All posts tagged neuroinflammation

The Brainstem, Vagus Nerve, Neuroinflammation and Chronic Fatigue Syndrome: The VanElzakker Way

In 2013, Michael VanElzakker produced one of the most intriguing hypotheses to date in ME/CFS. His Vagus Nerve Hypothesis proposed that an infection/inflammation near the vagus nerve was causing it to send an unending stream of messages to the brain, telling it to essentially shut the body down by producing fatigue, pain and other symptoms. Since then, he’s been particularly interested in the connection between the vagus nerve, the brainstem and the ME/CFS.

He’s not the only one interested in the brainstem. In 2019 once his brainstem compression was alleviated, Jeff completely recovered from his severe ME/CFS, POTS and MCAS. Since he published his story over a dozen people have been diagnosed with craniocervical instability – a condition which compresses the brainstem.

In this critical review paper, VanElzakker et. al. pick apart some of the research done and provide a guide to successfully getting at the brainstem and other regions of the brain. It’s called a “Critical Review” and is critical, indeed. It finds many past ME/CFS studies wanting, but then points a way to a better possible future. If brainstem problems play a role in ME/CFS these researchers demonstrate how to get at them.

One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods.  Michael B. VanElzakker, Sydney A. Brumfield and Paula S. Lara Mejia. Front. Neurol., 10 January 2019 https://doi.org/10.3389/fneur.2018.01033 https://www.frontiersin.org/articles/10.3389/fneur.2018.01033/full

First, VanElzakker et. al. examines one of the sacred cows in the chronic fatigue syndrome (ME/CFS) community – the preferred term for so many: myalgic encephalomyelitis (ME), which refers to muscle pain (myalgia) related to central nervous system inflammation (encephalomyelitis).

While muscle pain is common, it’s not universal. Even people with severe ME may not report pain.

Still, the core part of the definition deals with central nervous system inflammation – a description that, with the emergence of the 2015 Yakatomi and the 2019 Younger studies, seems more and more likely to stick. (A 2018 PET scan study also found neuroinflammation in fibromyalgia as well.)

The idea that inflammation plays a key role in this illness makes sense, given the infectious trigger so commonly (but not universally) found. The authors are just a few among many (Avindra Nath, Jarred Younger, Andrew Lloyd and others) who believe that an infectious event has triggered changes in the brain that are producing fatigue, pain and other problems in ME/CFS.

They point to three ways an infectious trigger could produce central nervous system inflammation in ME/CFS:

A) immune factors (e.g. cytokines) triggered by the infection could get transported across the blood-brain barrier (BBB) that protects the brain. The normally taut blood–brain barrier makes blood-borne infections of the brain rare, but it can, like the gut, become leaky in inflammatory states, allowing immune factors and pathogens entry. Once in the central nervous system, they could trigger a large inflammatory response, or

B) High concentrations of immune factors could allow pathogens to passively diffuse across the BBB, or

C) Immune factors in the blood could trigger the vagus nerve to send signals to the brainstem and brain, which then sparks an inflammatory response.

It’s the last option that primarily concerns these authors. VanElzakker is the author of the Vagus Nerve Hypothesis, which proposes that an infection/inflammation near the vagus nerve is causing it to send an unrelenting stream of signals to the brain, telling it to produce the flu-like symptoms that constitute “sickness behavior” (withdrawal to bed), which isolates infected people from the community and keeps them from spreading an infection.

The largest nerve in the body, the vagus nerve transmits sensory, autonomic, immune and other signals to the brainstem – making it potentially a key player in a possible neuroinflammatory disease like ME/CFS.

Studies indicate that inflammation in the periphery tends to produce a mirror inflammatory response from the immune cells (the glia) in the brain. Even small levels of cytokines in the periphery or body have the potential to activate the chemoreceptors in the vagus nerve, which then activate the immune system in the brain.

That brain activation, interestingly, tends to occur in regions (basal ganglia, limbic system organs (amygdala, hippocampus and hypothalamus), anterior cingulate cortex, prefrontal cortex, and thalamus), which studies suggest are also involved in ME/CFS.

The Brainstem

brainstem

The brainstem regulates many vital functions in the body

The authors believe the brainstem (which, as it name implies, is found at the very base of the brain, above the termination of the spinal cord), could play a key role in chronic fatigue syndrome (ME/CFS) for four reasons:

  1. Immune signals from the vagus nerve to the brain travel through the brainstem.
  2. The brainstem is dense with mast cells, and mast cell activation syndrome (MCAS) appears to be common in ME/CFS.
  3. The brainstem regulates autonomic nervous system functioning – a common trouble area for ME/CFS and related disorders.
  4. The brainstem also regulates immune functioning; in particular, it triggers an anti-inflammatory response that should limit the inflammatory response.

