Montoya Calls for New Research Focus
The Immune System! The ever-present, ever complex immune system – a place of so many hopes in CFS and such a tough nut to crack. In his opening address for the Infectious Pathogens section Dr. Montoya pointed out how inconsistent study results have made it difficult to get a handle on what’s going on. The natural killer cell dysfunction findings are solid and there’s a good deal of evidence for an inhibited Th1 and a dominant Th2 response but inconsistent results across major parts of the immune system (T-cells, tumor necrosis factor (TNF-a), IgG levels, IFN-y) have made it difficult to understand the role the immune system plays.
(A recent review of the topic stated : Despite many years of intense investigation there is little consensus on the presence, nature and degree of immune dysfunction in this condition. However, slightly increased parameters of inflammation and pro-inflammatory cytokines such as interleukin (IL) 1, IL6 and tumour necrosis factor (TNF) α are likely present. Additionally, impaired natural killer cell function appears evident. Bansal et. al. 2011 Chronic fatigue syndrome, the immune system and viral infection)
Rethinking CFS Research – For all the talk about the bad name, it’s much more likely that it’s the complexity of CFS, with its probable subsets, its many symptoms and variable presentations that has, more than anything else impeded research. Researchers probably don’t feel they can make progress in what they feel is a ‘wastebasket disorder’.
Dr. Montoya listed a plethora of problems that could be throwing immune tests off and was echoed by a recent review of the field by Bansal which cited the heterogeneity of the disorder, the marked day-to-day variability in symptoms, the difficulty of assessing cytokine levels, and the ‘marked variation in assay sensitivity and reproducibility’ (ouch!) and other problems.
Dr. Montoya called, as Dr. Vernon did two years at the last conference, for a pick yourself up by the bootstraps type approach with the CFS field committing itself to developing rigorous standards – a kind of Gold Seal Approach to CFS. Should it happen? Yes….Will it happen? Don’t hold your breath. The IACFS/ME is the logical choice to do this but there’s no evidence of a push there to do that.
The Innate Problem in CFS; Montoya Calls for a New Focus For Immune Research – Researchers and doctors are most familiar with the ‘adaptive’ immune response that kicks in a couple of days into an infection but the other immune response – the innate immune system that both alerts the adaptive immune system and keeps pathogens at bay early has not received much attention and Dr. Montoya thinks that’s been a big mistake.
Dr. Montoya is not alone in his belief that the key to ME/CFS may lie in the innate immune response. The best drug for ME/CFS, Ampligen, is believed to primarily affect the innate immune response. Conference presentations suggested the basal ganglia in the brain are heavily involved in ME/CFS and they are hit hard by innate immune cytokines (TNF-a, IL-1, IL- 12, chemokines, interferon) . A study published just last week suggested an innate immune system gene highlighted in CFS may cause severe fatigue in hepatitis patients. Dr. Maes has long been a proponent of the importance innate immune functioning plays in CFS and a recent paper of his asserts the innate immune system problems also play a key role in depression. The innate immune system is slowly coming of age in ME/CFS.
(There is no evidence of increased mood disorders prior to CFS ; ie they are not a risk factor for CFS but there is an increased incidence after ME/CFS. It’s likely that the same neuro-immune perturbations may be causing fatigue, depression, exercise problems and other symptoms – see the Clauw article Ottawa III : Most Expensive Disorder Ever? . )
Montoya’s emphasis on the innate immune response could very well reflect data his Chronic Infectious Illness group at Stanford has gathered. He’s expected to release several papers over the next six months but didn’t present any findings at the Conference. A surprisingly strong advocate for CFS given his position at one of the pillars of medical research the US, (Stanford is the fifth ranked university for medical research in the entire country!) Montoya has released papers slowly; which may be a good thing given that he’s probably got a huge target on his back at Stanford.
The XMRV results must have had mixed results for other researchers working in the CFS field. One can imagine the many interesting discussions they had with their colleagues when XMRV burst on the scene but the events of the last year gave room for researchers hostile to CFS to air their views. For researchers struggling to get their small programs off the ground it may have been a difficult year.
