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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.

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22 Comments

  • Troy

    December 31, 2018 at 9:41 pm - Reply

    “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”

    A reveleation to the medical community sure, but not to many of us. It’s a sad state of affairs when the medical community is so bogged down in dogma and unable to think out of the box. It seems like the only way they ever break out of these kinds of progress stifling ruts is by “stumbling” upon something that challenges their world view. Not calculated discovery, but stumbling. Unfortunately until they stumble in the right direction we all continue to get dismissed and miss out on the progress and treatment we need.

    That’s also very interesting about the cytokines. This is another avenue that the BPSers use to shore up their house of cards: pointing at the inconsistent findings of in regards to cytokine levels found in ME/CFS to refute those who tout that ME/CFS has immunological origins.

    How does Lenny Jason intend to replicate these findings in young people with ME/CFS if he needs to detect the elevated IL-10 before coming down with ME or at least very very early?

    • Cort Johnson

      January 3, 2019 at 4:17 pm - Reply

      SInce Lenny has samples from the college students before they get ill he’ll be able to check their cytokine levels then. Wouldn’t it be something if IL-10 levels were high prior to mononucleosis, high just after getting it, and then normal or near normal after six months?

  • Heidi

    December 31, 2018 at 11:13 pm - Reply

    Has any research been done in examining the chromosome 6 gene? It appears something affects the IL-6 and IL-10 cytokine (ebv perhaps?). Is it possible that a broken or damaged gene (similar to how Burketts lymphoma was discovered) could affect the immune system by causing low-grade inflamation?

    • Cort Johnson

      January 3, 2019 at 4:19 pm - Reply

      There actually are findings of increased levels of both IL-6 and IL-10 polymorphisms in ME/CFS/FM I believe. Those polymorphisms could alter the levels of cytokines produced during an infection.

  • Nancy B.

    December 31, 2018 at 11:13 pm - Reply

    It was of interest to me that (low) dopamine was once again implicated in ME/CFS. This led me on a tangent looking up supplements and medications that increase dopamine, with Mucuna prurian (Red Velvet Bean) being one of the most used (as a precursor). Tyrosine is also very important.

    I was also surprised that I already take many of the numerous recommended substances–which I stumbled on by trial and error. But not the ‘bean’…

    Now, not to be too obvious, if dopamine is implicated in fatigue, hasn’t anybody done a study using dopamine modifying drugs to see if they help ME/CFS?

    Cort, you may know about a study I have missed…

    Anyway, Happy New Year! And may everyone be blessed with a bit more energy!

    • Cort Johnson

      January 3, 2019 at 4:21 pm - Reply

      Such a fascinating area Nancy. I think we would to get the inflammation/oxidative stress down as you suggest.

  • Nancy B.

    December 31, 2018 at 11:19 pm - Reply

    Found it! This is a piece that you wrote about in 2014; https://www.healthrising.org/blog/2014/09/25/dopamine-basal-ganglia-chronic-fatigue-syndrome-treatments/
    Looks like the trail might go back to genetics… or oxidative stress…

  • Lora

    January 1, 2019 at 2:00 pm - Reply

    Thank you Nancy for posting your hunt as I am right behind you on this/that trail..May you and everyone have a Blessed New Year and Better days ahead..TY as always for your postings and comments Cort and all…

  • ManShadow

    January 1, 2019 at 10:01 pm - Reply

    Oh s@!t. Looks like I know how I developed CFS then. A bit of youthful experimentation led to HCV infection. In the 10 or so years between infection and diagnosis, my memory went to s@!t. I’d formerly been able to memorise equations, names, conversations and kung fu moves after seeing/reading/bearing them just a handful of times, to requiring hours and hours of exposure to memorise pretty much anything.
    After treatment with IFN-a and ribavirin nearly 10 years ago, I’ve become much worse and developed CFS/ME four years ago.
    If there is a way I can donate myself for testing, I’d be more than happy to.
    What interesting research, definitely aligns with my experience. Be great if we can reverse some of these side effects as I can then show people how awesome I used to be, rather than drone on about it from time to time and bore them to tears

    • Cort Johnson

      January 3, 2019 at 4:22 pm - Reply

      🙂

      Let’s hope! If inflammation in the brain is the problem Nancy Klimas is working on a way to reverse that. Hope to have a blog on that soon.

  • Dan

    January 2, 2019 at 8:26 am - Reply

    Can it be enough to take medication that is really primarily for ADHD or for example modafanil? It affects dopamine. Wellbutrin also to some extent, but there it is mostly norepinephrine.

    • Cort Johnson

      January 3, 2019 at 4:24 pm - Reply

      I think it can help some people but if the dopamine producing areas of the brain have gotten whacked because of inflammation/oxidative stress focusing on that might help.

  • Ruth Behan

    January 2, 2019 at 4:46 pm - Reply

    I am very interested in the dopamine angle and as more evidence ( anecdotal) I find that during musical performances ( if they are going well) I can endure much higher levels of activity than I normally can. I believe there is research showing that music can help people with Multiple sclerosis who can get enough dopamine to go through doorways but then they can if they hear music and dance their way through.

    • Cort Johnson

      January 3, 2019 at 4:25 pm - Reply

      Interesting! I found that activities which help me get into “flow” are helpful. For me the stress response is clearly implicated. It seems to be on all the time. Anything that calms that down – such as music – helps.

  • TK

    January 3, 2019 at 7:06 am - Reply

    I’m firmly in the inflammation-hypersensitivity camp as it explains the most including PEM from physical exertion. The basal ganglia theory also explains the “novelty effect” that elevates exercise tolerance while traveling or walking a new route or doing an intent activity. Dopamine supplement, however, did not do anything for me.

