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Autoimmune Model Proposes Chronic Fatigue Syndrome (ME/CFS) Begins in the Gut

Jonas Blomberg’s paper “Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model” was published in “Frontiers in Immunology”, an apt journal for a paper featuring an “explanatory model” of chronic fatigue syndrome (ME/CFS). Autoimmunity is definitely a new “frontier”; as Blomberg points out, it’s possibility not a reality yet, but like other frontiers it evokes new vistas – new opportunities and some new challenges.

European ME/CFS reseachers

Jonas Blomberg headed up a European group which produced an autoimmune model of ME/CFS

Blomberg has recently been immersed in a study designed to validate (or not) Dr. Scheibenbogen’s autoantibody findings in chronic fatigue syndrome (ME/CFS). The lead role the Europeans are taking on in exploring autoimmunity in ME/CFS is evident: Blomberg and Gottfries are Swedish, Scheibenbogen is German, and Mella and Fluge – of the Rituximab trial – are Norwegian.

(Carl-Gerhard Gottfries’ story is so unusual that it warrants a short retelling. Gottfries, a Swedish psychiatrist, recovered from ME/CFS using, of all things, a staphylococcus vaccine.  Gottfries opened an ME/CFS clinic, published his findings and treated patients with the vaccine for several decades until it was withdrawn from the market. Find out more about Gottfries’ fascinating story here.)

There are so many ideas floating around concerning the cause ME/CFS that one is tempted to throw up one’s hands. Is cellular energy production in the dumps? Are the autonomic nervous system problems keeping people wired and exhausted at the same time? Is an autoimmune process pummeling the body? Are hidden infections tormenting ME/CFS patients with never ending flu-like symptoms? Or as Cortene suggests, are problems in the HPA axis wreaking havoc on the rest of the body.

We could go on and on (ion channel dysfunction (Griffiths University); whacked out basal ganglia (Miller/Japanese); microbiome dysregulation (Lipkin & Hornig, Unutmaz, Lombardi), “traveling genes”  (RCCX – Meglathery); atypical sepsis (Bell); neuroinflammation (Younger), (mast cell activation in the hypothalamus – Theoharides. ).

The fact that so many people have proposed so many interesting hypotheses is encouraging, but the downside to such a munificence of possibilities is a kind of inertia. Until the ME/CFS field settles on one or a few models of disease, this small field is inevitably going to progress more slowly that we would wish.

In fact, the two Davises at Stanford (Ron and Mark – not related) have questioned whether the field should devote time and money to chasing down hypotheses at all.  Better, they have suggested, to gather more and more data and see what emerges. That said, something has been emerging – an explanatory model in which autoimmunity plays a key role.

An Autoimmune Model of Chronic Fatigue Syndrome 

Basically, the authors propose that it all starts with your genes and your leaky gut. Not the leaky gut you necessarily associate with ME/CFS but the leaky gut you had before, perhaps long before you came down with ME/CFS.

A Genetic Predisposition

Autoimmune diseases typically feature a strong genetic component and run in families. It’s not that rheumatoid arthritis shows up in family member after family member. It’s that a range of other autoimmune diseases do. Blomberg picks out three intriguing autoimmune diseases – thyroid disease, Sjogren’s Syndrome (SS) and lupus – which studies suggest run in ME/CFS families.

genetic predisposition to chronic fatigue syndrome

Evidence of a genetic predisposition is one of several factors suggesting ME/CFS could be an autoimmune disease.

ME/CFS itself is also associated with diseases Blomberg considers to be emerging autoimmune diseases including hypothyroidism, fibromyalgia and POTS, each of which has been associated with increased levels of autoantibodies. Blomberg clearly believes an autoimmune cluster containing many of the diseases associated with ME/CFS is emerging before our eyes.

High rates of two of those diseases (thyroid, SS) also recently showed up in a postural orthostatic tachycardia syndrome (POTS) study (along with antiphospholipid syndrome).

Blomberg then ploughed through genetic, immune and epigenetic data in ME/CFS, highlighting some findings suggesting autoimmunity might be present.

For instance, autoimmune diseases often occur when HLA molecules improperly display self-antigens to cytotoxic or helper T-cells.  T-cells, it turns out, are often huge drivers of autoimmunity, and when they produce autoimmunity, HLA issues are often prominent. Guess what: an HLA issue has been found in ME/CFS. (Ron Davis is studying HLA genes in ME/CFS.) Another study found that increased prevalence of genetic alteration (a SNP) in a T-cell receptor gene known to play a role in autoimmunity suggested that a T-cell based autoimmune process could be present.

Infections, EBV, Autoimmunity and ME/CFS

Infections often trigger autoimmunity. In fact, the infectious trigger that has sparked ME/CFS for many is one big clue that an autoimmune process may be present. With regard to autoimmunity, the more severe the infection, the better, and several studies show that deficiencies in IgG subclasses may have left people with ME/CFS more vulnerable to a severe infection.

Several gene expression studies showing alterations in T-cell and innate immune response genes suggested that ME/CFS patients’ immune systems could be fighting off an infection.

The Autoimmune Virus

EBV is especially interesting as a facilitator of autoreactivity. Blomberg et. al.

If you’re unlucky enough to first meet up with the Epstein-Barr virus (a common trigger of ME/CFS) during adolescence, it’s likely to trigger your immune system to produce a massive number of antibodies, including autoantibodies.  EBV also produces antigens with highly repetitive structures (e.g., Gly–Ala–Gly–Ala repeats in EBNA1) which tend to confuse the immune system and trigger the production of autoantibodies.

It’s no wonder, then, that infectious mononucleosis (glandular fever) significantly increases the risk of later coming down with at least two autoimmune diseases: multiple sclerosis (MS) and lupus. That’s an interesting enough intersection for Blomberg to assert that the immune responses that ME/CFS, MS and lupus have to EBV should be compared.

The Key Organ – the Gut

Anyone have gut symptoms (cramping, bloating, loose bowels, constipation) prior to ME/CFS?  I did – they weren’t major, but if one area of my body was a little bit off back then, it was my gut.

Blomberg believes your leaky gut may be the key to your illness. Not the leaky gut you necessarily have now, but the leaky gut you had before you got ME/CFS.

gut chronic fatigue syndrome

Blomberg believes a genetic predisposition and a leaky gut set the stage for ME/CFS

The gut is such a potential hotspot for autoimmunity because it contains so much foreign material. In fact the gut has been posited as something of a training ground for the immune system- it provides the immune system with the foreign materials it needs to learn how to distinguish self from non-self.

Gut disturbances are fairly common in autoimmune diseases, and the idea that alterations in gut flora are touching off autoimmune processes is being examined in a host of autoimmune diseases (multiple sclerosis, type 1 diabetes, RA, ankylosing spondylitis). The common occurrence of irritable bowel syndrome (IBS) – and the leaky gut that often comes with it – in ME/CFS presents a potential pathway for autoimmunity.

Blomberg proposes that the breach of your gut barrier created a state of low level chronic inflammation prior to you getting ME/CFS. The gut barrier is important because it’s a place in the body where tolerance (the ability to distinguish between self and non-self antigens) is more difficult to maintain. Given the extraordinary diversity and sheer number of gut bacteria, it’s easy to see how the immune system could be overwhelmed and lose it’s way.

Blomberg believes that slow leakage from the gut created a population of auto-reactive B-cells that remained mostly inactive or quiescent (in a state of anergy), almost like undercover agents infiltrating a city, waiting for the signal to pounce.  At some point a “decisive” immune event flipped them into action, and an autoimmune disease – ME/CFS – was born.

He bases his hypothesis of pathogenic autoantibody creation in ME/CFS on a process that appears to be occurring in lupus. The first step occurs when a genetically predisposed person meets up with bad gut bacteria. First, abnormal but not pathogenic B-cells, which have a “weak autospecificity”, appear. These weakly targeted B-cells are not strongly directed against a specific antigen or part of the cell and don’t appear to be particularly dangerous at first, but the body should still eliminate them. Blomberg proposes that it doesn’t.

Over time exposure to the bad gut bacteria causes the specificity of the B-cells to change – making them more targeted and dangerous. At some point an infection turns them on and they start producing clones of themselves which begin attacking the body. ME/CFS is born.

One possible sign that tolerance – the ability of the body to remove autoantibody-producing cells  – has been breached in ME/CFS are the TFG-B (and IL-10) findings. IL-10 and TGF-B, in particular, are the rare cytokines that are more or less consistently found dysregulated in ME/CFS cytokine studies. It turns out that T-helper cells use both these cytokines to regulate tolerance and anergy at the gut mucosa – the very place Blomberg believes the process of autoimmunity in ME/CFS begins.

Ian Lipkin’s recent study found a significant difference in gut composition between ME/CFS patients with IBS and those without. Some of those differences appeared to affect energy production.

Autoantibodies

It turns out that autoantibodies by themselves are not necessarily indicative of autoimmunity. Some “natural autoantibodies – (mostly IgM antibodies) are simply designed to rid the body of dead/apoptotic, damaged and infected cells and rarely cause autoimmune diseases. Other more dangerous autoantibodies need to be turned on by “cell danger” signals before they do harm. (This is why autoantibodies can often be found in healthy people.)

Autoantibodies have, of course, been found in ME/CFS and related diseases like POTS. At the Montreal conference Blomberg reported that his team was validating Scheibenbogen’s autoantibody findings in ME/CFS. They are one clue that autoimmunity is happening in ME/CFS but they provide, Blomberg reported, only circumstantial evidence of autoimmunity.

It’s the “erroneously activated” B-cells, he reported, that are “the root of the evil”, and it’s these cells that need more focus. Blomberg asserts that an in-depth sequencing of these deranged B-cells is needed. By sequencing the variable immunoglobulin chains found in them it should be possible to trace back to how they turned bad.

Other Possible Evidence of Autoimmunity

As noted earlier, Carl-Gerhard Gottfries successfully used a staphylococcal vaccine for years to treat himself and others with chronic fatigue syndrome (ME/CFS). That approach may have worked because the immune stimulation it provoked may have been able to induce tolerance; i.e. induce the body to remove the bad B-cells.

Since Rituximab knocks down B-cells, thereby removing misbehaving ones, it would seem to fit into Blomberg’s hypothesis. Unfortunately, the Rituximab trial failed, and if anecdotal reports are correct, more completely than we could have imagined.

Another possible indication that autoimmunity is present in ME/CFS are studies suggesting the incidence of Hodgkin’s lymphoma is increased in ME/CFS as it is in other autoimmune diseases.

In the end, though, Blomberg reports that the evidence that autoimmunity is at work in ME/CFS is circumstantial. It relies on the fact that people with ME/CFS often have other autoimmune diseases such as thyroiditis or diseases suspected of involving autoimmunity such as POTS, FM and IBS, that autoantibodies are present, and that immunostimulation (IVIG, staphyloccocus vaccine) may work.

Most of the work, though, needed to fulfill the Witebsky–Rose criteria for autoimmunity, remains to be done.

Primary Biliary Cirrhosis – An Autoimmune Roadmap for Chronic Fatigue Syndrome (ME/CFS)?

At the start of their paper, Blomberg et. al. proposed that their model could explain many of the facets of ME/CFS that have emerged – the most prominent of which are the energy production problems.

An autoimmune disease exists in which an attack on the energy producing processes in the body produces symptoms and findings similar to those found in ME/CFS.  In primary biliary cirrhosis  (PBC) antibodies attack a small fatty acid molecule (lipoic acid) that’s part of the energy producing machinery on the surface of the mitochondria.

pyruvate dehydrogenase

Pyruvate Dehydrogenase -By Jonathanmott09 – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18520937

The antibodies in PBC attack the pyruvate dehydrogenase (PDH) enzyme complex which regulates the transition from glycolysis (anaerobic energy metabolism) to the tricarboxylic acid cycle (aerobic energy metabolism). The same issue -the transition from glycolysis to aerobic metabolism – has shown up repeatedly in ME/CFS studies.

