All posts tagged inflammation

New Pathways: A Step Towards Fine-Tuning Treatments for ME/CFS?

Most chronic fatigue syndrome (ME/CFS) studies focus on females, but for once we have a study contrasting females and males. It makes sense that this group – hailing from Dr. Klimas’s Institute for Neuroimmune Studies, the University of Miami, the Veterans Center in Miami, the University of Rochester and the University of Alberta – would study both genders. Their modeling studies have made it clear that gender matters.

make-female

Gender matters…(How could it not?)

This small but intense study compared the gene expression of 23 females and 10 males with ME/CFS and 21 healthy controls. The U.S. and Canadian researchers then isolated the most impactful genes and compared them, gender to gender and ME/CFS patients to healthy controls.

They then used a variety of fatigue measures to identify which genes were most associated with fatigue. With these fatiguing genes in hand, they then cross-referenced their results with a genetic-drug database to see which drugs might potentially be useful in ME/CFS.

Results

Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules Mary G. Jeffrey, M.A.1,2; Lubov Nathanson, Ph.D.1,3; Kristina Aenlle, Ph.D.1,3,4; Zachary M. Barnes, B.Sc.1,4,5,6; Mirza Baig, M.P.H.1; Gordon Broderick, Ph.D.1,2,3,7,8; Nancy G. Klimas, M.D.1,2,3; Mary Ann Fletcher, Ph.D.1,3,4; and Travis J.A. Craddock, Ph.D.1,2,3,9. Clinical Therapeutics/Volume 41, Number 5, 2019

Size Matters –  for Men and for Women

The first thing that stood out was that sample size clearly matters.  While the men – probably due to the small sample size (n=10) – flunked out when it came to looking for differences in gene expression, the women (n=23) excelled.

The active pathways identified in the men (growth factors, immune factors, cardiac/blood factors, transcription factors, and mitochondrial factors) made sense but were identified as having only a small to medium effect on their illness.  On the other hand, some of the pathways identified in the women (mostly the same as the men) appeared to have large to huge effects on their illness.

Only one measly gene was significantly differently expressed in the men compared to healthy controls, but 189 were significantly differently expressed in the ME/CFS women.  As far as gender goes many of the pathways were similar in both genders,  but several gene modules were only highlighted in the women (TGF-b β Signaling signaling pathways, TNF-αa, and T-cell Receptor pathways).

That suggests that the illness has similar underpinnings for both genders. Whether you are male or female, ME/CFS, they asserted, is a “stress mediated illness with underlying endocrine, immune, and mitochondrial imbalances accompanied by autonomic and physical dysfunction”; i.e. it’s definitely a complex disease. Some of those imbalances, though, are probably different in men and women.

Given the preponderance of women with this disease (and fibromyalgia) one has to ask how gender could NOT be an issue. These groups are, thankfully, looking into gender issues further.  In fact, they may be the only research group that’s explicitly looking at the similarities and differences between men and women with ME/CFS.

Note the word “imbalance” in the group’s description of the disease (“a stress mediated illness with underlying endocrine, immune, and mitochondrial imbalances”). ME/CFS is not organ damage; Klimas and Broderick et. al. believe our systems are “simply” out of balance and that’s potentially good news; it’s easier to tweak, reprogram, reset a system than repair physical damage.

Rest Button?

System reset

The big question: which buttons to push to reset ME/CFS? (Image by Gerd Altmann from Pixabay )

They identified one possible reset button – the JAK-STAT pathway. When the stress response gets jacked up (and it may be jacked up all the time in ME/CFS) the JAK-STAT pathway transmits information from cytokines and growth factors to the cell nuclei. If that pathway is not working properly – and there’s some evidence that it is not in ME/CFS – every time the stress response system gets activated, a discombobulated JAK-STAT pathway tells your cells to do the wrong thing.

The Klimas group is not the only one to think the answer lies in signaling errors which cause our systems to overreact.  Jarred Younger believes the glial cells in ME/CFS patients’ brains may be pumping out cytokines at the slightest sign of trouble.  The massive reaction Alan Light found to muscle metabolites during exercise didn’t appear due to high numbers of muscle metabolites. Instead, small amounts of muscle metabolites appeared to be producing massive overreactions in ME/CFS patients’ immune and endocrine systems.

The Fatigue Systems

The gene expression modules the Klimas/Broderick groups found most associated with fatigue were particularly interesting. In a nice piece of synchronicity, the two systems that popped up – the immune system and metabolism – are major research topics in this disease.

In the immune system, two cytokines popped up: TGF-B and TNF-a.

TGF-b is notable for being the only cytokine found to be consistently upregulated in a metanalysis of ME/CFS immune studies. This TGF-B pathway – which is highly associated with “sickness behavior” – was highlighted in both men and women with ME/CFS. Upregulation of this pathway can impair “motor activity” (exercise), affect energy production, produce sleep problems and cognitive issues; i.e. increased levels of it in ME/CFS could be producing “malaise” or fatigue, problems with thinking, poor sleep, etc. that often occurs when we are fighting off an infection (“sickness behavior”).