Stress Helps!!…. Researchers – One thing that has been illustrated in spades, Montoya asserted, is how ‘incredibly important’ ‘stress challenges’ are to understanding this disorder. Putting patients through some sort of challenge – whether it is an exercise test, a psychological stress, tilt table test – whatever – is becoming more and more a requirement than an option for CFS researchers. Whacking CFS patients with stress tests could help dramatically study results because lab tests involving CFS patients often seem normal until a stressor is involved. It’s takem the research community a long time to understand the difference between a fatiguing and an exertion-based disorder but they’re getting it and that’s good news.
The Immune…er… ‘Natural Killer Cell’ Session
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Dr. Nancy Klimas
The Immune session was titled “the Latest Research in Immunology’ but it might as well have been titled “the Natural Killer Cell Session” as many of the presentations focused our favorite (J) immune abnormality – natural killer (NK) cells. NK cells have been studied on and off in ME/CFS for about 20 years and are getting more emphasis than ever before.
TWO LEADERS
The immunology section was dominated by two research groups; the PHANU group in Australia and the Klimas/Fletcher group in the US. Both have scored big successes recently; PHANU received a major grant from the Mason Foundation and Dr. Klimas is leading up the newly formed Institute for Neuroimmune Medicine at the Nova Southeastern University.
Focus on PHANU
The “Population, Health and Neuroimmunology Unit’ at Bond University in Australia, is one of the few research centers focused completely on ME/CFS. Overseen by Marshall-Gradisnik and Staines and now collaborating with Dr. Peterson and his non-profit foundation, Simmaron Research, PHANU is engaged quite
a bit of original and creative research. With no less than 7 presentations and abstracts, the PHANU/Peterson team was the most productive at the conference. With some studies looking in multiple areas at the same time (eg blood and spinal fluid) the PHANU studies were often notable for their depth. Some were quite preliminary, though, and we’ll have to wait for their completion to assess their effectiveness.
A ‘Gold Star’ Study
Disparities in Innate and Adaptive Immune Cell Activities in Chronic Fatigue Syndrome -Brenu, Staines, Marshall-Gradisnik, et. al.
Both Dr. Klimas and Dr. Peterson have suggested that one of the big guns of the immune systems – cytotoxic T-cells – might be suffering the same fate as NK cells. It turns out that while NK cells man the early immune response, and the more complex cytotoxic T-cells man the later adaptive response. they both use the same mechanism (perforin) to punch a hole into and kill infected cells.
The Perforin NK/T-Cell Connection – Perforin is a multidimensional protein that helps NK and T cells to first ‘burn’ a hole into infected cells and then directs the enzymes (granzymes) that kill the cell where to go. First described in 1985, perforin’s unusual structure and its similarity across species suggests it’s an ancient protein that has ‘universally essential biological properties’. While the immune system tends to have multiple redundancies perforin’s unique structure means there is no substitute for it…..once it’s gone there is no making up for it. The disappearance of perforin leads to a failure of the secretory granule system T and NK cells use to kill pathogens hiding inside of cells.
“ The loss of secretory granule function has catastrophic consequences for the survival of an organism challenged with …..intracellular pathogens: depending on the level of residual activity in this pathway, an individual either becomes increasingly susceptible to a pathogen, succumbs to overwhelming viral infection or develops immune dysregulation” Voskoiboinik et. al. Perforin: structure, function and role in human immunopathology.
Studies of perforin ‘knockout mice -mice which have been genetically breed to have reduced perforin levels – indicated that these mice are healthy until they are presented with a pathogen. These mice then develop a ‘plethora of immune deficiencies’ and are at greatly increased risk of developing immune cell cancers. Perforin deficient mice can also develop auto-immune induced encephalomyelitis. Perforin also plays an important role in combating intracellular bacterial infections.
Difficulty producing perforin in the lab, however, stalled study into its biochemical characteristic until 2005. That breakthrough reignited interest in perforin but after noting that perforin was ‘absolutely essential for cytotoxic T-cell functioning’, a recent review still stated perforin ‘is still the least studied and understood cytotoxic molecule in immune system”.
Perforin isn’t ‘gone’ in ME/CFS but it is lower than normal and the finding that reduced perforin can tweak immune system functioning suggests the perforin problems could contribute to the strange immune network effects Broderik has been documenting.
Perforin, of course, is not doing its job very well in ME/CFS but except for a hint in an earlier Klimas/Fletcher paper no one has examined how well it was operating in those other cells – the cytotoxic T-cells.