Even though PBC is considered a liver disease, it produces enormous amounts of fatigue as well as cognitive problems, orthostatic intolerance and sympathetic nervous system hyperactivity. In fact, Julia Newton, who studied PBC before she studied ME/CFS and started a Rituximab trial in PBC two years ago, stated back in 2013 that,

“…at this stage the muscle and cardiac abnormalities that we have seen in patients with ME/CFS are exactly the same as those that we have seen in patients with PBC.”

Another fascinating aspect of PBC is that the autoantibodies are attacking a molecule, lipoic acid, which is added to the PDH enzyme using a rare process called lipoylation. Because some gut bacteria (Novosphingobium) also use lipoylation, it’s possible that bacterial leakage initiated the autoimmune process causing PBC.

Blomberg suggested that pathogenic, as yet unidentified immunoglobulins directed against mitochondrial proteins could be the source of ME/CFS and exhorted researchers to compare the post-exertional malaise in ME/CFS to other diseases such as fibromyalgia, PBC, etc.

Autoimmunity or Oxidative Stress? 

Finally Blomberg et. al. suggested that oxidative stress could be producing the same energy depleting issues as autoimmunity. That’s an intriguing idea given the comforting consistency oxidative stress study results have had in ME/CFS.  The authors noted that it was recently shown that the oxidation of a critical part of the pyruvate kinase enzyme can effectively block the transition of glycolysis to aerobic metabolism.

Dr. Shungu believes the lactate accumulations and glutathione reductions his studies have validated in the ventricles of the brains of ME/CFS patients are associated with oxidative stress.

Conclusion

Blomberg’s autoimmune model proposes that the seeds for ME/CFS were lain possibly long before the disease appeared and only “sprouted” once a decisive immune event occurred. He believes that a genetic predisposition plus a leaky gut laid the groundwork over time for what eventually became an autoimmune disease.

Autoantibodies provide circumstantial evidence of autoimmunity in ME/CFS but are not nearly enough to validate it.  Blomberg asserted that an intensive study of the abnormal B-cells in ME/CFS could both help to validate that diagnosis and identify the precipitating event which triggered this illness.

If ME/CFS is an autoimmune disease targeting the mitochondria it may have a close cousin called primary biliary cirrhosis (PBC) which produces similar symptoms including enormous fatigue. In PBC autoantibodies disrupt the transition from anaerobic to aerobic energy production – the same process, interestingly enough, that appears to be affected in ME/CFS.

While autoimmune processes could produce the energy problems in ME/CFS, oxidative stress – which studies have found to be consistently high in this disease – could produce the same result.

System Reset? Study Suggests Pro-Inflammatory / Autoimmune Reset Occurred in Chronic Fatigue Syndrome (ME/CFS)

Epigenetics research holds the fascinating possibility of figuring out what shifted at the very beginning of chronic fatigue syndrome (ME/CFS).  For many with ME/CFS a sudden change occurred – some sort of biological reset quickly happened – which never relinquished itself.

epigenetic reset ME/CFS

Something triggered ME/CFS. Could it have been an epigenetic reset?

Finding out what “reset” occurred is what epigenetics is all about.  Epigenetics identifies changes in the expression of our genes that occur after we meetup with biological stressors such as pathogens, drug, toxin or even foods.

Most of our genes that produce proinflammatory cytokines, for instance, have a kind of a lock on them. Removing that lock leaves them free to express themselves and leaves us open to poor health.

Epigenetics explores how the biological challenges we encounter in life can remove those locks (or add to them) resulting in an entirely new genetic landscape – one that could perhaps cause something like ME/CFS.

Many people’s ME/CFS/FM starts with an infection, and viruses can exert major epigenetic changes to our genome.  Herpes simplex virus (the virus Dr. Pridgen is targeting in fibromyalgia) engineers changes to our genome which help the virus avoid destruction and enhance its replication. Those changes include a suppression of our immune system, which can result in an increased risk of cancer.

What goes around comes around, though.  Epigenetic News recently reported that an epigenetic modifying cancer drug was able to return the parts of the immune system that the  herpes simplex virus had disturbed to normal. The drug was able to effectively fill in the immune hole created by the herpes virus by boosting a number of immune factors (IFN-a, IL-8, IL-6, transcription factors, stress response factors). Mouse studies revealed that the drug also reduced reactivation of the virus.

That suggests that some similar drugs now in clinical trials could help in the fight against herpes and other viruses or could perhaps simply return to normal epigenetically modified genes that have suppressed immune functioning.

 “A new class of antivirals based on this study might be useful for patients who are resistant to existing antivirals like acyclovir and ganciclovir….. (or in) viral infections for which there aren’t pharmaceuticals to boost an individual’s immune response.” Dr Kristie

If epigenetics turns out to play the major role in ME/CFS that it does in cancer and other diseases, a cancer drug could someday be in store for ME/CFS treatment.

Epigenetics Study Highlights Immune Alterations in ME/CFS

The epigenetics story begins with gene transcription – the first step in the process of translating our genes into proteins.  Gene expression gets enabled by the removal of methyl groups that block transcription and/or by the addition of methyl groups that stop genes from being expressed.

Malay Trivedi and Lubov Nathanson at Dr. Klimas’s Institute of Neuroimmune Research at Nova Southeastern University recently published the most comprehensive study yet on epigenetics in chronic fatigue syndrome .

Just a few epigenetic studies have been done in ME/CFS and none like this one. For one, the group took advantage of a new breakthrough in genetic testing (an advanced Illumina array) to almost double the number of testing sites (from 450,000 to 850,000 sites). For another, the larger sample size (64 participants from two geographically distant locations) ensured a more comprehensive look at the epigenetic changes in ME/CFS. This allowed the group to produce what they called “consensus hypomethylated sites” they believe could be used in future studies.

The general findings of the study agreed with those from past ME/CFS epigenetic studies. Hypomethylation – the deletion of methyl groups, which make it easier for the genes to be expressed – was the theme, with 98% of differentially methylated sites in ME/CFS hypomethylated compared to controls. (Only 2% were hypermethylated compared to controls.)  The hypomethylation was most prominent in genes associated with immune cell regulation.

The high degree of hypomethylation was intriguing for several reasons. For one, Epstein-Barr Virus – presumably a common trigger in ME/CFS – overwhelmingly triggers hypomethylation and almost no hypermethylation of genes. Hypomethylation is also associated with pro-inflammatory gene expression in autoimmune diseases as well as in cancer promotion.

Multiple Sclerosis Breakthrough

A “global” hypomethylation, for instance, is also found in lupus and rheumatoid arthritis. The hypomethylation of a promoter gene for IL-6 in rheumatoid arthritis causes an overexpression of pro-inflammatory cytokines and other immune factors which ultimately results in joint damage.

Epigenetic changes to the HLA genes may have triggered MS. (HLA Gene Expression – by ZionLion77 – https://en.wikipedia.org/wiki/Human_leukocyte_antigen#/media/File:MHC_expression.svg)

The recently uncovered hypomethylation of an HLA gene in multiple sclerosis (MS) prompted researchers to state that epigenetic changes may even be “caus(ing) the disease”. That bold statement reflected the findings of a recent large study, which indicated that epigenetic changes were directly causing the largest risk factor found yet for MS.

That finding may have implications that go far beyond MS and could conceivably reach ME/CFS/FM.  Since the HLA region of the genome is associated with almost all autoimmune diseases, the authors believe their finding will impact other autoimmune diseases.

(Several years ago Ron Davis pegged the HLA region as a potential study area for ME/CFS. His Stanford Genome Lab has developed new methods of assessing this complex region of our genome, and he and Mike Snyder at Stanford are doing an intensive analysis of that HLA region in ME/CFS.)

Back to Chronic Fatigue Syndrome (ME/CFS)

The highest degree of hypomethylation in a genetic region in ME/CFS occurred in gene promoters associated with natural killer cell functioning, no less – the most consistent finding in ME/CFS.  That suggested that some sort of epigenetic reset – perhaps triggered by an infection – occurred in the NK cells of ME/CFS patients.

With regard to single genes, the authors highlighted the hypomethylation of genes associated with muscle hypotonia (low muscle tone) and cognitive impairment (MED13L), problems with protein synthesis (metabolism), and glucocorticoids (SGK3 gene – inflammation).

It was the immune genes, though, where the hypomethylation really came to the fore. Immune genes that regulate the adaptive immune response (T & B cells) and the production of immunoglobulins were hypomethylated. The authors asserted that those findings were in sync with reports of improvement from Rituximab.

Promoters (MMP14, MAP4K4, MAPK12 and CREB5), which may be activating tumor necrosis factor signaling pathways and thus contributing to the pro-inflammatory problems believed present in ME/CFS, were hypomethylated as well.

A gene (miRNA-148a) that impairs the innate immune response was also hypomethylated. Several of the hypomethylated genes were also found in prior ME/CFS studies.

Then there’s the IL21R gene. The hypomethylation of the IL21R gene promoter in ME/CFS could promote inflammation, autoimmunity, thyroid disease, intestinal inflammation, and others.  IL-21 also plays a critical role in triggering spontaneous experimental autoimmune encephalomyelitis – an animal model of brain inflammation.

Conclusion

IL-SR gene chronic fatigue syndrome

Unleashing the IL2R gene could contribute to inflammation (including neuroinflammation), thyroid disease and autoimmunity

Epigenetics is a relatively new science which is already proving to be a boon to the study of autoimmunity and cancer. Larger studies will be needed in ME/CFS for epigenetics to reach its potential, but the study from Dr. Klimas’s group suggested that, just as in some autoimmune diseases, enhanced hypomethylation may be increasing the expression of genes which promote inflammation and autoimmunity in ME/CFS.

The most encouraging thing about epigenetics is the possibility of reversing the epigenetic changes a pathogen, toxin or drug has caused. Much more study is needed to isolate any epigenetic culprits in ME/CFS, but epigenetic altering drugs are being developed for other diseases. One intriguing drug seeks to reverse the epigenetic changes caused by herpes simplex virus – thus returning the immune system to normal.  Another breakthrough suggests that epigenetic changes may be major drivers of multiple sclerosis.

This is clearly a field to keep an eye on.

Major Research Group Highlights Inflammation Energy Production Connection in ME/CFS

We propose that chronic low-grade inflammation induces and/or maintains persistent fatigue by inducing an imbalance between cellular-energy availability and cellular- and behavioral energy expenditure.  Lacourt et al. 2018

Neurosci. 2018 Apr 26;12:78. doi: 10.3389/fnbeh.2018.00078. eCollection 2018. The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Lacourt TE1, Vichaya EG1, Chiu GS1, Dantzer R1, Heijnen CJ1.

Inflammation, the brain and energy metabolism – it’s like the trifecta in chronic fatigue syndrome (ME/CFS) research. It seems like virtually everyone in the ME/CFS field believes that all three are involved but that belief only carries so much weight in a small field. What this field really needs is buy-in from outside researchers who can help move it forward.

That appears to have happened recently when a major research group lead by Robert Dantzer penned a review paper proposing that low-grade inflammation is causing energy production problems in chronic fatigue syndrome (ME/CFS) and probably many other diseases. The authors didn’t shy away from the chronic fatigue syndrome (ME/CFS) connection. In fact, they lead their review paper off with it, placing the fatigue in ME/CFS in the same context as the fatigue in cancer, MS, rheumatoid arthritis and others.

Major Stanford Study Indicates Chronic Fatigue Syndrome (ME/CFS) is Inflammatory Disorder

The study was published in the Frontiers in Neuroscience journal series which is touted as the 1st most cited series in the Neurosciences journal field.

