All posts in Immune System

Could the Gut Cure Neuroinflammation? An MS and ME/CFS/FM Inquiry

Gut Neuroinflammation Connection Revealed

“There is something very critical about how the gut and brain are connected, and we’re starting to unravel the molecular threads behind that clinical observation. It’s a great example of how fast science can move.” Jen Gommerman – co-author

Limiting our attention solely to chronic fatigue syndrome (ME/CFS), fibromyalgia (FM) and allied disorders might be a mistake. Recent studies indicate that ME/CFS and FM fit into the broad category of neuroinflammatory disorders which include multiple sclerosis (MS), Parkinson’s disease and others.

ME/CFS and FM neuroinflammatory

ME/CFS and FM may fit into a broad spectrum of neuroinflammatory disorders.

The same parts of the brain may not be affected in each disease, but it’s possible that each is undergirded by a similar inflammatory milieu. If the goal is to reduce neuroinflammation, then an approach that works in one disease could work in another.

The immense amount of research being devoted to these other neuroinflammatory disorders suggests they could provide critical insights into ME/CFS and FM as well.

A recent multiple sclerosis gut study provided a prime example of how progress in one neuroinflammatory disease may benefit others. It underscored the gut’s long reach and illuminated a potential treatment approach – not just for MS, but possibly also for other neuroinflammatory diseases.

It raised the possibility that manipulating one’s gut bacteria may at some point become an effective treatment approach in the fight against neuroinflammation.

Cell. 2018 Dec 21. pii: S0092-8674(18)31560-5. doi: 10.1016/j.cell.2018.11.035. [Epub ahead of print] Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10. Rojas OL1, Pröbstel AK2, Porfilio EA1, Wang AA1, Charabati M3, Sun T1, Lee DSW1, Galicia G1, Ramaglia V1, Ward LA1, Leung LYT1, Najafi G1, Khaleghi K1, Garcillán B4, Li A5, Besla R6, Naouar I1, Cao EY1, Chiaranunt P1, Burrows K1, Robinson HG7, Allanach JR7, Yam J1, Luck H5, Campbell DJ8, Allman D9, Brooks DG10, Tomura M11, Baumann R2, Zamvil SS12, Bar-Or A13, Horwitz MS14, Winer DA6, Mortha A1, Mackay F4, Prat A3, Osborne LC7, Robbins C15, Baranzini SE16, Gommerman JL17.

Their study started in the head and moved downwards. Researchers wondered where the heck the plasma cells (IgA antibody producing B-cells) showing up in the central nervous systems of MS patients were coming from. It turned out they were coming from the gut.  They found that B-cells were making their way to the gut where gut bacteria where flipping their switch – and turning them into IgA producing plasma cells. Now their one and only goal was to produce IgA antibodies.

IgA antibody gut chronic fatigue

IgA antibody producing cells that are formed in the gut appear to play a major role in tamping down inflammation in the brain

Eventually they made their way up the body to the brain, where (in the presence of IL-10) they were tamping down inflammation. Interestingly, the guts of the mouse model for MS were deficient in these cells. These plasma B-cells were so effective at reducing brain inflammation that boosting their levels in the mice’s guts returned them to health.

The levels of these plasma cells are also reduced in the guts of humans during MS relapses – presumably because they’re being recruited to the brain to fight the inflammation.

This finding cleared up a conundrum – why knocking out B-cells tended to help people with MS while knocking out only the IgA-producing cells made them worse. B-cells were believed to promote neuroinflammation and autoimmunity and they do. The B-cell inhibitors used are believed to reduce T-cell activation and suppress autoantibody production.

No one suspected, though, that specialized B-cells might also play a critical role in suppressing inflammation. Knocking those cells out resulted in the patients getting worse.

Gut Modification

“Showing that IgA-producing B cells can travel from the gut to the brain opens a new page in the book of neuroinflammatory diseases and could be the first step towards producing novel treatments to modulate or stop MS and related neurological disorders.” Sergio Baranzini – co-author

The next steps seem clear: find a way to increase the number of IgA-producing plasma cells in the guts of people with neuroinflammatory disorders in the hope that they will knock down inflammation in the brain. Because some bacteria – which ones is unknown at the moment – trigger B-cells in the gut to change to IgA producing plasma B-cells, the next step is to identify that microbe and find a way to increase its numbers.  In other words, find a way for the gut to naturally reduce inflammation in the brain.