Whether caused by a structural problem (as in Jeff’s case), inflammation or an infection, the brainstem is a centrally placed brain component that produces many of the issues in ME/CFS.

Could Craniocervical Instability Be Causing ME/CFS, Fibromyalgia & POTS? Pt I – The Brainstem Series

Seeing the Brainstem in Chronic Fatigue Syndrome (ME/CFS)

Consistent inflammation of the brainstem has not, however, been found in ME/CFS. The authors argue, though, that researchers have rarely used the right kind of imaging needed to investigate this.

The most commonly used method for measuring inflammation in the brain involves measuring the 18kD translocator protein (TSPO) with a PET scan. This protein is produced when the immune cells of the brain – the microglia – become activated. Because the microglia are the chief producers of inflammation in the brain, the TSPO provides a reliable way to indirectly measure neuroinflammation and its effects.

The Nakatomi Study

Nakotomi’s small ME/CFS study using TSPO made a big splash in 2014.   Tony Komaroff called the finding of central nervous system inflammation the most important study in decades. Five years later, Van Elzakker et. al. called it “important” and potentially “groundbreaking”. The study used TSPO imaging to find widespread neuroinflammation, particularly in the areas leading from the brainstem to the thalamus.

While the authors regard Nakatomi’s study as potentially groundbreaking, the study is not without significant issues. The authors, in fact, seemed a bit shocked that Nakatomi found as many effects as he did, given the techniques used.

The neuroimaging techniques Nakatomi used (and which most researchers use) were not designed to address brainstem inflammation. Nakatomi used a spatial “registration” technique that aligns the image on the neocortex or upper part of the brain. This kind of alignment is typically done because researchers tend to focus on the upper, “higher” functioning areas of the brain. It can, however, impair the sensitivity of imaging done on the lower, more densely packed, primitive areas of the brain, such as the brainstem, and lead to false negatives.

The PK-1195 tracer

Nakatomi also used an older tracer (PK-11195) which does not penetrate deeply into the brain and can bind to unintended elements in the brain. Differences in blood-brain barrier permeability between the ME/CFS patients and healthy controls – a distinct possibility – could have confounded the results, as well. Nakatomi’s use of the cerebellum as a kind of baseline measure could have introduced further issues if problems with the cerebellum (another possibility) exist in ME/CFS.

Plus, the hypometabolism believed present in ME/CFS could have resulted in lower amounts of the tracer being metabolized than usual – causing higher amounts of the tracer to reach the brain – and producing a false positive. Because exercise may affect how much of the tracer is taken up into the cells, Nakatomi’s use of healthy, non-sedentary controls instead of sedentary controls introduced another issue.

Finally, because the brainstem actually pulses with every heartbeat, that movement needs to be accounted for – and usually isn’t in ME/CFS studies.  The very small but important nuclei in the brainstem are also often not picked up with the standard imaging techniques used in ME/CFS research.

Nakatomi’s study results make sense given what we know, and were given a sort of validation by Jarred Younger’s recent results using thermal mapping – a new technology – but we need more validation.

The takeaway is that the brainstem – because of the role it plays in autonomic nervous system functioning, immune regulation and the transmission of motor signals – could play a major role in ME/CFS, but is essentially, according to these authors, still something of a black box.

Barnden’s Brainstem – the Australian Study

It’s not completely a black box, though. Researchers using other techniques have found evidence of brainstem problems in ME/CFS. Barndem in Australia, in particular, has done a series of MRI studies which have found striking brainstem issues in ME/CFS.

(During his talk at the 2019 Emerge conference, Barnden noted how he had to shift his MRI to avoid the alignment problem (that VanElzakker mentioned) which prevented him from getting a good image of the brainstem. )

One study found that reduced brainstem grey matter volume – suggesting that damage to the neurons in the brainstem had occurred – was correlated with autonomic nervous system problems in ME/CFS.