Focus on Cytotoxic T-cells – Once an invader is identified cytotoxic T-cells form hordes of identical clones that are specifically constructed, like little homing missiles, to focus in and take out that particular pathogen. Because it takes awhile to clone and produce these hordes of attackers, the cytotoxic T-cell response usually kicks in a couple of days after the innate immune response has identified (and temporarily held at bay) the invader. Given that the cytotoxic T-cells play a large role in cleansing the body of infections, it’s no surprise that they have been given a lot of attention by immunologists.
NK cells may not be doing well at fighting off pathogens as they enter the body but a finding that the ‘clean up hitters’ – the cytotoxic T-cells are also faltering – would suggest that both sides of the immune defense are hampered in CFS and that is what the PHANU team found in what Dr. Klimas called ‘a very important finding’. This large study (90 patients) found reductions in perforin activity in both NK and cytotoxic T-cells in ME/CFS patients.
Perforin Dysfunction in Cytotoxic T-cells in Humans – Thus far perforin problems have only been conclusively associated in one other disorder in humans: a rare and quickly fatal genetic disorder called familial haemophagic lymphohistocytosis (FHL). In FHL a total loss of perforin production results in massive and uncontrolled activation of T-cells and macrophages and greatly increased pro-inflammatory cytokine production. (Whether pro-inflammatory cytokine expression is increased in CFS depends on which study you’re reading but the Klimas/Fletcher lab consistently finds it.)
Herpesviruses and perforin – a bit of evidence suggests perforin deficiency may increase the risk of herpesvirus activation. T-cells used different ‘pathways’ to kill invaders and the one used to kill herpesvirus infections involves perforin. Perforin expression appears to be impaired in EBV associated nasal cancer and a death from chronic EBV infection – a rarer, more serious and often fatal type of infection than found in CFS – was associated with mutations in perforin genes.
THE Mechanism Identified? – Stating that this finding could get at the ‘mechanism’ allowing viruses to flourish in some patients, Dr. Klimas gave this study a ‘Gold Star’. When it’s published it will hopefully lift some eyebrows in the immunology community, prompting more immunologists to study ME/CFS.
Blasted At Birth? PHANU Looks at miRNA’s and Perforin..
Expression patterns of miRNA’s in Lymphocytes in Patients with Chronic Fatigue Syndrome (Brenu, Staines, Marshall-Gradisnik et. al.)
Two groups (PHANU at Bond University and the CDC) are trying to figure what’s causing the perforin problems. The Bond group turned to a rather new discovery – miRNA’s – to try and explain the perforin problem.
Focus on miRNA’s – micro or miRNA’s are short bits of RNA that regulate gene transcription. The first miRNA was discovered in the 1993 and it took seven more years for another to be identified but once miRNA’s were recognized as important biological regulators the field took off. With over 1,000 different miRNA’s identified, which effect 60% of human genes in the human body, miRNA’s are now believed involved in most biological processes in the body. Abberrant miRNA behavior been associated with many kinds of cancer, neurodegenerative disorders such as Alzheimer’s, Parkinson’s and spinal motor neuron disorder, heart failure, diabetes, pulmonary fibrosis, schizophrenia and others. miRNA’s are a fertile field of research and the Bond U study was the first to look at them in CFS.
Brenu et. al looked specifically at miRNA’s known to effect T and cytotoxic T-cell functioning. Their finding that six of 15 miRNA’s were downregulated in both NK and cytotoxic T-cells (Tc) in ME/CFS patients relative to the healthy controls indirectly validated their big finding of perforin problems in the Tc cells. The miRNA’s highlighted also appeared to mesh well with what we know about ME/CFS thus far; one of them effects the toll-like receptors (which Ampligen appears to work on), another may contribute to the Th2 dominance found in the immune system of people with CFS, another controls the production of the enzymes needed to produce perforin in both NK and T cells and two regulate cell suicide (a UK study found increased cell suicide in some immune cells).
The next step for these investigators will be to determine if they can validate these findings by showing that the genes involved in these processes are, in fact, being turned down.
Vaccinations – A Window into the Immune Problems in ME/CFS?