“If we can understand what these cells are reacting to, we can potentially treat MS by modulating our gut commensals. That might be easier than getting drugs into the brain, which is a strategy that hasn’t always worked in MS.” Gommerman – senior author

Potential Relevance to Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia, etc.

“As a clinician-scientist, it is exciting that our experiments linking preclinical animal models to the biology we see in real MS patients may have uncovered a general mechanism for how the immune system counteracts inflammation.” Pröbstel – co-author

Chronic fatigue syndrome (ME/CFS) is not MS but the two diseases might be more closely related than one might think. Having mononucleosis/glandular fever increases the risk of coming down with either ME/CFS or MS and infections often trigger relapses in both diseases. The most disabling symptom in MS tends to be fatigue and both diseases mostly affect women. Plus pregnancy often brings a (temporary) respite in both diseases.

A Simmaron Research Foundation sponsored spinal fluid study found similar levels of immune alterations in ME/CFS and MS, and pointed to a major, almost MS-like, alteration of immune factors in ME/CFS.

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

Jarred Younger, who knows neuroinflammation as well as anyone in this field, believes that MS and ME/CFS could turn out to be close cousins. Younger believes the neuroinflammation present in both diseases may be similar, with the notable distinction that the immune cells in MS have been tweaked to attack the neurons, while those in ME/CFS, thankfully, have not. (Younger has begun a low dose naltrexone trial in early stage MS patients to see if he can stop the neuroinflammation before it has irrevocably damaged the nerves.)

 

Jarred Younger III : Treatments – A Better LDN and the Hunt for Microglia Inhibitors

What works in MS could work in ME/CFS and it already has – at least in two cases. A MS drug called Copaxone was very effective in two ME/CFS patients who’d been misdiagnosed with MS. In fact, it was much more effective in those patients – resulting in significant reductions in fatigue –  than it ever was in MS.

The really exciting thing about this study is its potential relatability to other diseases.  These researchers appeared to have stumbled upon a basic gut induced anti-inflammatory pathway that may help with other neuroinflammatory diseases including, who knows, perhaps ME/CFS and FM.

It’s clear that we can’t view MS as strictly a brain disease. Yes, the overt physical damage occurs in the brain, but gut issues play a role as well. In fact, this study suggests the possibility that gut damage – in the form of a dysregulated microbiome – might even play a critical role in allowing MS to progress.

Could the Gut Be a Potential Drug Factory?

Given the possibility that harnessing an as yet unknown microbe in the gut could reduce inflammation in the brain, one has to wonder if the gut, with its trillions of microbes, is a potential reservoir of drugs.  Could we tweak the microbes in the gut to provide other factors that reduce disease? Will gut manipulation ultimately play an important role in treating chronic diseases?

Immune Factor May Jump Start Chronic Fatigue Syndrome (ME/CFS)

December 31, 2018

“For the first time, we have shown that people who are prone to develop a CFS-like illness have an overactive immune system, both before and during a challenge to the immune system. Our findings suggest that people who have an exaggerated immune response to a trigger may be more at risk of developing CFS.” Alice Russell

This British study is interesting in so many ways. Most importantly, it draws a link between an overactive immune system and CFS-like chronic illness in Hepatitis C patients who were studied before and after treatment with an immune stimulant. The authors believe it may tell us why some people come down with chronic fatigue syndrome (ME/CFS) after an infection. If so the Brits have found the first predictive blood factor for ME/CFS.

Psychoneuroendocrinology. 2018 Dec 14. pii: S0306-4530(18)30196-3. doi: 10.1016/j.psyneuen.2018.11.032. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Russell A1, Hepgul N2, Nikkheslat N3, Borsini A4, Zajkowska Z5, Moll N6, Forton D7, Agarwal K8, Chalder T9, Mondelli V10, Hotopf M11, Cleare A12, Murphy G13, Foster G14, Wong T15, Schütze GA16, Schwarz MJ17, Harrison N18, Zunszain PA19, Pariante CM20.

