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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.


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.


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.


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  • Issie

    November 23, 2019 at 12:12 am - Reply

    Mast Cell – Histamine (Immunotherapy With Histamine) | Health Rising’s Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia Forums

    This could be the answer. Affects JAK pathways (MCAS and many other illnesses) and inflammatory causes also affects T cells.

    I’m still reading this book. Very technical, but interesting. I have also been researching to verify what the book says and have found many medical papers verifying it. It’s an approach that few know of. Yet is getting benefit with MS, Leukemia, cancer, ALS and other problems.

    I’ve been saying for years…..Inflammation and Autoimmune. Now to get to the core of the cause.

    • Cort Johnson

      November 23, 2019 at 1:25 am - Reply

      At some point we’re going to get down to the signaling system that is causing so many potential hypersensitive’s: hypersensitivity perhaps to our own cytokines, to pain signals to god knows what, to so many different kinds of stimuli…

  • Gidget

    November 23, 2019 at 12:56 am - Reply

    This is so exciting. After 30 years it’s great to see progress.

    • Cort Johnson

      November 23, 2019 at 1:23 am - Reply

      I think this is the promise of the new technology. We need a lot more studies to validate this finding but I was simply astounded that they were able to zero in not just on TNF-a but on two particular pathways it affects. I’d never heard of anything like that before. I don’t know what it would kind of evidence it would take to allow trials of drugs that would affect these pathways but it’s encouraging.

  • Jennifer

    November 23, 2019 at 8:27 am - Reply

    What dose this research attempt to attach meaning to ME. or CFS? – the first is caused by infection and the second is open-ended.

  • Isabel

    November 23, 2019 at 9:38 am - Reply

    This is good news. I am just intrigued by the fact that Dr Klimas and Ron Davis seem to have such different approaches to this disease. Cort, do you know if there is any communication between them on their research?

    • Cort Johnson

      November 23, 2019 at 4:13 pm - Reply

      These are two of the biggest ME/CFS research groups and both are heavily invested into understanding the molecular basis of ME/CFS. Dr. Klimas, Travis Craddock, Gordon Broderick and their colleagues are unique, however, in the ME/CFS community in their emphasis on computational biology and modeling. In fact, they are leaders in the entire medical field in that area.

      Ron, of course, has his own unique approach with his nanoneedle, the metabolic hypothesis, the red blood cell deformability issue, the severe patient study and the muscle work going on at Harvard.

      I think its good to have a diversity of approaches. I don’t know how much their approaches overlap but as to communication I always think it’s an excellent idea. I don’t know given their different approaches if Dr. Klimas is a good fit for Ron’s working group but thus far she has not been part of it.

  • Matthias

    November 24, 2019 at 8:04 am - Reply

    It’s hard to know what to think about this study as studies seem to be all over the place with regards to cytokines. For example, a couple of studies came up negative on TGF-b and CFS in the past year or two.

    • Cort Johnson

      November 25, 2019 at 1:21 am - Reply

      I wonder if we will ever have true consistency with cytokine results. Check out VanElzakker’s recent paper on the difficulty of measuring cytokines ( It’s kind of scary actually.

      That said, TGF-B may be the most consistently found cytokine in ME/CFS – a recent overview of cytokine studies highlighted it so perhaps there is hope.

  • Bernadette

    November 24, 2019 at 3:37 pm - Reply

    The problem is that even established autoimmune diseases don’t affect the same pathways in all patients. Many patients clearly have the disease (RA for example), but can’t find an anti-cytokine intervention that works effectively for them even if there are many to choose from. I suspect that was why Rituximab didn’t work for the majority in the Fluge/Mella Study. I think we need to get down to the mechanism before cytokine release if we want to really solve the problem. I think Davis and Phair are really interesting in that way as serotonin and mast cells are involved in cytokine release.

    • Cort Johnson

      November 25, 2019 at 1:22 am - Reply

      Clearly subsets exist in more than ME/CFS.

  • Stephen Collier

    November 24, 2019 at 8:49 pm - Reply

    Good stuff! I gotta learn more about TNF-beta… along with the endless list of other things about these pathways & systems, heheheh.

    The “Byzantine medical age” will end when we switch to using computer models for the pathways that we can plug patient-specific results into. The more of both lab & genetic testing results we enter into a standard model, the more it can start pointing out & narrowing in the pathways that might be at the root of each patient’s problems. It will help at both the disease-level research and at the patient level. We’re going need to know the functional activity levels for the proteins encoded by all the specific alleles we find among all our genes for these models.

    Using the current system that attempts to use statistics to connect symptoms & lab results to diseases/pathologies hasn’t done well with multi-variable diseases, especially when so many immune cascades have common endpoints which makes the picture very muddy to statistics. Trying to understand something by viewing only the start and end points of complex systems is just inferior to understandings gained from modeling the process from start and thru all pathways to finish… or many, many finishes that depend on patient-specific inputs.

    This work is really looking like a pivotal point for humanity. A big one that goes far beyond this “little bout of the vapors we have in our humors” called Chronic Fatigue Syndrome. I’m hoping some funders of medical research catch on sooner rather than later.

    I’m also hoping I can sign up as Dr. Klimas & co’s guinea pig! The type of guinea pig with inside information that also encourages some invasive testing so he can have a chance of escaping his debilitation.

