedback loop as well as itaconate canb dampen many auto-immune diseases too.
[HYPOTHESIS4]
=> partial / frequent EBV reactivation offers the paradoxial potential to dampen this potentially dangerous / deadly feedback loop.
EBNA-1 and EBNA-3 are only produced during latency of the EBV infected cells, not during their activation. If / when EBNA specific activated T-cells risk to become the dominant risk to the human body for survival, the body could 'decide' to 'break' the production (or better said dampen its production) of EBNA by... ...letting / provoking / enticing the EBV infected cells to (partly and periodically) reactivate.
=> This may seem absurd at first glance, but if an overactive feedback loop risks permanent or even life-threathening risk, it would not be that unreasonable to do so *especially* if it could do so controlled.
=> As a matter of fact, many patients report frequent EBV reactivations and science ([REF6] below) is a strong indication that happens.
=> In this hypothesis, a 'partial' EBV reactivation of an EBV infected cell would halt and interrupt the production of all EBNA proteins inside that cell. Even a short EBV reactivation would trigger a new and significant delay before resuming EBNA production because the EBV infected cells would need time to go to the correct latency phase to restart producing the specific EBNAs. That should either significantly temporarily dampen EBNA production (in a cyclic fashion) or reduce the average *body wide* EBNA production if partial EBV reactivation did not always occured simultaneously in the body (e.g. different parts of the body experience EBV reactivation at different times). That in turn would significantly temporarilly (enough to take back part of the previous escalation of the feedback loop in the case of a cyclic event) or on average (if EBV reactivation was happening at different times in different places of the body) reduce the strength of the potentially dangerous EBNA - EBNA specific T-cell activation feedback loop. Potentially a partial reactivation of a modest percentage of EBV infected cells *might* be enough to signal *non-activating* EBV cells to temporarilly halt or reduce EBNA production as well, but this part is speculative.
[REF5]
Stress-Induced Epstein-Barr Virus Reactivation - PMC
Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses ...
pmc.ncbi.nlm.nih.gov
"Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is another disease associated with EBV reactivation [151]."
"Lastly, the authors showed that hypoxia-induced EBV reactivation"
[REF6] (from [151] above)
Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome - PubMed
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystem chronic disease. The etiology and pathogenesis of ME/CFS are unknown. Infections of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6) are suspected as etiological agents for...
pubmed.ncbi.nlm.nih.gov
"In ME/CFS plasma samples, EBV DNA was found in 24.1%, CMV DNA in 3.4%, and HHV-6 DNA in 1.7% of samples."
[HYPOTHESIS5]
=> From [REF5]: Reduced blood volumes and blood flow, as often seen in ME/CFS, could lead to sufficient episodes of (enough) hypoxia to partly reactivate EBV infected cells.
=> Since such potential hypoxia would be condition dependent (gravitational location toward the heart, quality of blood flow to that organ, recent exertion of that or other organs], it would affect specific and (in time) different *parts* of the body, giving a good clue of how 'partial' (as in only part of the body) and 'time shifted smaller but more frequent spikes' of EBV reactivation could occur (leaving many of those episodes just below the clinical threshold quantifying for 'real' EBV reactivation).
[REF6]
Latency and lytic replication in Epstein–Barr virus-associated oncogenesis - Nature Reviews Microbiology
Epstein–Barr virus (EBV) establishes latent and persistent infections in humans, and is associated with several cancers. In this Review, Münz discusses the evidence for EBV persistence without B cell transformation and the role of early abortive lytic replication as well as non-coding RNAs in...
www.nature.com
[REF7] from references from [REF6]
An Epstein-Barr Virus (EBV) Mutant with Enhanced BZLF1 Expression Causes Lymphomas with Abortive Lytic EBV Infection in a Humanized Mouse Model - PMC
Immunosuppressed patients are at risk for developing Epstein-Barr Virus (EBV)-positive lymphomas that express the major EBV oncoprotein, LMP1. Although increasing evidence suggests that a small number of lytically infected cells may promote ...
pmc.ncbi.nlm.nih.gov
"The SL mutant establishes an abortive form of lytic EBV infection in lymphoma cells."
"Furthermore, our results show that Z-expressing lymphoma cells in this mouse model contain an abortively lytic form of viral infection that does not appear to inhibit lymphoma cell growth"
[HYPOTHESIS6]
=> From [REF7]: In some cases, EBV reactivation *within* a single cell *could* be partial too, meaning that the activated cell does not follow the 'usual' path of quick viral production and lysis ('rupture') leading to the release of a large viral EBV load and the infected cell's death but to a 'recoverable' state where the infected cell increases EBV virus production more modest, the infected cell does not go into lysis (does not 'burst') and viral shedding from that cell is a lot more modest (again helping EBV reactivation easier to stay under clinical detection levels). The downside would be that the infected cell would survive, recover, go into latency again, produce EBNA again, reactivate again... ...and so on but in a modest 'slow motion' way rather then be eliminated by death through lysis.