It is interesting in one way, because it comes out of King’s College London – the longtime home of Simon Wessely, the British psychologist who developed the cognitive behavioral therapy (CBT) and graded exercise therapy (GET) approach to chronic fatigue syndrome (ME/CFS). Wessely, a leader of the biopsychosocial approach to ME/CFS, championed the idea that psychological and social factors largely perpetuate ME/CFS.  Psychiatrists Trudy Chalder and Mathew Holtorf also hail from King’s College.  (Anthony Cleare, another psychiatrist from King’s College, has done substantial research into the HPA axis in ME/CFS over the past 20 years. Cleare’s 1995 paper used cortisol tests to differentiate ME/CFS from depression.)

Kings College Medicine

King’s College London has been the home of several prominent pyschiatrists studying ME/CFS (By Stephen Craven, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=13848828)

Six years ago Medical Express reported that the PACE Trial – which Kings College researchers participated in – proved that CBT/GET practices “provide good value for the money“. Three years ago Queen Mary College of London and King’s College London dug their feet in to prevent the release of the raw PACE data.  It was King’s College that called the attempt to get the data “vexatious,” which in legal terms basically means without merit. The PACE findings are now in the throws of being discredited.

The study is also interesting because it was funded by the Medical Research Council (MRC), a United Kingdom based governmental agency that funds medical research. The MRC, which helped fund the PACE trial, has been a mixed bag. Funded studies on ethnicity, risk factors (biopsychosocial risk factors) and CBT speak to a strong behavioral thrust. However, the MRC has also funded studies on the mitochondria, the autonomic nervous system and now on an immunological model of ME/CFS.

A new generation of psychiatrists from King’s College appear to be taking a different tack. Carmine Pariante, who has focused for years on the physiological roots of depression, has been using hepatitis C patients to try and understand how immune mediated fatigue and depression arise.

A Model for ME/CFS?

It turns out that when hepatitis C patients are given interferon-alpha (IFN-a) about a third of them develop severe fatigue and/or become depressed. The realization that an immune activating drug was causing fatigue and depression in those who were not fatigued or depressed before was a revelation to the medical community. That led to the idea of sickness behavior, which posits that during an infection, the brain and immune system induce symptoms (flu-like symptoms) that force individuals to isolate themselves, stopping the spread of the infection.

trigger ME/CFS

Did high IL-10 levels jump start ME/CFS?

Since many people with chronic fatigue syndrome (ME/CFS) are by definition caught in a chronic case of “sickness behavior” (a chronic illness state triggered by an infectious event), hepatitis C patients provide the possibility of real insights into ME/CFS.  If researchers can determine how immune activation triggers flu-like symptoms and/or depression in people being treated for hepatitis, they may get clues to what is going on with ME/CFS.

In an action that proved enormously helpful, the group took baseline measures of immune activation prior to the introduction of the interferon drug, and then afterwards. They also assessed psychological factors and metabolites associated with the kynurenine system.

THE STUDY

Psychological Factors Play No Role

In a finding that must have disappointed Trudy Chalder and Mathew Hotopf – who were also part of the study – psychological factors struck out on all counts. Neither a history of depression, stressful life events in the prior six months or early life trauma had any effect on  those who became ill following the IFN-a administration.

Cytokines Not Perpetuating Fatigue

Cytokines weren’t, strictly speaking, perpetuating fatigue in the ill hepatitis C group either. The cytokine levels in both the recovered and the still fatigued hepatitis C patient were similar.

They may, however, have triggered it.

Possible Predisposing Factor Identified

The hepatitis patients who came down with severe fatigue demonstrated increased IL-10 and IL-6 levels early on – very early on.  In fact, hepatitis C patients who became ill had high IL-10 levels BEFORE they received the drug. High levels of IL-6, a pro-inflammatory cytokine which has been associated with fatigue, were found early in the illness.

IL-10

High Il-10 levels at baseline may be a biological risk factor for coming down with ME/CFS.

The researchers speculated that patients’ immune systems were primed to take off prior to their receiving the drug – and it was this immune priming which lead them to become ill after taking the drug.