The Dantzer group’s involvement in the intersection between inflammation and energy production is welcome but not entirely surprising; it’s a logical outcome of their past work. Dantzer spearheaded the now accepted idea that the immune system produces the symptoms of “sickness behavior” (fatigue, headache, muscle aches, sore throat, etc.) that occur during an infection which serve to reduce our energy usage and to keep us isolated from others (they posit to prevent pathogen spread).

What’s new is his group’s focus on the energy production process itself – a focus, interestingly, made possible largely by the work of ME/CFS researchers. The piece, with lead author Tamara LaCourt, shows how low-grade inflammation can cause the same energy problems we’re seeing in ME/CFS: a metabolic switch from energy-efficient, oxygen-based energy production process to a fast-acting, inefficient glycolysis-based approach.

Immune cells aren’t like other cells; jumping into action causes them to rev their motors up tremendously, placing enormous stress on their energy production systems. As they do this, they switch from a focus on aerobic energy metabolism to what the authors call “aerobic glycolysis” in order to churn out energy more quickly. That process results in less mitochondrial energy production and the increased production of toxic by-products like lactate.  Plus, over time this process results in reduced nutrient availability and less energy for the rest of the body.

low energy chronic fatigue

The authors believe that inflammation and metabolic and energy problems come together to produce a final common endpoint: fatigue.

Several studies from the Solve ME/CFS Initiative are examining whether the energy production of immune cells in ME/CFS is up to the task.

Prolonged inflammation also tends to result in two other energy production problems: increased insulin resistance and reduced glucose tolerance. Reduced glucose tolerance smacks glucose uptake by immune cells at the very time that they’re clamoring for it, causing the body to break down fats and proteins, thus removing resources it would ordinarily use elsewhere.  In yet another whack at the energy production, inflammation increases reactive oxygen species production which can hammer mitochondrial energy production.

The authors believe that neurons – which rely on glycolytic processes in astrocytes to get their energy – may be hit hardest by chronic inflammation.  This is because insulin resistance – a common outcome of chronic inflammation – destroys the glycolytic process in astrocytes, causing neurons to get their energy from fats – a slower and less efficient process.

Miller’s work on ME/CFS suggests that problems with the basal ganglia – the dopamine-producing center of the brain – may be causing problems with movement, reward and fatigue in ME/CFS. That’s a particularly interesting finding given that dopaminergic neurons in the brain are particularly vulnerable to inflammation. Shungu’s studies, which have consistently found high lactate and low gluthathione levels in the ventricles of ME/CFS patients brains, suggest that high levels of oxidative stress could be causing inflammation in the brain itself.

Plus, even low-level inflammation can disrupt a key element in ME/CFS and FM – sleep – which, in turn, increases fatigue. Simply altering one’s circadian rhythm (i.e. one’s sleep times) can have significant metabolic effects, leading to increased glucose levels and decreased insulin sensitivity.  The effects don’t end with sleep; sleep deprivation results in the need for increased energy expenditures the next day.

Is Poor Sleep Pummeling the Immune System in ME/CFS and Fibromyalgia? A Vicious Circle Examined

Then add in the extra ten percent in extra energy needs that chronic low-level inflammation imposes on the body – and the potential for a dramatic drop in energy production rises.   (We’ll find out more about total energy production in ME/CFS during the metabolic chamber tests in the NIH’s intramural study).

The authors believe that impaired energy production represents a “final common pathway” in persistent fatigue.

Leader in the Field

“In sum, most evidence for an association between fatigue and mitochondrial functioning comes from CFS, indicating lower levels of antioxidants and possible reductions in mitochondrial ATP production.” The authors.

We understandably don’t think of researchers in the small ME/CFS research field as being pioneers in the medical research field at large, but some have ploughed brand new ground. Suzanne Vernon’s computational biology work at the CDC was so novel that an entire issue of the Pharmacogenomics journal was devoted to it. Gordon Broderick and Travis Craddock’s expansion of that work at Dr. Klimas’s Institute of NeuroImmune Medicine has taken computational biology further – much further – in ME/CFS than in any other field. Ron Davis and Mark Davis at Stanford are using new HLA gene typing and T-cell technologies to try and nail down what is activating ME/CFS patients’ immune systems.

ME/CFS researchers’ attempts to understand the intersection between mitochondrial problems and fatigue are clearly breaking new ground as well.  According to the authors of this review article, 21 of the 25 studies examining the intersection between mitochondrial problems and fatigue have been produced by ME/CFS researchers. Researchers we all know ( e.g. Naviaux, Montoya, Hornig and Lipkin, Fluge and Mella) were cited again and again in the overview.

The authors even cited Workwell’s groundbreaking 2013 study which indicated that a shift to glycolytic energy production occurred during the second day of a two day exercise test in ME/CFS. They also singled out the 2017 Tomas study which found that under conditions of cellular stress, the mitochondria in ME/CFS patients’ cells were unable to rise to the occasion.

Turning to the metabolomics studies, the authors cited three ME/CFS studies which have pointed to “reduced metabolic activity”.  They believe the metabolic changes seen in ME/CFS reflect a chronic over-reliance and eventual depletion and abandonment of lipid metabolism, which results in a greater use of carbohydrate stores; hence the greater reliance on glycolysis and impaired aerobic energy production. In short, the authors believe the metabolomic studies in ME/CFS are demonstrating the same metabolic shift that the authors propose occur in states of chronic low-grade inflammation.

Interestingly, the authors proposed that many ME/CFS patients are probably exceeding their daily energy stores.  That, of course, makes perfect sense given Staci Stevens’s and Workwell’s findings that, for some patients, simply sitting upright puts them into an aerobic energy deficit.

For all its possible connections, the idea that fatigue in ME/CFS is simply the result of “low-grade inflammation” seems untenable given the disability present – unless that inflammation is found in the brain. The Simmaron Research Foundation is bringing the brain, the immune system and metabolism together in a way that’s never been seen before in ME/CFS.

The Simmaron Research Foundation’s first ME/CFS cerebral spinal fluid study suggested that an immune dysregulation, the likes of which approached that found in multiple sclerosis, may be present in the ME/CFS patients’ central nervous systems. Their second outlined an atypical ME/CFS subset. Their current CSF (cerebrospinal fluid) study – an expanded version of the first study which includes a metabolomic component – will be the first to potentially merge immune and metabolic findings in the most energetically active part of the body – the brain.

Peterson’s Atypical Subset Opens New View of ME/CFS in Columbia/Simmaron Publication

Plus, stay tuned for a report suggesting that inflammation is not just present, but pervasive, in ME/CFS patients’ brains.

 

Large NK Cell Study Points to Autoimmunity and Inflammation in Chronic Fatigue Syndrome (ME/CFS)

The observed differences in some of the subpopulations of T and NK cells between patients and healthy controls could define a distinct immunological profile that can help in the diagnostic process of ME/CFS patients, contribute to the recognition of the disease and to the search of more specific treatments. Rivas et. Al. 2018

Problems with natural killer (NK) cell functioning have been like an anchor in the storm for immunologists interested in chronic fatigue syndrome (ME/CFS). While other immune results like cytokines have flipped and flopped all over the place, the NK cytotoxic results have been solid. Almost every study has found that when given the chance to kill infected cells, the NK cells in ME/CFS patients poop out.  (The studies which have not found differences in NK cell functioning have tended not to use whole blood or used older samples – suggesting that something in the blood could be impairing NK cell functioning in ME/CFS.)

Dr. Daniel Peterson, Sierra Internal Medicine and Simmaron Scientific Advisor

The most extensive study – a year-long 2012 study involving Dr. Peterson and Griffith University in Australia – found reduced natural killer cell functioning at all time points. (Peterson has a long history of interest in natural killer cells; he was a co-author of the first study, over thirty years ago, to find deficient NK cell functioning in chronic fatigue syndrome (ME/CFS).)

NK cells are important because they maintain the lines of our initial immune defense, holding the fort, so to speak, until the big guns – the T and B cells- wipe out the infection. – They also regulate the immune response.

Normally our cells signal that they are infected by displaying peptide fragments from the pathogen (using MHC Class 1 molecules) on their surface. NK cells then hunt out and destroy these infected cells. However, some pathogens have learned how to prevent the cells they’ve infected from displaying these peptide fragments.

If NK cells and other parts of the innate immune response can’t hold back the invaders, the pathogens may invade more deeply into the body, potentially causing more problems before the adaptive immune response (T and B-cells) can kick in.

innate immune response

Mast cells, complement, phagocytic cells and natural killer cells man the early or innate immune response

A deficient early response to pathogens would then very likely translate into more symptoms. We don’t know when the problems with NK cell killing got started in ME/CFS, but if they were in place prior to the illness or occurred early in the illness they could have played a role in the inception of ME/CFS as people who have more trouble fighting off a pathogen; i.e. people with more severe symptoms, are more likely to come down with ME/CFS.

Once ME/CFS has begun, the inhibited NIK killing response could mean more trouble removing tumor and infected cells – particularly herpes virus infected cells- as people deficient in NK cells  have trouble fighting off herpes viruses.

NK cells, then, are vitally important, but attempts to identify issues other than cytotoxic killing abilities have been less successful. NK cells come in different types (cytotoxic and regulatory) and the balance of these subpopulations is important. Some studies have found differences in these subpopulations in ME/CFS and some have not.

Many of those studies, however, have been small and used less than stringent criteria for defining ME/CFS. A Spanish group decided to rectify those problems with a more definitive study which examined NK cell populations in a larger study (n=149) with patients who met the Canadian Consensus Criteria for ME/CFS. In order to ensure they captured all factors in the blood that might be whacking NK cells, they used whole blood and analyzed it within 6 hours of collection.

Then they tried to reverse engineer their results to see if a diagnostic test could be developed which simply charted which kinds of NK cells a person had. That was pretty good, but then they went further and asked if people who were worse off had different subpopulations of NK cells or more evidence of herpes virus reactivations (EBV, HMCV).

Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Jose Luis Rivas,1,* Teresa Palencia,1 Guerau Fernández,2 and Milagros García1,3 Front Immunol. 2018; 9: 1028.Published online 2018 May 9. doi:  10.3389/fimmu.2018.01028

This larger, fresher (quick analysis of blood), stricter (CCC patients only) and more comprehensive study found differences where others had not – and plenty of them.  This group validated – with a high degree of certainty (p = 0.0075) – previous findings of  an increased subpopulation of NK cells (NK CD56++(high)) which, get this, excrete more cytokines (particularly IFN-y), possibly causing more symptoms, but which have low cytotoxic activity.  Because these cells have unusually long life spans and pump out cytokines that cause more T-cell proliferation, higher numbers of them could contribute to autoimmunity and inflammation.

These cells were particularly high in the group of patients whose illness began without evidence of an infection. The Spanish group suggested that activation of the stress response via the HPA axis and raised levels of catecholamines such as norepinephrine (adrenaline) could have triggered the expansion of this potentially autoimmune affecting natural killer cell subset.

No differences were found, however, in the levels of several receptors (NKp46, NKp30, NKp44) that have been found elevated in some autoimmune/inflammatory conditions (Sjogren’s Syndrome, Crohn’s disease) or reduced in chronic infections (HIV, tuberculosis, influenza, etc.).

CD 69

Increased levels of the CD 69 marker suggested autoimmunity may be present in ME/CFS

Reduced levels of a receptor (NKG2C) were very common (p<0.0001) in ME/CFS. When this receptor, which is only found in NK cells, is activated by the presence of virally infected cells, it triggers an expansion of NK cells. Not surprisingly, NK cells become dotted with this receptor in people with chronic herpesvirus and other infections (HCMV, EBV) but ME/CFS patients’ NK cells had consistently lower levels of this receptor than did the healthy controls.  The authors didn’t speculate why this occurred, but it could involve lower levels of infection in ME/CFS – something Ron Davis is finding in his severely ill cohort – or a problem responding to infections that are present.