Barnden brainstem damage ME_CFS

Using the right imaging approach Barnden found extensive evidence of damage to the neurons (myelin) in the brainstem. (From the 2019 Emerge Conference Livestream)

Another study finding of impaired communication from the brainstem nuclei to other nuclei in the brain suggested the same, and found increased signs of myelination in the sensorimotor cortex of the brain.  Barnden proposed that decreased signaling from a damaged brainstem provoked a compensatory increase in myelination in the sensorimotor region as it bulked up to try to understand the limited signaling coming from the brainstem. The impaired brainstem-sensorimotor connection might be, Barnden thought, impacting motor functioning in ME; i.e. the ability to carry out physical activity.

Signals to move muscles pass from the motor cortex to the sensorimotor cortex down to the thalamus and then through the brainstem to the muscles. (Signals from the muscles to the brain pass up through the same pathways.) Barnden proposed that the movement problems in ME/CFS could start with the brainstem’s inability to properly relay signals to the motor cortex to activate the muscles.

Barnden’s most recent brainstem study validated the idea that inadequate communication between the brainstem nuclei and other nuclei in the brain, including the vasomotor region, hypothalamus and prefrontal cortex, was affecting autonomic nervous system functioning in ME/CFS.

Other Kinds of Brain Scans

Other kinds of brain scans, such as magnetic resonance spectroscopy (MRS), can pick up signs of neuroinflammation. Although almost 10 MRS studies of the brain in ME/CFS have been done, VanElzakker et. al. report that a clear and consistent picture of metabolite alterations in the brain has yet to emerge.

They believe that’s due largely to a common theme in medical research, found in this disease in particular – lack of standardization. Different diagnostic criteria, different types of healthy controls, different brain regions examined, and different metabolites targeted make it difficult to present a clear picture of the metabolic alterations in the brains of people with ME/CFS.

The Japanese Take

The Japanese probably couldn’t agree with Barnden more. Their studies indicate that, as the healthy controls became more fatigued, two core regions – both of which communicate with the brainstem ( the prefrontal cortex and the anterior cingulate cortex) – shut down.

As these regions begin to shut down, control of autonomic functioning becomes lost.  In particular, the ability to activate the parasympathetic nervous system (i.e. the vagus nerve) and tone down the sympathetic nervous system activity, is lost.

The Japanese believe a breakdown in what they call the facilitation system in the brain has occurred.  As we become fatigued, the facilitation system jumps in to increase the signals coming from the primary motor cortex to the muscles. This increased “drive” from the motor cortex prompts the muscles to work harder and activates more and more of them so that activity can proceed.

Fatigue – the Japanese Way: A Chronic Fatigue Syndrome Perspective

So long as new, fresh muscle fibers remain to be recruited, the activity can continue.  If no muscle fibers are left to be recruited or if the brain has a problem recruiting new muscle fibers, fatigue sets in.

A 2003 study suggested that reduced muscle recruitment due to reduced motor cortex output was indeed occurring in ME/CFS. That study suggested that, “… changing motor deficits in CFS has a neurophysiological basis [which] … supports the notion of a deficit in motor preparatory areas of the brain”.  That study titled, “Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome“, to my knowledge was never followed up on.

Fatigue Explained? Japanese Assert Brain Damage Causes Fatigue in Chronic Fatigue Syndrome

Conclusion

Several studies suggest significant brainstem issues may be present in ME/CFS. Problems with the brainstem could produce everything from autonomic nervous system problems to immune issues to problems with movement.

The authors critique past brain imaging studies and provide a “how to” guide to assess the brainstem in ME/CFS. Barnden’s Australian brainstem studies suggest that when done correctly, MRI imaging studies may indeed find extensive damage is present in ME/CFS including evidence of brainstem neuron demyelination, a compensatory remyelination in parts of the brain the brainstem connects with, and lastly, a reduced connectivity between these regions.

VanELzakker et. al.  assert that future imaging studies that focus on the specific functional connectivity pathways in the brain which are activated by inflammatory processes should be able to capture the neuroinflammatory processes occurring in ME/CFS.  (Two of the three pathways they cite include the brainstem.) The thalamus’s role in sensory stimuli activity presents another fruitful pathway to assess.  Lastly, the authors suggest that researchers target the nucleus of the solitary tract (NTS) where the vagus nerve enters the brainstem.

With help from an ME/CFS donor, VanElzakker has been employing brain imagining techniques to assess the brainstem in chronic fatigue syndrome (ME/CFS). He will be speaking at the NIH ME/CFS Conference in Baltimore in April.

One Theory To Explain Them All? The Vagus Nerve Infection Hypothesis for Chronic Fatigue Syndrome

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?

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.