The Effects of Vaccination on Immune Function in Chronic Fatigue Syndrome..Brenu, Marshall-Gradisnik, Staines, Van Driel, Ashton and Peterson
Another Bond study is looking at another long standing question in CFS, but one for which we have few answers – the possible effects of vaccinations on the disorder. The Bond/Peterson collaboration assessed immune functioning before and after people with ME/CFS were vaccinated and found evidence that vaccinations may be significantly affecting immune functioning. Their conclusion of this still very preliminary study was that vaccinations may be linked to the pathophysiological problems in ME/CFS.
A study indicating overt immune changes in a group following vaccinations should prick up a few ears, and would lend credence to the other studies indicating that abnormal immune networks and abnormal immune functioning are present in this disorder.
We’ll see more from the PHANU team in other session but these findings demonstrate how effective even a small Research Institute devoted to ME/CFS can be. Now is a good time to look at the work that researchers associated with the newcomer – the Institute for Neuro-Immune Medicine at NSU – headed up by Dr Klimas, is working on right now.
The Klimas/Fletcher/Rey Team
was the other big winner in the immune session. Now housed at the new Institute of Neuroimmune Medicine at Nova Southeastern University in Florida, this team should have more resources at its disposal shortly to dig into the neuro-immune issues in ME/CFS. In an interview Dr. Klimas focused on the ‘systems biology’ approach that she looks at how different system interact with each other to cause ME/CFS. First, though, let’s hear from Dr. Klimas as she talked about what the ‘Latest Research in Immunology” findings show.
“Latest Research in Immunology” by Dr. Nancy Klimas
Dr. Klimas noted that a really big study containing 200 patients had found that people with low natural killer cell functioning had significantly more severe symptoms and cognitive problems. She suggested that the data thus far supports the idea of EBV and HHV6 reactivation in a substantial number of patients.
Dr. Klimas, who is also employed by the Veterans Dept, has been studying Gulf War almost as long as she has CFS. Her data suggests that two disorders, which look so similar, are really quite different – in fact they almost represent opposite poles of the spectrum. Immune system pathways in CFS appear to be being turned off – their immune systems are underproducing for the most part – while the immune systems pathways in people with GWI are being turned on.
Her group has determined that while metabolic and immune networks are getting hit hard in CFS they may have identified a key cytokine (IL-1A) that gets upregulated when GWI patients exercise – causing inflammation. The identification of a key factor in GWI is, of course, good news for that group because it presents the possibility that a drug could be produced to block that cytokine activity and halt the inflammatory cascade that could be causing many GWI symptoms.
CFS, unfortunately, appears to be more complex but it is encouraging that researchers are making progress in the kind of maze of fatigue and pain producing disorders that surround us (GWI, Fibromyalgia, IBS, TMJ, etc.)
Biomarkers in CFS. Klimas, Fletcher – the Big Picture From the Klimas/Fletcher Group
Merging the results from several studies and several grants Dr. Klimas gave us the ‘big immune picture’. She asserted that 15 possible immune biomarkers have been identified in ME/CFS. They range from cytokines (IL-1b, 4, 5, 6, 8, 12, 13, 15), the stress hormone neuropeptide Y, which correlates with perceived anger and negative thoughts, defective natural killer cells, low response to lymphocyte activation factors and high levels of activated T helper and cytotoxic T-cells. All this evidence suggests that T-cells are ‘metabolically limited in performing their helper function’. The metabolic component appears to refer to both the ‘exhaustion’ both NK and cytotoxic T-cells experience with regards to perforin expression and the underactivation of the immune system her studies have found during exercise.
All these findings suggest that both inflammation and an abnormal stress response play a major role in ME/CFS.
Addition by Subtraction- Exercise Study Reveals Strange Immune Response to Exercise
Exercise Effects on Biomarkers in GWI, CFS and Healthy Controls. Barnes, Sol, Seng, Fletcher and Klimas
Nancy Klimas and Mary Fletcher always do nice tight studies, which is one reason they’re able to get NIH grants. In this exercise study they looked at a variety of immune factors in both CFS and Gulf War Illness (GWI).
They found that the cytokine levels went up significantly after exercise in the healthy controls but didn’t nudge at all in the CFS patients! It was really odd, as well, to see, neuropeptide Y, which is involved in autonomic nervous system regulation and is associated with emotions such as irritation and anger, shoot up in the healthy controls but not nudge at all in the CFS patients!