Six months later their IL-10 levels, interestingly, were normal – suggesting that IL-10 had done it’s work quickly and then faded into the background, leaving behind a chronic state of fatigue.

The beauty of this study is that it identifies possibly the earliest blood factor yet – increased IL-10 levels – that may set someone on the path to developing ME/CFS.

While the authors didn’t attempt to explain how these factors produce ME/CFS, some possibilities immediately present themselves. Higher than normal IL-10 levels could suppress one’s ability to quickly clear an infection.  High IL-10 levels and several IL-10 polymorphisms have also been associated with the development of lupus, an autoimmune disorder.

Andrew Miller of Emory University has some ideas of his own.

Miller Time

Andrew Miller, PhD also believes that the ‘sickness behavior’ he finds in hepatitis C patients given IFN-a is similar to what’s happening in ME/CFS.  Miller, however, came to that conclusion, by looking at the brain.

He found reduced activation of the striatum – a part of the basal ganglia that produces dopamine – in fatigued hepatitis C patients and people with ME/CFS. This finding suggested that reduced dopamine levels in ME/CFS may be producing problems with motor activation (physical activity) and fatigue. Indeed, primate studies indicate that immune activation in the presence of low dopamine levels results in enormous fatigue, motor slowing, and depression.

Unrewarding Reward: The Basal Ganglia, Inflammation and Fatigue In Chronic Fatigue Syndrome

Another study, taking a deeper look at what happens to a brain on IFN-a, found it took just four hours for IFN-a to produce microstructural changes in the left striatum – changes that were “strikingly correlated” with the development of fatigue. The authors reported that increased levels of lactate and altered pH – two problems found in ME/CFS –  may set the stage for these microstructural abnormalities.

Microstructural Havoc: The Immune System, Fatigue and the Brain – An ME/CFS and FM Scenario

Immune Hypersensitivity Syndrome?

This presents the possibility that infection-produced inflammation could knock out dopamine production permanently, leaving behind – and this may be the important part – a hypersensitized reaction to inflammation. Miller believes that dopamine deprivation causes the basal ganglia to over-respond to inflammatory signals, resulting in the fatigue and other symptoms associated with “sickness behavior”.

That sickness behavior includes mood changes. The British group found that a “biological sensitivity”, or over-reaction to IFN-a, predicted who would come down with depression while on the drug.

When Anthony Cleare of King’s College trashed Montoya’s cytokine findings last year because they didn’t show cytokine elevations, he missed the point that Montoya’s results may have pointed to a possible exquisite sensitization to cytokines in ME/CFS.

Conclusion

It was very good to see an MRC-funded physiological study pan out and get such abundant media coverage.  Thankfully, Lenny Jason is in a good position to follow up on this study result to see if IL-10 is indeed raised in young people who fail to recover from infectious mononucleosis. If that pans out, the first predisposing factor for ME/CFS in the blood will have been found.

That finding will then give us an entry point to determining how ME/CFS comes about. Avindra Nath’s and Derya Unutmaz’s studies of short-duration post-infectious ME/CFS patients would hopefully be able to piggyback on the British finding and begin to unravel the genesis of ME/CFS.

The basal ganglia/hepatitis connection is fascinating because it suggests that the Brits’ hypothesis, that fatigued hepatitis C patients present a good model for ME/CFS, may be correct. Andrew Miller’s and other studies suggests that the brain changes in ME/CFS replicate those of the fatigued hepatitis C patients. Interestingly, they affect the basal ganglia – a part of the brain involved in motor activation (physical movement), learning, cognition and fatigue.

Miller’s hypothesis that inflammation may knock out dopamine production in the basal ganglia resulting in a hypersensitization to immune signals in ME/CFS is compelling. Neuroinflammation has been linked to microglial activation and reduced dopamine levels.  Plus two studies have found reduced basal ganglia activation in FM. One study suggested the basal ganglia could be causing the movement problems in FM.

Spinning Fibromyalgia: Brain Findings Suggest Dopamine May Be Key

Given that the basal ganglia affects movement, fatigue and reward, it would seem to present a rich vein for ME/CFS researchers to mine.  In other fields, researchers would probably be vigorously digging away at a vein with this much potential ore in it, but in ME/CFS researchers are just scratching the surface. Getting  more out of the research community will require that the federal government fulfill its promise to invigorate this field.