    One thing I can’t explain with inflammation hypersensitivity is PEM from mental exertion. I personally haven’t experienced PEM from mental exertion, but literatures are clear on this: PEM from mental exertions is also delayed 24-48 hours and last several days. How does mental exertion trigger the PEM circuitry without accompanying physical inflammation from exercise or infection? An exercise results in inflammation for days, and so does low grade inflammation from a flu shot. The brain over-reacting to the minute inflammation then expresses as PEM in my theory. But I don’t see a clean explanation how mental exertion can trigger the over-reaction for days with 24-48 hour delays.. It needs to be explained, or the theory will have to be revised.

    • dejurgen

      January 3, 2019 at 10:16 am - Reply

      “How does mental exertion trigger the PEM circuitry without accompanying physical inflammation from exercise or infection? An exercise results in inflammation for days, and so does low grade inflammation from a flu shot.”

      I experience inflammation-like effects from mental activity a lot. Thinking too much (or more focusing too hard) is a mental exercise that consumes plenty of energy and oxygen in the brain. In my believe that oxidative stress is a key component in ME, thinking a lot is costing plenty of ATP. Creating plenty of ATP is a process creating oxidative stress and heat. In order to try and compensate for that increased oxidative stress the brain can try and produce NADPH/glutathione. I believe the brain of an ME patient already produces highly elevated NADPH/glutathione at rest to compensate for increased oxidative stress at rest.

      One of the problems is that producing NADPH/glutathione also produces heat as a byproduct. With mental exercise then we have the triple problem of: more oxidative stress at the brain, more heat production at the brain and even more need then the already high base needs to produce NADPH/glutathione. But the later would increase heat generation further in the brain and the brain is heat sensitive. Additional problem: for ME patients blood flow to the brain is poor so it is more difficult to take away the heat by cooling it with blood at a slightly lower temperature.

      Result: oxydative stress can’t be countered enough increasing brain inflammation and body temperature sinks the coming 24 hours potentially to allow the cooler blood from the body minus brain to better cool down the brain as cold therapies are known to fight inflammation IMO. With the cold body temperature the blood circulation is further deregulated. Combine that with brain inflammation and it’s part of PEM IMO.

      When focusing too hard or too long, I often get a very quick onset of confusion and quickly after that “it sinks to my legs” meaning my legs start to hurt a lot more and I often end up dragging myself on hands and feet the few meters too my room. It’s a very quick onset process followed by longer during PEM.

      • Cort Johnson

        January 3, 2019 at 4:28 pm - Reply

        More heat! Interesting! I imagine if you work out a brain with energy production problems you get something similar to the muscles. They, have, after all, found increased lactate and reduced glutathione in the brain.

        • TK

          January 3, 2019 at 5:23 pm - Reply

          That’s a good point. Immune system gets activated for days to repair the damage from physical exertion. Same thing could be happening in the brain for the mental exertion.

      • TK

        January 3, 2019 at 5:13 pm - Reply

        Yeah, I’m sure inflammation is involved in there somewhere. But it is not easy to explain the sickness lasting days after 24-48 hour delay. Oxidative stress/metabolic response/resolution should be relatively quick and it takes speculation (brain inflammation taking time to resolve, etc) to explain PEM there.

        In case of physical exertion, on the other hand, there is a rather straightforward explanation: IL-6 spikes up after about 24 hours and the immune response to exercise last several days. And CFS people, being hyper sensitive, keels over for days whereas healthy people don’t even notice.

        • dejurgen

          January 3, 2019 at 8:28 pm - Reply

          “Oxidative stress/metabolic response/resolution should be relatively quick”
          Not when living under conditions of chronic (very) high levels of total body wide oxidative stress IMO. That should tank glutathion levels (as is seen in many studies) and their building blocks in a chronic way. Adding an additional mental exhaustion should rip through the remaining stock very fast. Then ROS levels start to spike in the blood. ROS kills NO. With less NO blood vessels in the brain and body wide contract. Blood flow gets derailed to both brain and the rest of the body. Reduced blood flow puts strain on the hart, digestion and respiration. The respiration is hit by both reduced blood flow and the accompanying edema from reduced water removal due to reduced (returning) blood flow. Both poorer blood flow and more water in lung tissue make breathing a lot more difficult.
          Depleted stocks of glutathione and their building blocks plus low stocks of plenty amino acids (as seen by research) combined by lots of ROS and poor blood flow and breathing should be a good start to get hammered for a few days. The immune system gets hammered as well due to very low NADPH available. NADPH is essential to both the immune system and for glutathione recycling (oxidative stress defenses).

        • ManShadow

          January 4, 2019 at 2:50 am - Reply

          Apologies for lack of linkage. There was a study done where the CFS/ME patients had increased gut permeability at 24 and 72 hours after an exercise test. The control group did not and tests were discontinued after the 72 hours. Perhaps the leaky gut explains some of the inflammation and PEM after physical exertion?

          • TK

            January 4, 2019 at 6:27 pm -

            Could be. Or it could be a normal immune response to exercise. It’s been observed in athletes that inflammation comes in waves peaking after some delay and lasting several days. That plus inflammation hypersensitivity would be the most straightforward explanation for PEM in CFS. My problem is that hypothalamus is supposed to be the nexus between inflammation and the brain response and that doesn’t explain PEM from mental exertion. There must be a common path leading to the same brain response from both physical and mental exertion. Is gut the answer? Brain metabolic dysfunction? Who knows.. Any case, all theories must explain PEM and the sudden onset at the minimum, in addition to chronic fatigue. Many theories require gymnastics to explain those I’m afraid.

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