This is a ‘negative result’ that may really say something. Instead of over-responding to exercise the CFS patient’s immune systems basically stayed inert – suggesting that there is a normal and quite robust immune response to exercise that people with CFS don’t exhibit. This perhaps gets back to the weird ‘network’ effects shown in the Broderick studies where stress (exercise) triggers an odd immune response. This study reinforced the idea that something is ‘off’ in the immune systems of CFS patients.
The Wrong Metabolic Dysfunction – Metabolic Syndrome Not A Important Contributor to ME/CFS
Abnormal Cytokines Levels in Patients with CFS regardless of Metabolic Syndrome- Vera, Rey, Garcia, Harvey,……Fletcher, Klimas
The CDC with their ‘fat Georgia group” first raised the question of whether metabolic syndrome was playing a role in CFS. The term, which is controversial, was coined when researchers realized that several abnormalities set the stage for diabetes, heart disease and other cardiovascular disorders. According to one definition you have metabolic syndrome if you are obese (as judged by waist circumference) and have two of the following; high cholesterol, triglycerides, blood pressure or fasting glucose levels.
About 20% of the population in the US is believed to have metabolic syndrome. Age, stress, sedentary lifestyle, genetics and endocrine problems set the stage for it. At first glance, ME/CFS patients, with their more sedentary lifestyles, possible endocrine problems and the stress that having a chronic disorder bring, certainly appear to fit the profile in spades. In fact, just the sedentary lifestyle alone should put them at risk for all of the physiological abnormalities associated with the syndrome.
The Vera study, however, found that only about 25% of their CFS patients met the criteria for metabolic syndrome – just a bit above that found in the population at large. The study also found that cytokine levels were not increased in patients who had metabolic syndrome.
The earlier CDC study suggested that the risk of metabolic syndrome was 2 x’s higher in CFS but it may have been confounded by much higher rates of obesity in the randomly sampled Georgia group. The CDC study suggested that metabolic syndrome adds to the fatigue in CFS but the Vera cytokine results, at least, suggest this is not true either.
Centers for Disease Control
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Yes, the CDC showed up with some immune studies, which was something of a surprise given their past focus.
Getting at the Heart of the Perforin Problem – A CDC NK Cell Study
A CDC NK Cell Study? Things are changing at the CDC…. One of the few really consistent immune abnormalities in ME/CFS, NK cells have been studied in this disorder for about 20 years but the CDC hasn’t done a single NK cell study – until now.
Presented by an enthusiastic Virginia Falkenburg, the CDC attempted to determine if an overactive methylation process was silencing the genes needed to make perforin in NK cells. First the participants were given a stress test – which is known to affect natural killer cell activity – and then she measured perforin expression and DNA methylation.
Wacky Results – In another kind of shake your head type finding that CFS studies are so adept at times at producing – the study found that methylation was reducing NK function (as expected) in healthy controls but not in people with CFS. Falkenburg must have expected the opposite – that really high levels of methylation would be cratering perforin expression in ME/CFS but not in the healthy controls . (In fact at one point perforin expression was significantly higher in ME/CFS!)
An Abnormality – But in an Unexpected Direction – Methylation activity was increased in people with CFS but for some reason it did not reduce perforin gene expression. Why this occurred was unclear but one potential cause of reduced perforin expression and NK cell dysfunction was been ruled out.
Cytokine Faceoff at Ottawa
Cytokines are kind of the bete-noire of ME/CFS immunological research. Their ability to cause the symptoms associated with the ‘sickness behavior’ that shows up when we get an infection (fatigue, muscle pain, fever, etc.) have made them a prime target for decades but the findings have been all over the map. With three research groups looking at virtually the same cytokines the Ottawa conference gave us a chance to see if things have settled down a bit.
Cytokines on the Mat: The CDC vs the Klimas/Fletcher Labs vs PHANU – Divergence or Convergence?
CDC Study – Transient responses of inflammatory cytokines to an acute Stressor: comparisons between CFS and NF. Whistler, Kryson, Ganicker, Unger.
The Whistler CDC study, which is just one part of a series of studies done during a three-day in hospital study, looked to be a good one. The patients were exposed to a stressor , their blood was taken nine times and 10 cytokines were measured. They found higher levels of pro-inflammatory cytokines (IFN-y and IL-8) at in the healthy controls at baseline and differences in IL15 and IL12. They didn’t find much but what they did find fit; both cytokines regulate NK and cytotoxic T-cell functioning.