In the meantime, it’s good to see the MRC and the Brits, psychiatrists most of them (!), make good on a physiological study, hopefully set the stage for more to come.

Immune Study Adds to Evidence Of Body-Wide Problems With Energy Production in Chronic Fatigue Syndrome (ME/CFS)

Increased expression of CD24 …could thus reflect abnormalities in maintaining appropriate ATP generation (in ME/CFS). The authors

Numerous studies suggest problems with energy production exist in chronic fatigue syndrome (ME/CFS). The huge energy needs exertion places on the muscles and brain suggest they’re an obvious place for energy production problems to show up. Ramping up to fight off pathogens also places extreme demands on energy production in immune cells. Now comes a study which suggests that energy production problems in a subset of B-cells could be setting people with ME/CFS up for problems with inflammation and autoimmunity.

B-cells and ME/CFS

The first couple of successful Rituximab trials brought renewed interest in the immune cells most effected by the drug – the B-cells. The last, large Rituximab trial unfortunately failed – the drug does not work in ME/CFS – but the Rituximab effort succeeded in other ways.

First off, it brought two creative and dedicated researchers, Oystein Fluge and Olav Mella to the field and energized ME/CFS research in Norway.

B-cell

A B-cell producing antibodies to fight pathogens

Secondly, the B-cells – which play a huge role in immunity (and autoimmunity) – finally got some study in ME/CFS.  Keeping with ME/CFS’s time-honored tradition of falling between the cracks in medicine, several studies found no indication of altered levels of “classical B-cell markers”.

Something unusual did, however, pop up, in an extended analysis, which went well beyond the classical markers usually explored. In 2015 a study found that a molecule called CD24 was highly expressed in a group of B-cells.

CD24 is an adhesion molecule which turns on various signaling networks – it basically tells cells what to do. It is most highly expressed on early stage or transitional B-cells as they emerge from the bone marrow.

During the normal transition from immature to mature metabolically active B-cells, early B-cells are tested again and again for evidence that they may be turning into autoantibody producing cells and many are removed.  Over time, as these cells transform themselves into mature B-cells, the CD24 molecule gradually disappears from their surfaces. High levels of these molecules in people with ME/CFS suggested that a problem with B-cell maturation might be present.

Since antibody producing B-cells play a major role in fighting off infections, having a bunch of immature B-cells hanging around the immune systems of ME/CFS patients could constitute a problem.

Plus there’s evidence that the CD24 molecule plays a role in several diseases.  CD24 polymorphisms (genetic variants of CD24) have been associated with increased risk for and accelerated progression of autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. CD24 can also be over‐expressed in many cancers, including B cell lymphomas.

In short, it’s not a molecule you want to ignore.

Energy Production Problems in the Immune System

Front Immunol. 2018 Oct 22;9:2421. doi: 10.3389/fimmu.2018.02421. eCollection 2018. CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Mensah FFK1, Armstrong CW2, Reddy V1, Bansal AS3, Berkovitz S4, Leandro MJ1, Cambridge G1.

In a 2018 study, a UK and Australian group took B-cells from ME/CFS patients and healthy controls, stimulated them and then monitored what happened.  As before, they found an increased frequency of CD24+ B-cells in ME/CFS patients.

What made the increased frequency of these naïve CD24 packed B cells in ME/CFS so interesting, though, was their mode of energy production.

Examining the metabolism of the ME/CFS patients’ cells, the researchers found a “strong(ly) positive” association between the amount of glycolysis and lactate produced and the expression of CD24 molecules on ME/CFS patients’ B-cells. Put another way, the more glycolysis was used to produce energy and the greater the lactate production (a by-product of glycolysis) – the more the CD24 molecule showed up on ME/CFS patient’s B-cells.

energy production me-CFS

Findings suggesting that a body-wide problem with energy production are present in ME/CFS are piling up.

Lower levels of mitochondria in these cells suggested one reason ME/CFS patients’ B-cells may be stuck in this mode.  Not surprisingly, the authors found this more prominent B-cell subset in ME/CFS was also largely unresponsive to stimulation.