That second possibility was buttressed by an inverse correlation found between a marker of infection (CD 57+) and the lower expression of a marker (NKp46) which is often reduced in herpesvirus infections. The authors suggested that the scenario found in ME/CFS (increased cd57+, lower NKp46, high NKG2C) could reflect HCMV (cytomegalovirus) reactivation.

Watch Natural Killer T-cells (red) Swallow Up Antigen Presenting Dendritic Cells (green)

 

Increased levels of the CD69 marker (p= 0.011) provided another suggestion that ME/CFS may be an autoimmune/inflammatory disease. This important marker, which is found on many immune cells, stimulates NK cell cytotoxic activity. More importantly, CD69 has been described as a master regulator for autoimmunity in rheumatoid arthritis (RA) through its upregulation of TGF-B – one of the very few cytokines that has usually been found increased in ME/CFS.

A “descent” in T regulatory cells similar to that found in autoimmune conditions such as lupus and RA was also found. Finally, an inverted Th17/T regulatory cell ratio, which is also found in autoimmune conditions like lupus, wrapped up the autoimmune connections found in this study.

Using a mathematical classification model, the group was able to correctly diagnose 70% of ME/CFS patients and healthy controls simply by using the findings from this in depth study of natural killer cell populations.

Conclusions

This large Spanish study of NK cell subpopulations found numerous irregularities in NK cell types in ME/CFS, several of which pointed to issues with autoimmunity and/or inflammation. As in other studies, this study indicates that larger is indeed better when it comes to studying ME/CFS.

The study validated prior findings of an unusually large set of NK cells which produce more cytokines – conceivably causing more symptoms and immune activation – but which are less effective at killing infected cells.  That finding seemed to jive with a picture of highly symptomatic ME/CFS patients who may have trouble fighting off infections.

While no differences were found in the levels of receptors which can be elevated in autoimmune conditions, several other findings suggested that NK cells may be fighting off herpesvirus infections or may be involved in autoimmune/inflammatory processes in ME/CFS.

Finally, using just NK cell subpopulation data, the authors were able to correctly identify 70% of patients and healthy controls, indicating that significant NK cell differences exist. All told, the study identified several natural killer irregularities that could participate in autoimmunity and dysregulate other parts of the immune system.


Montreal ME/CFS II: Stopping PEM, the Antibody Subset and Unutmaz’s Big Surprise

The second part of a several part series on the Montreal ME/CFS conference focuses on the immune system.

Part 1: The Montreal ME/CFS Conference: Metabolism and Exercise can be viewed here.

Dr. Nancy Klimas: From Biomarkers to Modeling and Clinical Trials; GWS and ME/CFS

Years of work appear to be coming to fruition for Dr. Klimas. Her ability to hook into GWS funding has made a huge difference in her ability to test out her modeling protocols.  It’s remarkable to see the Dept of Defense lay down $40 million per year for the vets affected during the Gulf War 27 years ago, while ME/CFS gets so little. The vets undoubtedly deserve it and they deserve more – many lives were shredded as a result of the war and they’ve fought for years to get recognition. However, the disconnect between the way the feds have treated GWI and ME/CFS – a disease which affects far more people – is startling.  The Dept of Defense hasn’t done great by its vets, but it’s been much more responsive to them than the feds have been to ME/CFS and fibromyalgia.

Nancy Klimas

Years of work appear to be coming to fruition for Dr. Klimas

Dr. Klimas noted that the more we look, the more immune abnormalities are being found.  Cytokines may not tell us what is causing ME/CFS, but they sure could help us find drugs to combat it.  Klimas is comparing the immune signatures she’s seeing in ME/CFS with those of other diseases and then checking out what’s working in those diseases. The good news is that immune-affecting drugs are big business now, with more and more coming on the market. If ME/CFS is, at its heart, an immune disorder, or if the immune system plays a large role – as many think it does – drugs developed for other diseases may be able to help.

Dr. Klimas and her researchers have been asserting for years that ME/CFS patients are stuck in a kind of suboptimal, self-reinforcing homeostatic space; i.e. their systems have been rewired to produce a new normal.

That idea doesn’t seem to be all that far from Naviaux’s belief that people with ME/CFS are stuck in a Dauer state or Dr. Cheney’s report that while he could push patients towards health, something would pull them back.  Both Klimas and Naviaux believe a series of structured moves will be needed to move the system back to normal. Neither believes it’s easy; Klimas says real “force” will be needed to move the system back into health.

Klimas should know – she’s been intensively charting how ME/CFS patients’ systems go off the rails during exercise for several years now. She’s measured every cytokine, neuropeptide, etc. she can at 8 timepoints before, during and after exercise in 50 women with ME/CFS, 25 women with FM, 50 men with ME/CFS and 50 men with GWI.

She’s gathered a vast amount of data and that data is telling her that ME/CFS patients’ immune systems basically go nuts during the first 15 minutes of exercise.  Four hours later, oxidative stress kicks in and the autonomic nervous and endocrine systems and metabolism get hit — but it’s the immune system that kicks everything off.

The big surprise is how different chronic fatigue syndrome (ME/CFS) is from Gulf War Illness. The metabolism gets hit hard in ME/CFS – everything gets shut down – but in GWI, all the pathways are ramped up. They’re two completely different illnesses which from the outside look exactly the same.

Dr. Klimas and her team have been running sophisticated modeling techniques on supercomputers to figure out how to get our systems back to normal. Initially, they ran into trouble with women who, no surprise, have much more complex systems than men. Back to the drawing board they went. In the end, Dr. Klimas’s team was able to create a virtual clinical trial in GWS. First, they brought down brain inflammation using etanercept, and then readjusted the HPA axis with a glucocorticoid receptor blocker, mifeprestone.

It worked on the computer – their virtual GWS patient returned to health system – but the big test came with their Gulf War Syndrome mouse model.  When the drug combo was able to return the GWS mouse to health they really knew they were onto something. An open label phase I trial in GWS is under way as we speak.

supercomputers ME/CFS

Her team has used supercomputers to create virtual clinical trials

Dr. Klimas noted that the $30 million the DOD is providing for GWI has made a big difference where the rubber meets the road in medicine – in ten clinical trials that are underway. That’s in a disease that effects fewer people than ME/CFS but which receives federal funding for clinical trials.  That’s not true for chronic fatigue syndrome (ME/CFS) – federal funding for clinical trials is pretty much blocked.

Researchers can apply for clinical trial funding at NINDS and other institutes, but ME/CFS doesn’t have a chance against diseases like Parkinson’s and Alzheimer’s. The big issue is that the program announcement for ME/CFS – which lists subjects researchers can apply to study – doesn’t allow them to submit clinical trials proposals.

Dr. Koroshetz’s promise last year to get that language embedded into the ME/CFS PA hasn’t paid off yet. Getting that wording embedded into the PA for ME/CFS could open up funding for clinical trials. That would be a big step forward.

Dr. Klimas doesn’t have a mouse model for ME/CFS but she’s been doing the same computer modeling she used in GWS on ME/CFS. It’s clear that nobody at this point understands more about what happens during exercise in ME/CFS than Dr. Klimas. Nobody has been able to translate mountains of exercise data into virtual clinical trials. Nobody has proposed a staggered two-drug approach to ME/CFS, and nobody probably has a better shot at stopping PEM than her.  This is new stuff not just for us but for the medical field in general. Let’s hope it works out.

The GWS trial is underway and she hopes to get her chance at halting the PEM in its tracks in ME/CFS in a small trial later this year. Getting funding, of course, will be crucial.

ME/CFS rather suddenly has several drug/drug trial possibilities: they include Cortene, Dr. Klimas’s drug combo, immunoadsorption (see below), Fluge and Mella’s Norwegian cyclophosphamide trial,  Ampligen and Dr. Kaiser’s Synergy drug-nutrient combination – and, of course, Rituximab is still surely in the picture for a subset of patients.

Carmen Scheibenbogen

Scheibenbogen is a mover and shaker. She’s published six papers on ME/CFS in the past three years, is a leader in the Euromene Group, has been talking to pharmaceutical companies about drugs, and is organizing a fatigue conference in Germany to get some good networking going.

Rowe - scheibenbogen - ME/CFS

Dr. Rowe called Dr. Scheibenbogen’s antibody findings one of the most exciting ME/CFS research findings in years.

Peter Rowe called her recent autoantibody papers one of the most exciting recent developments in the field. Scheibenbogen, interestingly, got the idea to do those studies from similar recent findings in POTS (postural orthostatic tachycardia syndrome).

Scheibenbogen rattled off some of the commonalities between autoimmune diseases and ME/CFS. Both predominantly affect women, both are often triggered by an infection and she’s found a high family history of autoimmunity in ME/CFS.  Plus, Epstein-Barr virus – a common trigger in chronic fatigue syndrome (ME/CFS) – invades B-cells which are the main drivers of autoimmunity. The difficulty ME/CFS patients and others have fighting off the virus when exposed to it later in life apparently gives the immune system plenty of opportunity to make a mistake and begin attacking our own tissues.

Check out a recent breakthrough in EBV-associated autoimmunity

The Autoimmune Virus? Groundbreaking EBV Finding Could Help Explain ME/CFS

Rituximab is used to treat autoimmune diseases. The Rituximab ME/CFS trial’s main endpoint failed but Scheibenbogen asserted that we shouldn’t count Rituximab out at all. She believes, and she would know, because she’s studied Rituximab patients, that Rituximab will be shown to be effective in a subset of patients.  An effective treatment in a subset of ME/CFS patients would be a big deal – particularly for those patients.

Scheibenbogen found increased levels of antibodies in about 40% of ME/CFS patients, and Bergquist’s study that is currently underway thankfully had similar results. At least right now it appears that the 40% figure is solid, but the search for antibodies in ME/CFS is not over. When I asked Scheibenbogen if other antibodies might be involved, she said, yes, other antibodies probably will apply. If that’s so, that 40% number could go up. Scheibenbogen noted that the B2 and muscarinic antibodies that have been showing up in ME/CFS are part of a larger network.

Interestingly, these are not autoantibodies; they’re natural antibodies which affect breathing, the circulation and the gut. Their high levels in ME/CFS appear to be throwing those systems off.

Immunoadsorption

Immunoadsorption is another possible immune treatment for chronic fatigue syndrome (ME/CFS). Immunoadsorption, which is similar to, but more effective than plasmaphoresis, removes IgG autoantibodies from the blood. It’s an expensive treatment – about $20,000.

Like Rituximab it will probably be effective in a subset of patients. Scheibenbogen’s small immunoadsorption trial of ME/CFS patients with specific autoantibodies found that the treatment did what it was supposed to do – it significantly reduced antibody levels for at least six months.

Symptoms improved in most patients and some patients completely recovered. Three are still in remission a year after the treatment ended. One person completely recovered for 6-7 weeks but then relapsed. After she relapsed, she could hardly walk again. The trial suggested that Scheibenbogen is on the right track with her autoimmune studies. The fact that POTS is so prevalent in ME/CFS and has similar autoantibody issues suggests that the outcome is not such a surprise.

The trial was small and carefully curated to those with high antibody levels but most patients improved and some recovered

The trial was small and carefully curated to those with high antibody levels but most patients improved and some recovered

A follow-up study is beginning. If that works out, Scheibenbogen hopes for a big trial that will settle the issue definitively.  In a good sign, she reported that the company that produces the immunoadsorption treatment (not available in the U.S.) is quite interested in ME/CFS.

(Even if the treatment is not available in the U.S., a successful trial could do a couple of things: it could prompt the company to make the treatment available in the U.S., and it would surely enhance autoimmunity research. We’ll see what happens, but if we can come up with several treatments – each of which is effective in a subset of patients – we’ll start to whittle the disease down.)