Biomarkers in CFS/ME. Nancy Klimas and Mary Fletcher
The Klimas/Fletcher immune study did not involve a stressor AND it found many more abnormalities; increased levels of IL 4, IL 5, IL-6 and IL-12 and decreased levels of IL-5, IL-8, IL-13.
Note that while the Klimas/Fletcher labs did find more evidence of cytokine dysregulation there is some convergence; both groups found altered levels of IL-15 and IL-12 and both found reduced IL-8 levels.
When we consider that Klimas/Fletcher gene expression study suggested that exercise induced immune activation is diminished in ME/CFS patients after exercise we might have one possible explanation for the differing results.
Another explanation could be the patient set. Since Dr. Whistler was presumably using patients gathered using random sampling diagnosed using the Empirical Definition and Dr. Klimas was using patients she diagnosed, we can assume that Dr. Klimas had a ‘tighter’ group of patients. Earlier studies suggested that patients derived from random sampling surveys tends to slip in and out of ‘having CFS’ fairly commonly. This suggests they are a kind of a ‘CFS-lite’ group and may not be representative of those patients found in ME/CFS practices. This idea, was squashed somewhat by the findings of the next paper by a group with a presumably ‘tight’ group of patients.
Longitudinal Assessment of Adaptive Immune Regulation in CFS. Brenu, Driel, Hardcastle, Staines, Marshal-Gradisnik
The PHANU study looked at the expression of Th1 and Th2 cytokines, IL-1a, IL-1b and TGF-B over a year using a different technique. They found increased IL-10, TNF-a, and IFN-y at baseline, increased levels of IL-2 after six months and 2 and reduced levels of IL-10 and IL-17a at 12 months. With the findings differing at every test point no consistent pattern of cytokine abnormalities was found and their findings did not fit either of the other two groups.
Dr. Montoya’s admonition that the CFS research community try and pull itself up by its bootstraps and create consistent sampling and study design protocols came to mind.
NK Study Strikes Out
Natural Killer Cell Number and Function in a Prospective Cohort of Adolescents with Chronic Fatigue Syndrome and Controls Following Mononucleosis. Katz and Taylor
Renee Taylor got a nice hefty NIH grant to look at what happens to adolescents after they come down with infectious mononucleosis (glandular fever) and papers have and will be coming out over the next year or so. This small study, surprisingly, found increased (not decreased) NK cell functioning in adolescents who came down with CFS following IM compared to those who recovered (ach!). That finding, which may be the first ever not to find decreased NK cell functioning, set off a round of questions from Dr. Klimas and Dr. Fletcher about procedures and why Katz and Taylor got such an unusual finding. (Could one possibility be that natural killer cell dysfunction shows up later in the disease?)
Conclusions
Montoya’s push to focus more on innate immune functioning seems to be a cinch given the findings pointing in that direction but finding the perforin dysfunction in T-cells – the big immune finding in the conference – will also hopefully give a boost to adaptive immune study as well. It would help a lot if a consensus could be formed around the role the main immune mediators in the body – the cytokines- play in ME/CFS. Given the symptoms patients experience and the infectious trigger present seems they must be involved. We did see some convergence of cytokine results but the field is far from consensus on this topic.
In their 2011 immune review Bansal et al. asserted that longitudinal studies correlating symptom severity with immune functioning are urgently needed. (That work ( the ‘Good-day, Bad-day’ study) is thankfully underway with Dr. Klimas and Dr. Fletcher). The UK has not been known as a bastion of physiological research but in their review these Kings College UK researchers proposed a model of viral activation and immune dysfunction for ME/CFS that Dr. Montoya, Dr. Klimas and other US immunologists would surely support stating:
“It is likely that an initial viral infection or stress acting singly or in combination leads to a state of impaired cellular immunity, immune memory dysfunction and disturbed NK cell activity. This promotes reactivation of previously acquired EBV or related virus infection and wide dissemination of the original viral infection. EBV and other viral proteins stimulate the release of pro-inflammatory cytokines which contribute to fatigue, low grade fever, aching, disturbance of sleep and inactivity. The severity and prolonged nature of these symptoms encourages further stress leading to continued immune paresis and production of immune dysregulating viral proteins.”
The next year will be interesting as these findings hopefully make their way into publication.
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