  • Matthias

    November 25, 2019 at 3:36 am - Reply

    Cort, re: your comments on subsets above….this is interesting from a Jonathan Kerr study from earlier this year:

    “A variety of features suggest that CFS/ME may be an autoimmune-like disease. CFS/ME may be triggered by virus infection, and its course characterized by a typical “viral” flu-like illness (7). These observations have led to the recognition that the immune response plays a large and significant role in the pathogenesis of the disease. There are striking similarities between CFS/ME and various autoimmune diseases, for example, Multiple Sclerosis (MS). And, the existence of subtypes of CFS/ME is a further parallel to autoimmune diseases, in which subtypes are well recognized. There are various examples of subtypes of autoimmune diseases exhibiting specific pathogenetic mechanisms, such that particular subtypes of particular autoimmune diseases may be amenable to specific treatments while other subtypes of the same autoimmune disease are not. Studies have demonstrated a variety of immune abnormalities in CFS/ME patients (Table 2), many of which are also found in patients with autoimmune disease. A variety of autoantibodies have been demonstrated in serum of CFS/ME patients including those against nuclear and membrane structures, neurotransmitters and their receptors, cytoplasmic intermediate filaments, EBV dUTPase, and neoepitopes resulting from oxidative or nitrosative damage (53). There is considerable co-morbidity of CFS/ME with other immune or autoimmune diseases, including fibromyalgia (30–77%), postural orthostatic tachycardia syndrome (POTS) (11–40%), Hashimoto’s thyroiditis (17–20%), and a family history of an autoimmune disease (18–41%) (53). We have also found upregulated EBI2 mRNA expression in a subset of CFS/ME patients which also occurs in autoimmune diseases (see below).”

  • Matthias

    November 25, 2019 at 3:53 am - Reply

    It’s interesting how many CFS studies you can stumble across when you search. This one from early 2019 is very interesting and I had never heard of it:

    It suggests intense immune activation at the start of the illness, but not during its chronic cycle.

  • Jody

    November 25, 2019 at 2:40 pm - Reply

    Thousands of us recover our energy using Dr. R. Paul St. Amand’s guaifenesin protocol. It works when it’s done as written. It’s not quick and not magic, it’s good science.

  • Tracey Anne

    November 28, 2019 at 8:38 pm - Reply

    I know people have very different symptoms and there seems to be subsets of the illness but my immune system seems to be at the centre of what’s going wrong with me.

    Though I did have Glandular fever as a teenager and was aware of what seemed to be re-activations of the illness, if I became run-down during my 20’s and 30’s, for most of my life I’ve been fairly healthy, apart from the incessant struggle with being too fat etc.

    So I came to the realisation that maybe, despite such debilitating symptoms for the last 12 years, that underneath I may still be reasonably ok, even though I felt my body was wracked with illness. Most tests came back normal and certainly didn’t reflect the way I felt.

    I was totally unaware of the whole ME/CFS world. I just tried to figure out what was triggering my symptoms – food, and then cut that out. I began to feel much better. However nothing stayed the same, so over the years I lost more and more food that I could eat. Possibly high stress levels and hormonal changes were influencing this decline.

    I used to check in with how I was feeling as I drove to one of my homecare clients at the same time each day. One time, as I drove, feeling tired, miserable and with my thick head spinning again, I said to myself ‘Oh, I have a cold, I’ll get over it.’ However I didn’t actually have a cold and was, in fact, feeling quite anxious about why I continually felt so weird. But the cold symptoms fit perfectly and even though I just made it up, my anxiety levels dropped. It didn’t seem to matter that I was essentially lying to myself – my body was reacting as though it had a cold and that now made sense.

    More recently I remembered the months a few years ago, when my legs seemed to get very weak. Like they would buckle under me and I could hardly walk. Thinking back that would be how I would feel if I had the flu. I think it was linked to me eating nuts. I was very pale and losing weight as I couldn’t find food that I could eat. I got out of this strangely by eating chocolate. I wonder whether it worked, not just because of the energy but due to me being intolerant to ingredients within it and that this then triggered a different part of my immune system? From being pale and thin, I then became fat with rosy cheeks and my leg strength returned.

    However my blood pressure started climbing and then all sorts of problems with the high carbs triggering inflammation started appearing.

    Recently I came across an interesting article online called ‘How the flu hijacks your body to make you feel so wretched.’ by Professor Laura Haynes from the University of Connecticut in The Washington Post. I found it very useful as it explained how the immune response manipulated different parts of our bodies if we have the flu.

    However people with ME/CFS don’t actually have the flu but our bodies may mistakenly think we do. For me, one aspect of this illness that stands out, is the not knowing what was going on. To begin to realise that more than likely my immune system has become dysregulated and that it is capable of inducing so many symptoms has helped me make sense of what’s going on.

    I used to get annoyed when people would say I needed to go and see someone to get myself sorted out. I had become fed up with getting nowhere and wasting money and energy. I knew I needed to balance my blood sugar and bring down my inflammation – I just didn’t know how I was how I was going to do that.

    However with a bit more knowledge of what I’m trying to achieve – not trigger an immune response through food, eating anti-inflammatory foods, getting better quality sleep, lowering my stress response, taking various supplements, I am aware of my health returning.

    I was most worried about my brain, as that took a hit from a very high temperature I had a few years ago (41°c). However my brain and memory have improved, which is a massive relief. If I make a ‘mistake’, which I frequently do my brain function will deteriorate, memory is hopeless etc but it subsides again and I improve.

    What would be great is if there was some sort of medication that may down regulate my immune system enough, without disabling it entirely, so that I don’t have remain so vulnerable to reactions.

    I do sometimes see my immune system as being led by a deranged, autocratic General, who has lost touch with reality – who mistakenly still thinks there’s a war on, and they’re desperately attempting to save me from all the threats.

    If something could be found to calm them down, I’d be very grateful!