=> Things like increased potentially interferon / itaconate within these cells plus reduced production / supply of ATP which is consumed at high rate during viral replication might 'better allow' for such hypothesized partial / slow *within cell* EBV activation rather then full activation and lysis. It sort of would be a 'Dauer within the infected cell'.
[HYPOTHESIS7]
=> CMV, another virus popping up frequently in ME/CFS discussion, is a latent / reactivation virus too and hence could trigger similar problems.
[REF8]
title: "Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis"
"One study demonstrated cross-reactivity between EBNA1 amino acids 394 to 399 and GlialCAM (18), and we have previously demonstrated the same for EBNA1 amino acids 431 to 440 with ANO2 (17). In addition, EBNA1 amino acids 411 to 426 and myelin basic protein cross-reactivity has been demonstrated in experimental autoimmune encephalomyelitis (EAE) (36), and EBNA1-specific T cells have been shown to react to a mixed myelin antigen pool (33)."
[NOTE1]
ANO2
"ANO2 include Von Willebrand Disease, Type 3 and Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2L.Among its related pathways are Infectious disease and SARS-CoV-2 Infection."
TMEM16B regulates anxiety-related behavior and GABAergic neuronal signaling in the central lateral amygdala - PubMed
TMEM16B (ANO2) is the Ca<sup>2+</sup>-activated chloride channel expressed in multiple brain regions, including the amygdala. Here we report that <i>Ano2</i> knockout mice exhibit impaired anxiety-related behaviors and context-independent fear memory, thus implicating TMEM16B in anxiety...
pubmed.ncbi.nlm.nih.gov
"TMEM16B (ANO2) is the Ca 2+-activated chloride channel expressed in multiple brain regions, including the amygdala.Here we report that Ano2 knockout mice exhibit impaired anxiety-related behaviors and context-independent fear memory, thus implicating TMEM16B in anxiety modulation."
Cellular functions of TMEM16/anoctamin - PMC
Ca2+-activated Cl− channels (CaCCs) are a class of Cl− channels activated by intracellular Ca2+ that are known to mediate numerous physiological functions. In 2008, the molecular identity of CaCCs was found to be anoctamin 1 (ANO1/TMEM16A). Its ...
pmc.ncbi.nlm.nih.gov
"ANO1 is known to mediate Cl− secretion in secretory epithelia such as airways, salivary glands, intestines, renal tubules, and sweat glands. ANO1 is a heat sensor activated by noxious heat in somatosensory neurons and mediates acute pain sensation as well as chronic pain. ANO1 is also observed in vascular as well as airway smooth muscles, controlling vascular tone as well as airway hypersensitivity. ANO1 is upregulated in numerous types of cancers and thus thought to be involved in tumorigenesis."
=> ANO1 affects mucus quality, a published (need reference) suspect in ME/CFS
=> Also controlling blood flow (vascular tone), chronic pain, involved in types of cancer...
GlailCAM
GlialCAM, a glial cell adhesion molecule implicated in neurological disease - PubMed
GlialCAM (also named HepaCAM) is a cell adhesion molecule expressed mainly in glial cells from the central nervous system and the liver. GlialCAM plays different roles according to its cellular context. In epithelial cell lines, overexpression of GlialCAM increases cell adhesion and motility but...
pubmed.ncbi.nlm.nih.gov
"In epithelial cell lines, overexpression of GlialCAM increases cell adhesion and motility but also inhibits cell growth in tumor cell lines, leading to senescence."
=> Another relation to chloride channels (mucus) and cancer (inhibition or lack of inhibition of tumor cells depending on expression)
meylin
=> Well known to be the component attacked by the own immune system in the auto-immune disease MS.
[REF9]
Epstein-Barr Virus in Systemic Lupus Erythematosus, Rheumatoid Arthritis and Multiple Sclerosis—Association and Causation - PMC
Epidemiological data suggest that the Epstein-Barr virus (EBV) is associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. However, it is not clear whether EBV plays a role in ...
pmc.ncbi.nlm.nih.gov
"Sequence or structural similarities between microbial and self-antigens are believed to cause cross-reactivity of T-cells, B-cells and antibodies. It has been shown that cross-reactive antibodies are involved in the pathogenesis of Sydenham chorea, Guillain-Barré syndrome and HTLV-1 associated myelopathy."
"In SLE, autoantibodies against epitopes on SmB’ and SmD1 have been shown to cross-react with different domains of EBNA-1"
[NOTE2]
For completion, with [REF9]:
"In contrast, although there is strong circumstantial evidence [170,171] and the mechanism is shown to be relevant in animal models of autoimmune diseases [172], cross-reactive T-cells have so far not been shown to mediate human disease."