TNF-a is a major, major cytokine in any immunologist’s book. Increased TNF-a expression in the ME/CFS group was associated with a host of problems including worsened vitality, physical functioning, social functioning, pain levels, fatigue, and sleep disturbances. TNF-a could also be contributing to the “malaise” in ME/CFS via its activation of the excitatory neurotransmitter glutamate in the brain.

TNF-a is an excellent cytokine to show up in ME/CFS for a couple of reasons: it’s known to be dangerous, it’s associated with many serious diseases, it’s getting a lot of research work, and drugs have and are being developed to affect it.

The “metabolism of protein module” was, remarkably, associated with virtually every aspect of fatigue tested (physical functioning, physical limitations, SF-36 total score; general fatigue, physical and mental fatigue, reduced activity). That module, the authors suggested, could reflect an mass of inflammatory metabolites being pumped out in ME/CFS: in other words, it may all goe back to inflammation.

Building the Foundation for Fine-tuned Drug Interventions

Now that they’d identified some possibly key immune issues in ME/CFS, they asked what treatments might help. Dr. Klimas has for several years evinced a strong desire to begin immune based treatments in ME/CFS. This study was clearly intended to help build the evidentiary basis for using immune drugs in ME/CFS.

Cross-referencing the gene expression results from the women with a National Institutes of Health (NIH) funded pharmacogenomics database called PharmGKB yielded several drug possibilities. The PharmGKB database provides clinical guidelines on using a person’s genetic information to determine which drugs might be effective. As far as I know this is the first time this database has been used in ME/CFS research.

In what appeared to be another first, the researchers didn’t simply look for drugs that could affect TNF-a – an immensely powerful cytokine which can affects many different pathways. In a step forward for personalized medicine in ME/CFS, they looked for drugs that could affect the specific pathways (M18, M41) the study indicated TNF-a was disrupting in this disease.

immune pathways

The goal: finding the precise immune pathways affected in this disease – and a treatment to match them. (Image by Siggy Nowak from Pixabay )

A search for the M41 pathway, for instance, found a host of potential drugs (selective immunosuppressants, sulfonamides, aminoquinolines, and TNF-a Inhibitors) which could potentially tweak that pathway in ME/CFS. No specific FDA approved drugs, on the other hand, are focused on TGF-B, but the authors noted that TGF-B is an area of active research.

It will certainly take time and much bigger studies glean out the specific immune pathways that are disrupted in ME/CFS, and to provide the evidence base that could allow doctors to prescribe drugs for them.

This study suggests, though, that this is not rocket science. We have the technology to help identify the precise pathways disrupted in ME/CFS. We simply need the funding (and the large sample sizes) to do that.

One wonders if, at some point patients will be able to get drugs designed to tweak the specific immune pathways at play in their ME/CFS.

A Complex Disease Demands A Complex Effort

“As such, there exists the potential for symptom subtypes of ME/CFS for which a single overarching treatment strategy may not be effective. Beyond this, the presence of comorbid conditions adds a layer of complexity”  The authors

As the article ended the authors focused on how complex the disease with its multisystem presentation, and many comorbid illnesses, is. ME/CFS, they asserted, is not a “one disease, one-target” disease; it’s probably going to take multiple treatments aiming at a variety of targets to turn this disease around.

Possibly preparing us for some underwhelming results, they stated that their original treatment model for ME/CFS – the etanercept/mifepristone drug combination that was designed to first smack inflammation down, and then reset the endocrine system – needed some tweaking.

“While in our previous studies the profile of ME/CFS in women suggested targeting the Th2 immune cytokines followed by inhibition of the glucocorticoid receptor system, this predicted drug course has not yet been optimized.

The fact that their model is going to get some more tweaking is no surprise at all given the complexity of the systems they’re trying to effect. The surprise would be if the models weren’t being continuously tweaked as new data trickles; i.e. the models should only get better over time.

 

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.

Your Brain on Viruses: Study Finds Even Common Viruses Cause Cognitive Declines

The ‘Manhattan Project’

The Northern Manhattan Study is an immense project that’s taking a deep look at health in Northern Manhattan, New York . The project consists of  analyzing basic health characteristics of several  thousand people over time and it’s spinning out studies at a dizzying rate.  The project is not on chronic fatigue syndrome, but because it’s  looking at factors that have shown up in ME/CFS it may shed  some  light on what’s happening there.  In fact it may shed a lot of light.

Manhattan

The ‘Manhattan Project’ is examining health issues in a wide swath of the population. Several findings may have relevance to ME/CFS/FM

For instance, each of the studies below looked at a factor that’s been found (in at least some studies) in ME/CFS and  each of the findings seemed to make sense what we know of ME/CFS.

Increased IL-6 levels were associated with cognitive declines in one study, and increased  soluble tumour necrosis factor receptor 1 (sTNFR1) levels were associated with increased  mortality in another.  Increased levels of daytime sleepiness in the elderly were associated with increased risk of stroke, heart attack and vascular events in another.   Metabolic syndrome was associated with cognitive declines in another. Eating a Mediterranean diet was associated with  reduced ‘white matter hyperintensity volume’ a marker of small blood vessel breakage in the brain and reduced vascular events such as stroke.