As she left for the airport, Scheibenbogen said she hopes that in the next five years ways to diagnose and treat ME/CFS will be found. Let it be so…

Guidelines to Biomarker Produced

Euromene, the new ME/CFS European research group Scheibenbogen is working with, recently laid out a step-by-step pathway to develop a biomarker. She noted that we have lots of interesting findings, but none that are unique to ME/CFS. Plus, the findings we do have overlap too much with healthy controls.

In short, we haven’t found that key signature – that key physiological mark – which says a person has ME/CFS. (That may not be a surprise: until we find the core of ME/CFS, we may not be able to find a unique biomarker). Scheibenbogen did wonder, however, given Maureen Hanson’s recent inability to find subsets in her metabolomic data, if the biomarker for ME/CFS will be metabolic in nature.

 

Unutmaz’s Big Surprise

Ron Davis has noted things often don’t work out the way researchers expect them to. Apparently, Derya Unutmaz feels the same way.  Unutmaz got a T-cell result that pointed straight at the gut and then was pleasantly shocked when a look at the gut confirmed his findings.  He was expecting a few more twists and turns from the body! It’s not usually so easy.

He noted that over the past decade a tremendous amount of work has been done on the effects the gut microbiome (gut bacteria) have on the immune system. It’s now clear that a shift toward more inflammatory bacteria in the gut can result in inflammation in other parts of the body. In fact, Unutmaz reported that just about every disease is associated with a change in gut bacteria.  The bacteria play such a vital role that oncologists can even determine how effectively patients will respond to immunotherapies by assessing the kind of bacteria they carry in their guts.

That makes sense for ME/CFS, since every gut bacteria study has thus far found substantial alterations in the bacteria in ME/CFS patients’ guts.

Unutmaz is a T-cell guy. He knows that bacterial metabolic by-products trigger unusual T-cells called  MAIT T-cells (Mucosal associated invariant T cells) to get into action. Once these cells, which are found in our gut lining, liver, lungs, etc., come across those metabolites, they secrete pro-inflammatory cytokines. Those cytokines turn monocyte cells into hairy monsters called macrophages which then gobble up the bacterial-infected cells.

MAIT cells, then, play a key role in turning on our immune response to the bad bacteria that can live in our guts. They apparently lurk in the gut lining as a kind of last line of defense against those bacteria getting into our blood stream and invading the rest of the body.

gut bacteria chronic fatigue

Unutmaz’s findings suggested that T-cells in the ME/CFS patients’ guts had been repeatedly exposed to bad bacteria

Unutmaz found that a high percentage of MAIT cells had been repeatedly activated in ME/CFS patients – suggesting a plethora of bad bacteria was present. In true ME/CFS fashion, Unutmaz also found that ME/CFS patients’ MAIT cells were activated — but “punked out” at the same time. (A wired and tired immune cell?).  Seemingly exhausted by the continual stimulation, they (like their natural killer cell cousins) had problems killing infected cells. That hearkened back to the Lipkin/Hornig immune finding of activated immune systems in early-duration ME/CFS patients and depleted immune systems in longer- duration patients.

Unutmaz is now trying to identify which bacteria are tweaking ME/CFS patients’ MAIT T-cells so much as to possibly burn them out. If he’s successful, he may have found a target that could quiet down a possibly overworked and burnt-out immune system and allow it to rejuvenate.

Are Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Immune Exhaustion Disorders?

Part 1: The Montreal ME/CFS Conference: Metabolism and Exercise

 

Did a Multiple Sclerosis Study Give Us Clues About ME/CFS and Fibromyalgia?

Why should a blog focused on chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) be interested in multiple sclerosis? Because some distinct similarities exist between the three diseases, and when diseases like ME/CFS and FM aren’t getting much research, sometimes it pays to pay attention to diseases that are. You never know what insights might open up.

MS and ME/CFS

A recent study indicated that ME/CFS was more functionally disabling than multiple sclerosis

For the record, while multiple sclerosis is not as disabling as ME/CFS (yes – studies indicate that ME/CFS is more disabling than MS), MS is considered one of the most fatiguing diseases known.  (Dr. Light’s study actually found more fatigue in MS but much less post-exertional malaise ME/CFS.)

A “Fatigue” Disorder No More? – What Multiple Sclerosis Taught Us About Fatigue and Chronic Fatigue Syndrome

Additionally, MS like ME/CFS and FM, mostly strikes women in mid-life. Plus, having mononucleosis/glandular fever increases the risk of coming down with either ME/CFS or MS and one suspects, FM as well.  Infections often trigger relapses in both MS and ME/CFS. Pregnancy also often brings a respite for women with either MS or ME/CFS (often unfortunately followed by a relapse.) Central nervous system involvement is present in all three diseases. In fact, Simmaron’s spinal fluid study found similar levels of immune dysregulation in ME/CFS and multiple sclerosis.

Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome

A New Multiple Sclerosis Study Breaks Through

Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1520-E1529. doi: 10.1073/pnas.1710401115. Epub 2018 Jan 29.Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility. Russi AE1, Ebel ME1, Yang Y1, Brown MA2.

A new MS study highlights a vital aspect of medical research – an animal model – that both chronic fatigue syndrome and fibromyalgia lack. It illuminates how researchers can use animal models to crack complex medical mysteries.  Tantalizing leads are present in both FM and ME/CFS but no one has been able to meld them into a bonafide breakthrough. That appears to have happened in MS.

Let’s see what happens in a well-studied, well-funded disease. As a bonus we’ll see that the hopeful breakthrough in MS could even have relevance to ME/CFS and FM.

One of the huge questions facing ME/CFS, fibromyalgia, MS and many autoimmune diseases is why so many more women than men get ill. Women don’t just get more autoimmune diseases, they tend to get them earlier than men and tend to have more severe cases.  No one knows why but researchers have been scratching around a possible answer for at least a decade.

The gender divide in MS has been well explored. The fact that puberty sparks an increase in MS incidence in females suggests a strong hormonal component is present.  A 2015 review agreed that sex hormones probably play a major role. Another noted that the autoimmune component of MS is greatly increased in women.

A Serendipitous Mistake Sparks a Major Finding

mouse animal study

A mistake in differentiating male from female mice led to a major discovery.

As so often happens in research, a serendipitous mistake sparked this discovery.  It began when a Northwestern University graduate student accidentally used a male mouse instead of a female mouse in an experiment. (Female mice are apparently hard to distinguish from male mice.) The researchers were using female mice to find genetic mutations that could help prevent the progression of MS – a female dominated disease.

When they ran the experiment they found, to their great surprise, that the genetic mutation that was protective in female mice actually made things worse for the male mice. (Talk about a gender divide.) Digging deeper, the team found that the genetic mutation in male mice blocked the activity of immune cells (ILC2) that are protective against multiple sclerosis in female mice. These cells halt the production of TH17 T-cells that initiate the attack on the myelin sheaths of neurons in MS.

Mast Cells Make Good

Mast cells are usually associated with allergic responses and in ME/CFS/FM with a condition called mast cell activation syndrome (MCAS) but this study revealed that mast cells can have a protective side as well.

Testosterone

A male hormone, testosterone, then reared its head.  In men testosterone triggers mast cells to produce a substance called IL-33 which stops the production of the TH17 cells in their tracks.  In fact, when the Northwestern University researchers removed the mast cells from the male mice their neurons came under attack and they developed mouse MS.  In the presence of testosterone, then, mast cells are a very nice thing to have.

testosteron

Testosterone levels could possibly could help explain the gender divide in MS as well as ME/CFS and FM.

Female mice, which have seven to eight times less testosterone than male mice, don’t produce enough testosterone to induce their mast cells to produce IL-33. Instead, female mast cells produce cytokines which increase inflammation and the TH17 T-cells that have been fingered in MS.

Testosterone has been on MS researchers’ radar for quite some time. A recent review of hormonal related changes in MS asserted that there is “compelling evidence that estrogen, progesterone, and testosterone control MS pathology by influencing immune responses and by contributing to repair mechanisms in the nervous system”.

Testosterone levels that drop as men age track with an increased incidence of MS in later life. (Interestingly the men who do get MS tend to have a tougher time with it than women.) Lower testosterone levels in men with multiple sclerosis are also associated with greater disability.  Some similar findings have been found in women. Women with MS tend to have lower testosterone levels, and increased lesions were associated with reduced testosterone levels in one study.

A very small clinical trial suggested testosterone supplementation might be able to increase white matter volume in the brains of men with MS.  If that finding is validated in larger studies, testosterone might be the first substance found that can reverse some of nervous system damage found in MS.

Testosterone, ME/CFS and FM

Testosterone levels could possibly could help explain the gender divide in MS as well as ME/CFS and FM.

A few studies have implicated testosterone in two other gender-imbalanced diseases – chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM).

Two studies have found low levels of testosterone in fibromyalgia, and testosterone levels have strongly been linked to pain sensitivity in animal models. One recent study suggested that lower levels of testosterone in combination with other factors was associated with increased rates of depression and poorer sexual functioning in FM. Recently, Jarred Younger’s small “good-day, bad-day” FM study found that lower levels of two hormones, testosterone and progesterone, were associated with more severe FM symptoms.

Fibromyalgia – the Testosterone Connection

Despite concerns about the use of testosterone in women, White found that a 28 day course of testosterone gel reduced pain significantly in women with FM. (More about that later.)

In ME/CFS Broderick’s modeling efforts suggest that testosterone in men is protective.  Plus the high rate of gynecological issues in ME/CFS and fibromyalgia suggest that sex hormones are involved in ME/CFS.

High Rates of Gynecological Disorders Implicated in Chronic Fatigue Syndrome and Fibromyalgia

Sex, Autoimmunity and Chronic Fatigue Syndrome … or Why More Women Than Men Get ME/CFS

Testosterone and Autoimmunity

No one knows if ME/CFS and FM are autoimmune diseases, but both could be and the link could have something to do with testosterone. The evidence that testosterone is protective against some autoimmune diseases is building.

Adding the gut contents of male mice to female mice (another mouse model) reduced their risk of type I diabetes – an autoimmune disease. Interestingly, the protective element again appeared to be testosterone, the levels of which were highly influenced by the composition of the mice gut flora.

Declining testosterone levels in men as they age increases their risk for rheumatoid arthritis. Declining testosterone levels may also be responsible for the gender parity seen in RA by age 75, and could explain why men tend to get multiple sclerosis at a later age than women. Low androgen levels in both men and women also appear to put them at risk for autoimmune disorders.

The gender divide extends to opioid use. Regular opioid use suppresses testosterone in men but not in women.

A TH17 Connection

ME/CFS may share another connection with multiple sclerosis – a deranged TH17 response. TH17 T-cells defend against extracellular pathogens and have been found to play a significant role in the development of inflammatory and autoimmune disorders. TH17 cells appear to help initiate attack on the neuronal sheaths in MS.

Several studies from Dr. Klimas’s group suggest a TH17 associated process may be in play in ME/CFS.  Exercise provoked a Th17 response  in both ME/CFS and Gulf War Syndrome patients.  Broderick’s modeling effort found that as few as five cytokines associated with TH17 activation could identify approximately 80% of ME/CFS patients with an infectious trigger. TH17 cytokines showed up again prominently in Broderick’s network analysis study which found they functioned as “preprogrammed immune component”.

Treatment

The question now is how induce a testosterone-like response in women without actually using testosterone. Drug studies suggest that testosterone can be helpful in MS but the study authors stated that women can’t take much of it without becoming masculinized and experiencing other significant side effects.

Instead this new MS study’s importance lies in the discovery of a key cytokine (IL-33) that can apparently turn off the destructive nerve processes in MS and even restore the nerves. If researchers can develop a way to promote IL-33 activity without using testosterone in women, they may have gotten a handle not just on MS but possibly on other gender imbalanced autoimmune diseases as well.

A New Approach to Autoimmunity?

The authors were quick to suggest that the findings may apply to other autoimmune diseases as well and could ultimately signal an entirely new approach to them. That’s welcome news given the harsh side effects of many of the immune suppressants used in autoimmune diseases.