=> Maybe the circumstantial evidence is not wrong, and further research could show it can and does mediate human disease?
[NOTE3]
From Wikipedia (good enough reference for general disease discription for now): "Sydenham's chorea, also known as rheumatic chorea, is a disorder characterized by rapid, uncoordinated jerking movements primarily affecting the face, hands and feet."
From Wikipedia too: "Guillain–Barré syndrome is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain often in the back along with muscle weakness, beginning in the feet and hands, often spreading to the arms and upper body."
[HYPOTHESIS8]
=> From [REF8] and [NOTE1], latent EBNA proteins and the trained immune response to them (as a means for cytotoxic T-cells to try and eliminate latent infected B-cells) could be at a crossroad between auto-immune disease MS, several other auto-immune diseases, several types of cancer and ME/CFS.
In other words: *in the case / subgroup of 'EBNA dominant ME/CFS'*, ME/CFS could be the (as proposed by dr Naviaux) 'Dauer' or inhibition in order to stave off risk of developping auto-immune diseases (MS and select others) or EBNA related cancers. In other words: 'Dauer' would not only be real but could 'hide, inhibit, shelter' against *actual modern day serious risks* rather then merely be an ancient genetic program we inherited from far ancestors.
=> That would also mean that 'without looking at EBV / EBNA status' or quality research 'breaking' this hypothetical 'EBNA Dauer' vicious circle *might* trigger an unknown (in size) risk to accelerate the alternative auto-immune and cancer routes. Care needs to be taken.
=> People infected at young age with EBV would be at far lower risk due to far less strong initial infection EBV disease strength, very strongly reducing the risk to create a self sustaining immune loop.
[REF10]
Cytomegalovirus Latency and Reactivation: An Intricate Interplay With the Host Immune Response - PubMed
CMV is an ancient herpesvirus that has co-evolved with its host over millions of years. The 236 kbp genome encodes at least 165 genes, four non-coding RNAs and 14 miRNAs. Of the protein-coding genes, 43-44 are core replication genes common to all herpesviruses, while ~30 are unique to...
pubmed.ncbi.nlm.nih.gov
"Spontaneous reactivation induced by cellular aging/damage may explain why extensive expression of lytic genes has been observed in recent studies using highly sensitive transcriptome analyses of cells from latently infected individuals. Recent studies with animal models highlight the potential for harnessing the host immune response to blunt cellular injury induced by organ transplantation, and thus, prevent reactivation of CMV and its sequelae."
=> Indicates that 'EBV herpes family relative CMV' is *likely* able to partly reactivate even during latency
[HYPOTHESIS9]
=> From [REF10]: the body *might* indeed be capable to 'use' *well controlled!* reactivation of herpes type virusses in order to suppress (auto-)immune reactions (often occuring after organ transplantation). In the paper it involves herpes type CMV, but EBV is also a herpes type virus.
[NOTE4]
Epstein Barr Virus Reactivation during COVID-19 Hospitalization Significantly Increased Mortality/Death in SARS-CoV-2(+)/EBV(+) than SARS-CoV-2(+)/EBV(−) Patients: A Comparative Meta-Analysis - PMC
Epstein–Barr virus (EBV) reactivation in acute-phase of COVID-19 disease was recently discovered but it is not clear in terms of degree of mortality caused, and this was the aim of the current study. Six databases and three non‐databases were ...
pmc.ncbi.nlm.nih.gov
=> Covid-19 infection seems to be quite able to reactivate EBV. EBV is a rather opportunisitic virus that tends to reactivate when patients are at their weakest. That reactivation (if not very well controlled) *could* significantly increase the number of EBV infected cells, significantly (and long lasting) increasing the amount of EBNA produced and the amount of EBNA specific T-cells and with it strongly increase the strength of the above mentioned EBNA - EBNA reactive T-cells immune loop (hence creating ME/CFS similar disease long-Covid)
[NOTE5]
(Prior) EBV infection is NOT needed to get struck with ME/CFS as a number of cases confirm. However few adults have zero latent herpes virus infections and other pathogens might pull similar tricks.
[HYPOTHESIS10]:
=> From many of above risks for different auto-immune diseases due to EBNA specific reactivity, many of the symptoms ME/CFS patients experience ‘could come from a fairly strong but incomplete suppressed auto immune-like reaction to EBNA’.
=> In other words: Many patients might show some amount of indications of a ‘grouped’ spectrum of auto-immune diseases but often (by a small or bigger margin) fail to qualify for a diagnose for any of these diseases.
=> In practice, many patients describe symptoms similar to *multiple* / a series of the above mentioned ‘alternative routes’ to EBNA reactivity (the list with EBNA related auto-immune diseases).
Last edited:
![ME/CFS lecture | Dr Nancy Klimas | 2011 [Chronic Fatigue Syndrome / SEID / New Zealand] - YouTube](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