Infectious Burden

Neurology. 2013 Mar 26;80(13):1209-15. doi: 10.1212/WNL.0b013e3182896e79.Infectious burden and cognitive function: The Northern Manhattan Study. Katan MMoon YPPaik MCSacco RLWright CBElkind MS.

The most applicable study to ME/CFS, however, is clearly the latest one which determined if infectious disease burden was associated with cognitive declines.  In this study the researchers tested  blood from a broad swath of the population in New York  for antibodies to common bacteria and viruses (three of them herpes viruses) and gave the participants  cognitive tests.  Then they created an index of infectious burden (IB) and determined if more infections meant more problems with cognition…and found they did; the more active infections present, the  worse the cognitive impairment.

Infections

This study suggested that having more infections, active or latent, are associated with reduced cognition.

No ME/CFS studies have attempted to associate pathogen load with cognitive declines but given the increased  rate of infections Dr. Peterson and other immunologically oriented ME/CFS  doctors have found and the documented cognitive impairment in ME/CFS, the finding made sense. Cognitive impairment is  associated with brain issues but the researchers didn’t zero in on the brain; instead they focused on cardiovascular problems which interfered with blood flows to the brain.

It turns out that studies have linked common infectious agents to inflammation, coronary artery disease and stroke and a past ‘Manhattan project’ study found  that high infectious burdens  were associated with an increased risk of stroke and increased carotid plaque buildup.

Many viral pathogens in the herpesviridae family, characterized by latent or persistent infection, were implicated in increased stroke risk.

It appears that chronic infections often play havoc with cardiovascular functioning. Infectious organisms can impact cardiovascular functioning in various ways. They can directly invade the vascular walls. C. pneumoniae and H. pylori DNA was found in aetherosclerotic lesions in 26%  and 37% of cardiac bypass patients in one study.  With regards to pathogens commonly found in ME/CFS, high rates of active HHV6 infection  found in Italian cardiac patients who did not have aetherosclerosis suggested the virus may play a role in heart patients who have idiopathic heart disease.

Cardiovascular Issues

At the 2008 HHV6 Symposium in Baltimore, a German researcher, Dr. Lassner reported that heart biopsies he’d done in German heart patients commonly revealed parvovirus B-19, HHV-6, enterovirus and/or Epstein-Barr Virus infections.  He noted that HHV-6 infection of the blood vessel walls results in the production pro-inflammatory cytokines which can constrict the blood vessels, impair capillary production and reduce heart blood flows. HHV6’s ability to trigger blood vessel wall constriction is intriguing given studies suggesting it may play a key role in ME/CFS.

Blood vessels

Pathogens can affect the cardiovascular system and cardiovascular problems appear to be rife in ME/CFS.

Lassner, interestingly, found antivirals (IVIG-parvovirus, interferon-enterovirus) to be effective in virus infected heart patients, but reported much the same treatment response  pattern found in many ME/CFS patients; improvement while on antivirals followed by relapse when off them.

Infections can also turn on the macrophages which help create the dangerous plaques, they can confuse the immune system into attacking parts of the body and they can help an inflammatory state that is damaging, etc.

These observations, along with the results of this current study lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, may be an important etiologic factor of atherosclerosis.

Simply the presence of active herpesvirus or other infections  can contribute to an inflammatory mileu that can be detrimental.  Katan reported that an inflammatory state could lead to aetherosclerosis, ‘subclinical stroke’ and dementia. Subclinical strokes (ie transient ischemic attacks from which patients recover) primarily effect executive functioning, one of the cognitive processes known to be impaired in ME/CFS.  Changes in mood and  the ability to organize and take on multiple tasks could be a sign of a ‘subclinical stroke‘.  Other symptoms can include feelings of numbness or weakness, double vision, dizziness/vertigo, confusion, inability to speak, loss of balance or coordination.

Cardiovascular issues have been found in ME/CFS and more and more attention is being given to this area. Cardiovascular control is impaired,  reduced cardiac vagal tone is associated with cognitive declines, impaired blood pressure variability,  reduced cerebral blood flows, reductions in stroke volume and cardiac output (all this in the past year and a half)  provide ample evidence of impaired cardiovascular functioning in this disorder.  Interestingly autonomic nervous system issues similar to those found in ME/CFS were correlated with cognitive declines in fibromyalgia.

All in all the finding of decreased cognitive functioning with increased infectious burden in the  Northern Manhattan Study findings may not be surprising for many people with ME/CFS. At the most recent HHV6 Conference in Paris Dr. Peterson reported on several ME/CFS patients who’s cognitive abilities rebounded remarkably following Vistide infusions for herpesvirus infections and Dr. Lerner has reported similar results in his herpesvirus infected patients.

Conclusions

The latest Manhattan project study should be helpful in highlighting not only the cognitive declines but the cardiovascular risks that are associated with common or  chronic latent or active infections. Since active infections are part and parcel of ME/CFS, this study’s important association of decreased cognitive function with increased infectious burden suggests that measuring both those factors in ME/CFS should be routine, and may offer objective measurements of treatment efficacy.