“This suggests a mechanism for the reduced incidence of multiple sclerosis and other autoimmune diseases in males compared to females. These findings could lead to an entirely new kind of therapy for MS, which we greatly need.” Melissa Brown, PhD.

Perhaps it will lead to new direction in research for ME/CFS or FM.

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

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

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

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

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

cytokines chronic fatigue syndrome

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

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

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

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

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

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

Results

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

cortisol

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

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

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

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

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

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

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

Wyller - neuro-endocrine-immune disease

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

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

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

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

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

Mold Connection?

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

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

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

 

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

“In this monograph I would like to explore the concept of neuro-immune fatigue as a metabolic illness resulting from a series of events beginning with an infection, toxic exposure or neurologic injury.” Dr. David Bell, 2007

This is one of a series of blogs highlighting hypotheses mostly written by doctors or other professionals with ME/CFS, or in this case, doctors who have cared for them. The hypothesis examined in this case: Dr. Bell’s idea, produced in his monograph, “Cellular Hypoxia and Neuro-immune Fatigue”, that chronic fatigue syndrome (ME/CFS) could be a kind of “slow sepsis”.

Bell’s “Cellular Hypoxia” book was published in 2007, long before he was probably acquainted with Dr. Naviaux’s and others’ work and before the recent explosion of interest in cellular energy production in ME/CFS. Naviaux and others would probably smile, though, at Bell’s prediction that with ME/CFS and other diseases, “we may be witnessing the emergence of the next era of medicine: the diagnosis and treatment of cellular metabolic diseases”.

Sepsis is a life-threatening response to infection or trauma that can lead to tissue damage, organ failure, and death. In some ways, sepsis sounds similar to autoimmunity. For reasons the medical profession does not understand, sepsis begins when the immune system resets itself, stops fighting pathogens, and turns on the body.

The results are often devastating. The near complete body breakdown that results makes sepsis the most expensive disease hospitals treat.  Forty percent of patients with severe sepsis do not survive.

Chronic Fatigue Syndrome (ME/CFS) – A Mild but Chronic State of Septic Shock?

ME/CFS is obviously not sepsis, but it does share some interesting characteristics.  With his “cellular hypoxia” monograph published in 2007, Dr. David Bell suggested that people with ME/CFS may exist in a “mild, but chronic state of septic shock”. Bell came to this conclusion after finding that sepsis and ME/CFS produces what he believed is a similar kind of oxygen dysfunction. In sepsis and in ME/CFS, Dr. Bell notes that oxygen is actually abundant: it’s abundant in the air, the lungs and the blood of ME/CFS patients, but it’s just not getting taken up by the tissues.

Bell reports that in septic shock, the following events occur (note the last one):

  • a serious infection occurs which –
  • results in the production of cytokines which –
  • increases nitric oxide levels which then –
  • interfere with the production of cellular energy.

Bell noted that when nitric oxide blocks the flow of oxygen in severe septic shock, a patient can still die despite doctors giving him/her as much blood and oxygen as they need.

Bell suggests a similar process to sepsis occurs more gradually in ME/CFS. First, an initiating infection or toxic exposure triggers the immune system to produce pro-inflammatory cytokines and nitric oxide (NO). From there, NO increases peroxynitrite and superoxide (Martin Pall’s hypothesis), which causes oxidative stress and interferes with mitochondrial function.

Ultimately, the cell becomes hypoxic (oxygen-starved), and neuropathies and autoimmune and other problems develop.

The idea that impaired oxygen intake might be limiting energy production has gained some currency since Bell wrote his monograph.  Vermoulen’s exercise studies suggest that impaired oxygen intake, not mitochondrial problems, is the key issue in energy generation. The early stages of Ron Davis’s collaboration with an San Jose State University bio-engineer suggest that the red blood cells may have difficulty getting to the tissues. Other researchers have found autoantibodies to receptors that open and close the blood vessels in a subset of ME/CFS patients.

Last year, Chris Armstrong in, The “Starvation” Disease? Metabolomics Meets Chronic Fatigue Syndrome Down Under“, took the sepsis/ME/CFS notion one step further when he noted that many of the metabolomic anomalies (reduced amino acids, reduced lipids and increased glucose levels) found in ME/CFS are also found in sepsis and starvation.

Remarking that during sepsis, immune cells rely entirely on glycolysis to proliferate, Armstrong speculated, much as Bell did years earlier, that an infection or autoimmune process might have triggered a sepsis-like condition which lead to a state of chronic metabolic starvation.

A last tie to sepsis is an incidental one.  Ron Davis and Ron Tompkins of the Open Medicine Foundation worked on sepsis together. Based on his work there, Davis has said ME/CFS could be a kind of atypical sepsis.

Two Vascular Diseases?

blood vessels

Blood vessel damage could play a central role in both sepsis and ME/CFS

Bell noted that a vasculopathy – inflammation of the blood vessels – was the first symptom (reddened cheeks) he noticed in ME/CFS.  (That suggested to him that a parvovirus may have swept through his area.)

Cardiovascular issues could be central in both diseases. Perhaps the most interesting possible intersection between sepsis and ME/CFS occurs in the blood vessels – specifically the small blood vessels.

Recently an NIH Panel redefined sepsis as: “severe endothelial (blood vessel) dysfunction syndrome in response to intravascular and extravascular infections causing reversible or irreversible injury to the microcirculation responsible for multiple organ failure”; i.e. at its heart, sepsis is a small blood vessel disease caused by a pathogen attack – which is complicated by the immune storms that follow.

Sepsis has also been called a “malignant intravascular inflammation” characterized by excessive coagulation which blocks blood flows to the small blood vessels, reducing blood volume and lowering blood pressure.

Indeed, as Bell points out several times in his monograph, vascular issues show up again and again in ME/CFS, POTS, orthostatic intolerance and similar, related diseases.

Blood Pressure

Altered blood pressure is another sign of cardiovascular issues in both diseases. A sudden drop in blood pressure associated with an infection is an indication that sepsis has begun.

Blood pressure regulation problems are found in ME/CFS but anecdotal reports suggest that declines in blood pressure may be common as well.  Bell writes that most, but not all, people with ME/CFS have low blood pressure – something that the medical profession has little interest in – unless you’re in the ICU.  It’s ironic, Bell notes, that an ME/CFS patient with a blood pressure 75/40 will get little notice but put someone with that blood pressure in an intensive care unit and the sirens will go off.

Blood Volume

Low blood volume is common in sepsis and great efforts are made to increase it. Low blood volume, of course, is very common in ME/CFS as well. Sometimes blood volume is so low in ME/CFS as to stagger the mind, yet it’s received little attention.

Increasing blood volume can, of course, be helpful in ME/CFS, but is not as helpful as one would think, given the low blood volumes found. (Could microcirculatory problems be to blame?)

Blood Flows

In sepsis, blood flows in the microcirculation become so low as to damage the organs. That doesn’t appear to happen in ME/CFS, but even back in 2007, Bell was able to point out studies showing reduced blood flows to the brain and muscles was present.

Pathogen Damage

Sepsis was long thought to result from an overwhelming immune response to an infection but that’s no longer thought to be true. In 2010, however, that changed. The Working Group on Blood Systems Response to Sepsis, convened by the NIH’s National Heart Lung and Blood Institute (NHLBI), concluded that a cytokine cascade was not, as had been previously believed, the main culprit. The real issue in sepsis, they asserted, is damage to the blood vessels caused by an uncontrolled infection.

The damage is then exacerbated by many inflammatory factors (including Dr. Bell’s nitric oxide metabolites).  A period of reduced immune activation or “immuno-paralysis” (caused by an overactive anti-inflammatory response/immune exhaustion) that follows then sets the stage for the reactivation of latent viruses such as EBV, HSV-1 and others which amplify the damage.

The immune response is still recognized to be important, particularly in the later stages of the disease, but the infections themselves and the damage they do mayt be the key factor.

That’s an intriguing finding given that the biggest factor in determining who gets ME/CFS and who doesn’t after an infection appears to be the severity of the initial infection. Could a severe infection kick off a low-grade, chronic type of sepsis in ME/CFS?

It’s possible that the difficulty NK cells – and probably T-cells – have in killing off pathogens in ME/CFS might just give those pathogens enough time to damage the blood vessels.  Or, perhaps in other cases, an autoimmune process is sparked which does the same. (An autoimmune process appears to occur in some types of POTS).

Post-Sepsis Syndrome (PSS)

Interestingly, sepsis appears to be another potential trigger for chronic fatigue syndrome (ME/CFS). Post-sepsis syndrome (PSS) – a condition occurring in about 50% of sepsis survivors – indicates that surviving sepsis – perhaps like surviving the infection, injury or whatever that appears to trigger the onset of ME/CFS – is often not nearly the end of the story.

Extreme fatigue, problems with cognition, muscle and joint pains, insomnia and other sleep problems, that can last months or even years are common outcomes of sepsis.  In fact, a sepsis trust has produced a support document specifically for post-sepsis patients experiencing “chronic fatigue“.

The medical profession has been content thus far to simply to document the extent of PSS – with little attempt to understand or treat it.  The causes of the fatigue and chronic pain in PSS are completely unknown. This is despite the fact that several studies have made clear that PSS is a significant and enduring problem: statistics suggest that about 250,000 people a year come down with PSS.

The disease is clearly pathophysiological, but the only help The Sepsis Alliance could provide for the many chronically ill survivors was to get emotional and psychological support (counseling, cognitive behavioral therapy or neuropsychiatric assessment) or physical therapies.

Treatment

Sepsis is also confusing to treat. The first line of defense is a hearty dose of antivirals, fluid support, etc.  From there it gets trickier.  People with sepsis may have a pro-inflammatory phase followed by immune suppression (or both may be occurring at the same time).  (Could ME/CFS be a kind of drawn-out sepsis with a longer pro-inflammatory phase followed by immune exhaustion?)

Researchers and doctors focused on reducing pro-inflammatory responses, but drug trials targeting the pro-inflammatory response have been ineffective.  Now, researchers are targeting immune checkpoints in hopes of unleashing the power of the innate immune system.

Check out a more technical take on sepsis and ME/CFS which brings Systemic Inflammatory Response Syndrome (SIRS) into the equation: IS SIRS, CARS, MARS – AND NOW PICS – CAUSING THE “CHAOS” IN ME/CFS?

Conclusion

dr. david bell

Dr. David Bell

Chronic fatigue syndrome (ME/CFS) is not sepsis but the two diseases do share some intriguing characteristics. Both sepsis and ME/CFS often start with an infection; oxygen delivery to the tissues appears to be a problem; blood pressure, blood volume and blood flows are affected, and sepsis often results in a syndrome that symptomatically looks very much like ME/CFS.

As Roberts points out what’s happening in the very, very complex disease known as sepsis is still unclear. Whether or not the new drugs being developed for sepsis will play a role in ME/CFS is, of course, unknown as well. Drugs being developed to turn off the anti-inflammatory response are intriguing given the state of “immune exhaustion” that some studies have found in ME/CFS.  If ME/CFS does turn out to be a kind of “slow sepsis” it will be a good idea to keep an eye on the developments there.

Stevens, in fact, suggests that the ME/CFS and sepsis communities stay in close touch.

It seems logical that the ME/CFS community should begin to share knowledge and resource with the sepsis organizations such as International Sepsis Forum (ISF), Global Sepsis Alliance and Sepsis Trust and Post Sepsis Syndrome patients. The curative challenges ahead are monumental, involving complex pathways which have yet to be researched, and will no doubt result in individualized treatments.

Simmaron Patient Day Part II: The Hanson Report

Maureen Hanson has been making waves.  An ace molecular plant biologist prior to entering the chronic fatigue syndrome (ME/CFS) field, Hanson has worked on mitochondrial and gene studies in plants dating back decades. Now, with her son ill from ME/CFS, she’s turned her talents to this field, and has made a difference in a hurry.