That suggested that not only do the energy problems in ME/CFS extend to the immune cells but that they could be impacting immune functioning – in this case by keeping ME/CFS B-cells in a naïve state – that may be associated with disease.

Plus increased levels of the CD24 molecule have also been associated with a damaging state called “senescence”.  Instead of undergoing a process called autophagy during which a cell’s contents are safely recycled, during senescence – which is often associated with aging –  damaged mitochondria cause cells to slowly deteriorate while producing scads of pro-inflammatory factors.

An exercise physiologist, Graham Salmun, recently reported that his exercise study results suggest senescence is indeed occurring in ME/CFS.  He believes problems with aerobic energy production are a) impairing ME/CFS patients ability to produce energy and b) creating a senescent state that is causing chronic inflammation.

Anaerobic Thresholds, Fatty Acid Problems and Autophagy: Dr. Klimas’s Exercise Study

Conclusion

This study provided an intriguing metabolic snapshot of the immune system. The fact that increased expression of the CD24 molecule has been associated with autoimmune disorders and cancer makes the CD24 finding in ME/CFS interesting, but the metabolic connection the researchers found may be more important.

Their findings suggest that the same problems producing energy found elsewhere in ME/CFS may also be occurring in their immune cells.  Plus the findings suggest that a state of senescence, chronic inflammation and cellular unresponsiveness may be present as well. The possible penalties of having an immune system with a broken aerobic energy production system could go beyond fatigue and pain and extend to problems with autoimmunity, and perhaps in rare cases, cancer.

Studies finding an increased reliance on anaerobically produced energy in the muscles, the brain, in neutrophils and now in some of the B-cells all suggest that a body-wide disruption in energy production may be present in ME/CFS.

 

Could “Junk DNA” Be Causing Chronic Fatigue Syndrome / Myalgic Encephalomyelitis?

Carmen Scheibenbogen

Dr. Scheibenbogen continues to successfully plough new ground

It seems like every time you turn around another part of the genome pops up. It’s amazing how far our knowledge of the human genome has progressed since the Human Genome Project was completed just 15 years ago. Thankfully the small band of researchers involved in chronic fatigue syndrome / myalgic encephalomyelitis (ME/CFS) seem to be keeping up with the latest findings.

Dr. Scheibenbogen seems intent on ploughing new ground. First she re-energized the search for autoantibodies in ME/CFS. Then she examined the effectiveness of a promising treatment called immunoadsorption. With her latest study she and her colleagues at Institute for Medical Immunology, Charité-Universitätsmedizin in Berlin became the first in this disease to examine a peculiar part of our genome called long non-coding RNA’s.

Hope for an ME/CFS Autoimmune Subset: A German Researcher Steps Forward

When most people think of RNA they’re probably thinking of the messenger RNA (mRNA) which carries the genetic code from the DNA in the nucleus of our cells to ribosomes. The ribosomes then translate the mRNA into proteins – which then do the work of our cells.

pre mRNA

pre-mRNA -(Wikipedia—httpsupload.wikimedia.orgwikipediacommonsthumbaa4Pre-mRNA-1ysv-tubes)

Not all RNA produces proteins, however. Formerly termed “junk DNA“, non-coding RNA’s – RNA’s which do not encode proteins –  make up a substantial part of our genome.  (They lack the “reading frames” necessary for the process of translation from RNA to protein to begin). Long non-coding RNA’s (lncRNA) are particularly long pieces of RNA (>200 nucleotides long) which do not encode proteins.

While their presence has been known for decades, it wasn’t until the 1990’s that the first hint of the role they play in regulating gene expression and epigenetics  appeared. Research since then has shown that lncRNA’s play an important role modulating the activity of transcription factors which turn the expression of our genes on and off.

Epigenetics –  heritable changes in gene expression that do not involve changes in the underlying DNA sequence – is all the rage now. The ability of infections and other stressors to turn genes on or off via epigenetics presents an intriguing explanation for how an infection could result in ME/CFS. Because lncRNA’s can regulate the epigenetic process, they could provide even more basic insights into how ME/CFS began.