A trusted researcher, Hanson scored one of the few XMRV grants and in a short period of time has produced studies on the gut, mitochondrial DNA, exercise, and metabolomics in ME/CFS. Last year, Hanson, created one the few chronic fatigue syndrome (ME/CFS) research centers in the U.S. (the Cornell Center for Ennervating NeuroImmune Disease, ) and this year she and her colleagues received one of the three NIH ME/CFS Research Center grants. She’s also a member of the Simmaron Research Foundation’s Scientific Advisory Board.

Last year Hanson was awarded a smaller NIH grant (R21) to do preliminary work assessing the energy production in ME/CFS patients’ immune cells using the Seahorse XF Analyzer.  In this blog we take a closer look at the work underway.

A Breakthrough Technology

It’s safe to say that the Seahorse machine is changing how researchers do research. In the mid-2000s the Seahorse folks introduced something new to the medical world called “extracellular flux (XF)” technology. A monolayer of cells is placed in a very small, 10 ml sensor chamber and then stimulated.  Every few seconds a sensor placed 200 microns above the cell monolayer takes a measurement.  Where past techniques required hours to assess oxygen metabolism, the Seahorse can do it in minutes.

This technology allows researchers to determine the energy consumption of cells by analyzing changes in oxygen and acid levels occurring in the media outside of them.  The amount of oxygen present indicates how much energy is being produced through glycolysis and by the mitochondria.

The ability to place energy stimulating or inhibiting or other drugs in the sensor chamber brings the possibilities of the Seahorse machine to an entirely new level. If the inability to produce energy turns out to be a key factor in ME/CFS, the Seahorse machine’s ability to test how drugs and other substances effect the energy production of cells could be a big boon indeed

Agilent, the company that produces the Seahorse machine, reports the machine has been used in over 250 studies. HIV researchers, for instance, recently used the machine to determine the effectiveness of the immune response in HIV patients. It turns out that in order to meet a threat, many of our immune cells undergo a huge metabolic shift as they get transformed from a resting to an active state. That shift coincides with large increases in glycolysis in particular.

A similar approach is being used in chronic fatigue syndrome (ME/CFS). Tomas’ recent Seahorse study suggested that ME/CFS patients’ immune cells (PBMC’s (T, B and NK cells, monocytes))are having severe problems producing energy. Tomas’ study opened up an important possibility but it was limited by its inability to determine which cells were having problems.

https://www.healthrising.org/blog/2017/11/11/cellular-energy-hit-chronic-fatigue-study/

Hanson is taking the next step in assessing immune functioning in ME/CFS with her R21 NIH grant. That grant gave her the funds to assess the energy production of individual immune cells separately (T, B and NK cells).  (Isabel Barao is also examining energy production in NK cells).

Each of these cell types has been potentially implicated in ME/CFS. The T-cell problems Derya Unutmaz of Jackson Labs saw are what attracted him to ME/CFS, and Mark Davis of Stanford recently found signs of unusual clonal expansion in ME/CFS patients’ T-cells.  The success some ME/CFS patients have with Rituximab suggests B-cell issues are present, and the problems ME/CFS patients’ natural killer cells have with killing have been known for decades.

T-cells are a particularly good subject because springing into action to kill other cells or to produce clones of themselves to fight invaders requires enormous amounts of energy. If energy production is flawed in ME/CFS, it’s probably going to show up in patients’ immune cells.

Glycolysis OK

Metabolomic studies suggest glycolysis might be inhibited in ME/CFS, but at the OMF’s Stanford Symposium Hanson stated that she hasn’t found impaired glycolysis. When glucose was given to the immune cells to stimulate their glycolytic processes, the cells were able to use it, but their respiratory capacity (oxidative phosphorylation) was blunted.

In another study, which the SMCI helped to fund, Hanson’s Metabolon metabolomics study found lower glucose levels (a surprise) as well as differences in fat and lipid metabolism (i.e. energy production), and in the sphingolipids that play a big role in Naviaux’s findings.

Hanson noted that low glucose levels are not a good sign, either. Low glucose levels have been associated with increased cortisol responses (possibly leading to exhaustion) and inflammation. Plus they may be able to mess with a person’s endurance.

The last sport anyone with ME/CFS is going to engage in is an endurance race.  That might make sense given that athletes with lower glucose levels tend to do worse in endurance sports. Overall Hanson’s metabolite findings suggest increased inflammation and reduced recovery from metabolic stress are part and parcel of ME/CFS. Metabolic stress, of course, is exactly what she’s measuring in her Seahorse study.

Hanson’s finding of normal glycolysis in ME/CFS patients’ T-cells mirrors the findings of Tomas’ recent Seahorse study. However, Hanson’s early findings are suggesting that, at least in the immune cells, the mitochondria are the issue.

Hanson has found that ME/CFS patients’ T-cells use less of their “respiratory capacity” when provoked than do healthy controls’ cells. If I’m reading this right, the capacity to produce energy is there, but it’s not being used.  The next step is to determine if the T-cells, when they become activated, can produce enough energy to be effective. If Dr. Hanson finds they’re not up to the task of producing adequate energy, she said, “they may also be unable to effectively respond to an immune challenge.”

Lethargic T-cells could have major implications for the immune system, as T-cells are important in just about every immune system activity. At least four different kinds of T-cells exist:  T-helper cells activate B and NK cells, T-killer cells destroy virally infected and cancerous cells, T-memory cells alert the immune system to danger, and T-regulatory cells help keep the immune system humming.  Small studies suggest that cytotoxic or killer T-cells have the same problems with killing infected cells that NK cells do.

Whether or not something in ME/CFS patients’ blood is essentially putting their cells to sleep is one of the more fascinating questions facing this field. Several researchers including Ron Davis of the Open Medicine Foundation and Fluge and Mella in Norway believe something in the blood is doing just that. Energy production issues in ME/CFS patients’ cells that have been isolated from the blood suggest that something may be wrong with the cells themselves. It’s possible, therefore, that problems may lie in both the blood and the cells.

Since the Seahorse machine allows researchers to insert different substances in the medium the cells are bathed in, I asked Dr. Hanson if she could use the machine to determine the effects ME/CFS patients’ blood may be having on their immune cells.

Dr. Hanson replied that the Seahorse machine could determine if something in ME/CFS patients’ serum affects mitochondrial function in immune cells from healthy people, but the Seahorse technology would not be able to tease out what factors in the serum are responsible.

The Seahorse requires large samples of difficult to obtain immune cells. T-cells are relatively easy to obtain; B and NK cells – not so much.  Getting Maureen Hanson the resources she needs to do her work is where the Simmaron Research Foundation comes in: it’s supplying the cells she needs to do her work.  Dr. Hanson stated that, “We are grateful to Simmaron Research for supporting the collection of additional samples from which individual cell types— such as B and NK cells—can be purified for analysis of glycolysis and oxidative phosphorylation”.

Next up, Dr Hanson will analyze the cellular energetics of those NK and B cells. Despite the Rituximab failure, B-cells are still of great interest in chronic fatigue syndrome (ME/CFS). It’s still possible, for instance, that the drug works for a significant subset of patients. Plus B-cells are heavily involved in autoimmunity. Dr. Light has proposed that energy depleted B-cells may increase the risk of an autoimmune process beginning.

The desire to examine NK cells is obvious. Reduced NK cell cytotoxicity is a hallmark of ME/CFS, and reduced cytotoxicity of T-cells appears to be present as well. Could that poor killing power be caused by the most basic of all problems – the inability to generate enough energy? Given the high energy requirements of activated immune cells, that’s a distinct possibility. Dr. Hanson’s work will take us closer than any other yet to answering that most fundamental of all questions.

 

Major Stanford Study Indicates Chronic Fatigue Syndrome (ME/CFS) is Inflammatory Disorder

There’s been a great deal of controversy and confusion surrounding ME/CFS — even whether it is an actual disease. Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.” Mark Davis

There’s nothing like a high-profile study from a major university. For one thing it can get you publication in one of the most prestigious journals around. The  journal the Montoya/Mark Davis study was published in, The Proceedings of the National Academy of the Sciences, is the official publication of the National Academy of Sciences. Its website gets about 21 million hits a month; this study is going to get around.

Dr. Jose Montoya, the leader of the Stanford Myalgic Encephalomyelitis/Chronic Fatigue (ME/CFS) Initiative  has been talking about this study for years. Now that it’s finally here, it’s making an impact with many media outlets picking it up.

The results were positive and that was good news indeed. This was one study we really didn’t want to fail.

Too Big To Fail?

Cytokine signature associated with disease severity in chronic fatigue syndrome patients Jose G. Montoya, Tyson H. Holmes, Jill N. Anderson, Holden T. Maecker, Yael Rosenberg-Hasson, Ian J. Valencia, Lily Chu, Jarred W. Younger, Cristina M. Tato, and Mark M. Davis.  Proc Natl Acad Sci U S A. 2017 Jul 31. pii: 201710519. doi: 10.1073/pnas.1710519114. [Epub ahead of print)

The study examined the levels of a very large number of cytokines (n=51) in the blood of a very large number of patients and healthy controls (ME/CFS=186; healthy controls= 388). Age, sex, race and something called “nonspecific binding” were accounted for.

missing the mark

This was one study we really didn’t want to fail

One of the biggest ME/CFS immune studies ever undertaken, done at a top University, this was a study that we dearly didn’t want to fail. This is the kind of study likely to be labeled “definitive”. It was on scale with the Columbia cytokine study, where co-authors Ian Lipkin and Mady Hornig analyzed 51 cytokines in 298 patients and 348 healthy controls.  If the results of these two hallmark studies were discordant, it would have had negative consequences to any immune interpretation of this disease.

Smaller cytokine studies in ME/CFS have a history of inconsistency, making the similarities in these two studies important.

Results

The first news was not good. The levels of only two cytokines, TGF-Î (elevated) and resistin (lowered) were different in the patients compared with controls.  Displaying an unusual level of consistency for ME/CFS, TGF-B has now been found elevated in about six out of the ten studies it’s been tested in.

TGF-B has not received a lot of attention possibly because researchers are not sure what it means. An anti-inflammatory cytokine that can have pro-inflammatory properties, the authors noted that TGF-B is elevated in a number of dissimilar conditions (cancer, liver disease, inflammatory bowel diseases among others). The authors suggested TGF-B may have pro-inflammatory properties in ME/CFS; instead of tamping down inflammation, they proposed it may be “may be a major factor in promoting relentless inflammation.”

Big Finding

“Remarkably, 17 cytokines were associated with severity in ME/CFS patients.” The study authors

Dr. Montoya got the money for the study and conceived it, and Mark Davis advised him on it, was the senior author of the paper, and tested the samples in his lab.

Davis has won a slew of prizes (The Paul Ehrlich Prize, The Gairdner Foundation Prize, The King Faisal Prize, the General Motors Alfred P. Sloan Prize) and is on the Open Medicine Foundation’s Scientific Board. He’s a big deal in the immune world.

bulls-eye

Montoya and Davis hit the bulls-eye when they threw severity into the mix

I talked to Davis a couple of days after the study’s publication.  I asked him about the main results; those 17 cytokines that predicted severity – was that a lot?  It’s an important question. A couple of cytokines popping out might mean that the immune system is involved but is not a major player – time to look someplace else.  A lot of cytokines showing up, on the other hand, suggests the immune system may very well be it in ME/CFS – time to dig deeper.

Was 17 cytokines a lot? Even in the staid language of scientific journals the surprise at the size of the effect came through: “Remarkably”, the paper said, “17 cytokines were associated with severity in ME/CFS patients.”