LncRNA’s can also catalyze biological reactions and respond to cellular signals. Their extreme flexibility allows them to interact with proteins, DNA and RNA to affect many physiological processes. One review stated they, “can impact almost all physiological functions.” Another review called them, “a new and crucial layer of biological regulation”.

They’re certainly providing a fresh look at complex diseases. Search for long non-coding RNA’s in PubMed and you’ll get a long list of diseases they may be implicated in. A recent review of the role lncRNA’s may play in cancer called them, “new players in the old battle against cancer”. Some regulate mitochondrial synthesis and energy production.  Pathogens can induce the production of lncRNA’s in humans that then promote viral survival.

It’s become increasing apparent that they can play a role in fundamental developmental processes that can produce chronic disease states. One review called them “arguably the hottest area of RNA research” today.  Still much remains to be learned about the roles they play.

“Remarkable” Finding

The expression signature of very long non‑coding RNA in myalgic encephalomyelitis/chronic fatigue syndrome. Chin‑An Yang1,2,3,4 , Sandra Bauer5, Yu‑Chen Ho3, Franziska Sotzny5, Jan‑Gowth Chang1,3,4† and Carmen Scheibenbogen. Transl Med (2018) 16:231 https://doi.org/10.1186/s12967-018-1600-x

In this study – the first of its kind in ME/CFS – Dr. Scheibenbogen examined the expression of ten very large lncRNAs (> 5 kb) involved in immune regulation, or which influence genes involved in the stress response and/or metabolic and neurologic processes.

The authors were clearly surprised by their findings.  After all, they’d simply taken ten lncRNA’s that they thought, based on findings in other diseases, might play a role in ME/CFS.

In a finding they called “remarkable”, the expression of those ten lncRNA’s was enough to distinguish ME/CFS patients from healthy controls. In fact, the expression of any two of three of these lncRNA’s (NTT, MIAT and EMX2OS) was all that was needed to pick out most ME/CFS patients.

Diagnositic accuracy

The elevated expression of just three lncRNA’s was enough to identify most ME/CFS patients

Then seeking to understand if the chronic illness state present in ME/CFS could be turning these lncRNA’s on by exposing them to biological stressors known to be present in ME/CFS. They found that punishing cell lines with oxidative stress did, in fact, increase the expression of the lncRNA’s. Subjecting the cell lines to a viral stressor also increased expression of one of them. Doing it increased the expression of a gene associated with chronic inflammation and blood vessel dysfunction – two problems that are believed to be present in ME/CFS.

ME/CFS seems to revel in producing findings that baffle researchers and this study was no exception. The enhanced expression of one lncRNA (EMX2OS) was something of a mystery as it is rarely found in the cells (peripheral blood mononuclear cells) they examined. It is, however, increased in brain hypoxia; i.e. low oxygen levels in the brain – which Dr. Shungu’s studies suggest may be present in ME/CFS.

Study Suggests “Bad Energy” is Core Problem in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)

Finally, the authors noted that it took just three lncRNA’s (NTT, MIAT, and EMX20s) to do what it took Kerr 88 genes and Naviaux 8-13 metabolites to do – differentiate ME/CFS patients from healthy controls. One wonders if Scheibenbogen’s examination of lncRNA’s is getting at some basic components of ME/CFS.

Treatment Implications

No direct treatment implications were mentioned. In the short-term they’re viewed more as providing excellent diagnostic biomarkers. For instance, lncRNA’s are now being used to one of most difficult diagnostic scenarios of all – prostate cancer. They’re now being used in men with high PSA levels and negative biopsy results.

Direct treatments based on lncRNA’s are probably years away but should be noted that lncRNA’s are a very active area of research for a good reason: turning down their expression could turn off basic processes that cause disease. The author of a recent study which found that LncRNA’s play a role regulate fat metabolism reported:

“We are still in the early stages of figuring out how lincRNAs function in human disease, but what used to be considered ‘junk’ in the genome may actually point us towards the jackpot of developing effective therapeutic approaches for cardiometabolic diseases,” Jennie Lin, MD, MTR

This new exploration of ME/CFS patient’s genomes further substantiates the notion that ME/CFS is a disease of immune dysregulation. Given the study’s strong results surely more lncRNA study in ME/CFS is on the way.

 

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.