When I asked Davis if it was really a lot, I heard him take a deep breath:  “it’s a lot – really a lot” – he said. Getting a third of the immune factors to show up suggests massive immune involvement. Davis – who is involved in constructing immune signatures for different diseases and health – said everything he’s seen about this disease suggests autoimmunity.  That’s a particularly meaningful statement  from such a well-known immunologist. He’s getting to know ME/CFS pretty well: Montoya’s study is the biggest study his public lab has run.

(Mark Davis has two labs – his private research lab and a larger, more public lab he set up to run many more samples at a time. That lab, which got a big federal grant, was designed to bring the same kind of rigor he uses in his private lab to bigger studies.  Researchers like Dr. Montoya can bring their samples to the lab and have the lab test them. That’s what happened in this study)

A Different Kind of Disease?

Mark Davis thinks ME/CFS is probably an autoimmune disease. You don’t see the kind of overt cytokine increases in ME/CFS that are seen in autoimmune diseases like rheumatoid arthritis  and lupus.  This study, in fact, suggested that cytokines were not increased in the patient group as a whole relative to healthy controls.

Adding severity to the mix, however, suggested that cytokines were heavily involved in this disease. Mark Davis said he’d never seen a disease with mostly normal cytokine levels but which presented such clear indications that cytokines affected symptoms.  He suggested that other diseases like Alzheimer’s might display similar patterns if researchers started looking for them.

In an interview with Miriam Tucker, Dr. Montoya echoed the unusual nature of the disease: he simply called the immune activation in ME/CFS – as he has for some time now – a different kind of inflammation.

“Inflammation is much more complicated than two imperfect old measures [sed rate and C-reactive protein]. We’re showing an inflammation that has not been seen before.” Jose Montoya

Three Options?

But what could be causing this bizarre pattern?  Higher cytokine levels could certainly explain the more severe fatigue in some ME/CFS patients, but how do the low or normal cytokine levels explain the fatigue in the more moderately fatigued patients? They do have ME/CFS after all; even if they are less ill than the severely ill, they are still enormously fatigued but their cytokine levels aren’t elevated at all. In fact the cytokine levels are lower than normal in some of them. Three options have been suggested.

(1) Loss of Immune Control In the Severely Ill

One possibility the paper presented is that the healthier patients with lower levels of pro-inflammatory cytokines are able to control them to some extent. Their immune systems are grinding away but they’re keeping – probably at some cost – the pro-inflammatory elements under control. The control mechanisms of the sicker patients, though, have collapsed – they’re bearing the burden of unremitting cytokine activity.

(2) A Localized Infection

In conversation Mark Davis suggested that a localized infection could also be causing the immune system to react – not with the huge increases in cytokines seen in systemic inflammatory or autoimmune diseases but with small, harder to detect ones.  He’s not the first to suggest that. A couple of years ago Michael Van Elzakker proposed exactly that scenario for ME/CFS.

Different

ME/CFS may be a different kind of inflammatory disorder

Van Elzakker proposed that localized infections – probably involving the vagus nerve – were causing small, hard to detect elevations of cytokines. Meanwhile the infections were playing havoc with the vagus nerve’s ability to communicate sensory and immune information to the brain.

I asked Van Elzakker about the study.  He believes the cytokines this study picked up in ME/CFS are probably spillovers from an infection or injury. He cited Robert Dantzer, an important figure in sickness behavior research and pyschoneuroimmunology, who in a (2014) Trends in Neurosciences review, The Neuroimmune Basis of Fatigue agreed that with regard to fatigue:

 “The measurement of circulating concentrations of cytokines represents the main limitation of the present studies on fatigue and inflammation. Given that cytokines are autocrine and paracrine communication factors, their circulating levels have little functional value and represent mostly spillover from the site of cytokine production and action.

Given how profoundly limited many people with ME/CFS are – Van Elzakker believes these localized infections probably exist in the neuroimmune nerves such as the vagus or trigeminal nerves.

(3) Context  – Is Context King?

There’s another possibility. Gordon Broderick’s modeling work in chronic fatigue syndrome (ME/CFS) suggests that context may be king in the immune system.   During a recent phone call Broderick described the co-expression study he did that found a changed immune landscape in ME/CFS.  Cytokines such as IL-1b, 2, 4, IFN-γ, TNF-α  and IL-10 had larger than expected impacts in ME/CFS patients relative to healthy controls while other cytokines had less impact.

If Broderick’s right, none of the cytokines found in Montoya’s study need to be elevated to have a significant effect – they simply have to be embedded in a dysregulated immune network.

Leptin is Back

This is the second time leptin has shown up in a Stanford study, and the researchers suggested that it might be the keeping the chronic inflammatory state in ME/CFS intact. It turns out that adipokines – cytokines secreted by fat cells – like leptin may be able to trigger neuroinflammation. They’re also found in higher levels in women and may be a particularly important trigger in female dominated inflammatory diseases such as multiple sclerosis.

 Duration

In contrast to the Lipkin/Hornig and another study, this study found little evidence of increased cytokine levels earlier in the disease or decreased levels later in the disease. The small numbers of short duration patients (n=30) in the study, however, could have prevented any findings from reaching statistical significance. Interestingly, the study did not find that disease duration was correlated with severity; i.e. patients who had been ill longer were not necessarily worse off.

 Diagnostic Test?

Mark Davis suggested the findings might prove the basis for a diagnostic test but in conversation indicated we’re far from one right now. Much more study is needed.

The diagnostic test problem is greater in the low to moderately ill patients who have similar cytokine levels to healthy controls. How to devise a test to distinguish them from the healthy controls with similar cytokine levels is the big question.

Montoya reported that his team was working on a five-cytokine panel that would require a doctor first classifying each patient by severity. If Montoya can devise specific cytokine signatures for each level of severity, a test might be feasible, but it’s clearly going to be a complex undertaking.

Big Study (Too Big?)

Montoya rather courageously put a lot money into an area of research – cytokine analyses – that have had their problems in ME/CFS. As the Lipkin/Hornig study and this study showed, when it comes to immune studies size is definitely better.

While it is possible that this study had more controls than needed, at least Montoya didn’t err on the other side – too few patients; that might have been fatal to this study. Mark Davis thought that given all the noise in the data, that a smaller study might not have found much.

 Don’t Think Too Much: the Zen of ME/CFS

In a kind of Zen-like statement Mark Davis cautioned about “thinking too much” about this disease at this point.  Davis wasn’t suggesting not inquiring about the disease, but not coming to conclusions about it.  We’re not there yet. We’re more in a space of creative inquiry than anything else.

tea-house-mt-fuji

Mark Davis warned against coming to conclusions; more views of ME/CFS is what we really need

Things got even more zen-like when Davis referred to a famous series of paintings called Thirty-six views of Mt. Fuji to underscore where we are with ME/CFS right now. The celebrated series by Japanese artist Hokusai shows Mt Fuji from different perspectives including from at dawn, from a window in a house, from behind a huge wave, etc., etc.

To Davis, ME/CFS is like Mt Fuji; we need to look at it from a lot more angles to fully understand it. The most important thing we can do now is to test, test, test and let the data guide us.

This study may demonstrate that more than anything. It, after all, had four highly unusual results – very little evidence of immune dysregulation compared to healthy controls; massive evidence (17 cytokines!) on the other hand, that the immune system is effecting severity, a substantial number (on the other, other hand) of individuals with low or low-normal cytokine levels, and finally two cytokines with abnormal levels which didn’t have anything to do with severity at all.

This study, then, boosted interest in the immune system in ME/CFS, while raising a lot of questions about it at the same time. A lot of work – a lot of exploratory work –  remains to be done to figure this puzzle box of a disease out.

In fact, exploration is largely carrying the day in ME/CFS research. Montoya got hundreds of samples, tested them as widely as possible, analyzed them a bit and then stood back. Ditto with the Ian Lipkin/Mady Hornig immune study,  the metabolomics studies from Armstrong and Naviaux, (Naviaux, however, has a hypothesis), Ron Davis and the Open Medicine Foundation with their severe ME/CFS Big Data study, and Avindra Nath and his deep Intramural NIH study.  They’re all exploring.

Mark Davis’ talk at Open Medicine Symposium on Saturday should be a good one.  NINDS Director Dr. Koroshetz talked up Davis’s exciting findings in the recent NIH Telebriefing, and Ron Davis thinks they may be even more significant than this paper. If you’re at the Symposium you can ask him about his work or Mt Fuji or just say hello and thanks.

Treatment

This study is a major legitimizer and a big spur for more immune studies – particularly big immune studies. One thing it doesn’t present are clear treatment options. When I asked Mark Davis about treatment options, he was unwilling to commit to any line of treatment based on the results. He agreed that basing treatment options off of this study would be like shooting fish in a barrel.

That doesn’t mean the study won’t help on the treatment end. The severity results, after all, scream inflammation. That suggests anti-inflammatories might very well help. Ron Davis noted that many immune affecting drugs are under development right now which might be useful for ME/CFS in the future. We simply need more study to assess which targets might be best.

If Gordon Broderick’s right, though, it may take more than knowing a cytokine’s levels to find the right target. Broderick’s working on complicated models that incorporate the effects hormone levels, in particular sex hormone levels, have on immune factors in ME/CFS.  Broderick believes he’ll be able to devise a treatment approach that pushes the immune system one way and then another in order to nudge it back to a stable and healthy state.

Fatigue or Functioning?

While the multi-dimensional fatigue index used to assess fatigue has been validated as a good measure of fatigue across many diseases, one wonders if a functionality scale might have worked better. Fatigue is what ME/CFS is known for, but it’s real impact is on functioning. It’s possible to be very fatigued and still work, or to be pacing effectively – and not doing much work – and be less fatigued.

The MFI worked well in this study and past ME/CFS studies have used it, but one wonders if a scale that tracks functionality – how much activity one is actually doing – might have been more effective at tracking severity.

 Slow Progress

Montoya has been given much (reportedly $8 million donation in 2008) and promised much, but the ME/CFS work has been slow. He’s a toxoplasmosis expert, possibly the top expert in the country, and he’s been pouring out toxoplasma studies – fourteen since 2015 – but the work in ME/CFS has gone much slower.  Since 2009 he’s been the senior or lead author on just four ME/CFS studies – two of which involved the valganciclovir trial and predated the opening of his ME/CFS center.

This latest study was the most important one – it will undoubtedly help the field – but one hopes that with this monster study out of the way Montoya will be able to move faster on his other ones. His current research projects page lists ten studies. Two involve the Zinns who, unable to publish their work at Stanford, exited to work with Lenny Jason. Those studies are surely not extant.

The eight others, though, involve brain imaging, neuroendocrine, gene expression, cardiovascular, immune and pathogen studies. In a telephone conversation Mark Davis referred to some scintillating results he and Montoya are working on using the immune data Montoya gathered.  Let’s hope we’ll see those results and more from Montoya’s Chronic Fatigue Initiative in the not too distant future.

Conclusion

lighthouse

This study, as did the Lipkin/Hornig study, suggested you have to approach ME/CFS differently than other diseases to be successful.

One of the things that emerged from this study is that ME/CFS really, really is different and woe to any researcher who assumes that it’s not. The regular rules of the road do not apply – you can’t just measure cytokine levels and expect to get anything. You have to dig deeper, and what this study and the large Lipkin/Hornig study before it demonstrated was that if you do dig deeper, you might stumble on something extraordinary.

The study’s excellent pedigree – it’s size, the lab it took place in and the journal it was published in – guarantees it will get noticed and that’s a good thing. The most important aspect of the study may be the legitimization it confers on the illness. Hopefully the study will introduce new researchers intrigued by what could be a new type of inflammatory disorder to the field.  While more work is needed, the study also points to possible future effective treatment options. Lastly, the study indicates, as did the Lipkin/Hornig study, that bigger really is much, much better in ME/CFS research. Hopefully funders will take a cue from these large studies, and support the bigger and more definitive studies this disease needs to move forward.