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Large NK Cell Study Points to Autoimmunity and Inflammation in Chronic Fatigue Syndrome (ME/CFS)

The observed differences in some of the subpopulations of T and NK cells between patients and healthy controls could define a distinct immunological profile that can help in the diagnostic process of ME/CFS patients, contribute to the recognition of the disease and to the search of more specific treatments. Rivas et. Al. 2018

Problems with natural killer (NK) cell functioning have been like an anchor in the storm for immunologists interested in chronic fatigue syndrome (ME/CFS). While other immune results like cytokines have flipped and flopped all over the place, the NK cytotoxic results have been solid. Almost every study has found that when given the chance to kill infected cells, the NK cells in ME/CFS patients poop out.  (The studies which have not found differences in NK cell functioning have tended not to use whole blood or used older samples – suggesting that something in the blood could be impairing NK cell functioning in ME/CFS.)

Dr. Daniel Peterson, Sierra Internal Medicine and Simmaron Scientific Advisor

The most extensive study – a year-long 2012 study involving Dr. Peterson and Griffith University in Australia – found reduced natural killer cell functioning at all time points. (Peterson has a long history of interest in natural killer cells; he was a co-author of the first study, over thirty years ago, to find deficient NK cell functioning in chronic fatigue syndrome (ME/CFS).)

NK cells are important because they maintain the lines of our initial immune defense, holding the fort, so to speak, until the big guns – the T and B cells- wipe out the infection. – They also regulate the immune response.

Normally our cells signal that they are infected by displaying peptide fragments from the pathogen (using MHC Class 1 molecules) on their surface. NK cells then hunt out and destroy these infected cells. However, some pathogens have learned how to prevent the cells they’ve infected from displaying these peptide fragments.

If NK cells and other parts of the innate immune response can’t hold back the invaders, the pathogens may invade more deeply into the body, potentially causing more problems before the adaptive immune response (T and B-cells) can kick in.

innate immune response

Mast cells, complement, phagocytic cells and natural killer cells man the early or innate immune response

A deficient early response to pathogens would then very likely translate into more symptoms. We don’t know when the problems with NK cell killing got started in ME/CFS, but if they were in place prior to the illness or occurred early in the illness they could have played a role in the inception of ME/CFS as people who have more trouble fighting off a pathogen; i.e. people with more severe symptoms, are more likely to come down with ME/CFS.

Once ME/CFS has begun, the inhibited NIK killing response could mean more trouble removing tumor and infected cells – particularly herpes virus infected cells- as people deficient in NK cells  have trouble fighting off herpes viruses.

NK cells, then, are vitally important, but attempts to identify issues other than cytotoxic killing abilities have been less successful. NK cells come in different types (cytotoxic and regulatory) and the balance of these subpopulations is important. Some studies have found differences in these subpopulations in ME/CFS and some have not.

Many of those studies, however, have been small and used less than stringent criteria for defining ME/CFS. A Spanish group decided to rectify those problems with a more definitive study which examined NK cell populations in a larger study (n=149) with patients who met the Canadian Consensus Criteria for ME/CFS. In order to ensure they captured all factors in the blood that might be whacking NK cells, they used whole blood and analyzed it within 6 hours of collection.

Then they tried to reverse engineer their results to see if a diagnostic test could be developed which simply charted which kinds of NK cells a person had. That was pretty good, but then they went further and asked if people who were worse off had different subpopulations of NK cells or more evidence of herpes virus reactivations (EBV, HMCV).

Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Jose Luis Rivas,1,* Teresa Palencia,1 Guerau Fernández,2 and Milagros García1,3 Front Immunol. 2018; 9: 1028.Published online 2018 May 9. doi:  10.3389/fimmu.2018.01028

This larger, fresher (quick analysis of blood), stricter (CCC patients only) and more comprehensive study found differences where others had not – and plenty of them.  This group validated – with a high degree of certainty (p = 0.0075) – previous findings of  an increased subpopulation of NK cells (NK CD56++(high)) which, get this, excrete more cytokines (particularly IFN-y), possibly causing more symptoms, but which have low cytotoxic activity.  Because these cells have unusually long life spans and pump out cytokines that cause more T-cell proliferation, higher numbers of them could contribute to autoimmunity and inflammation.

These cells were particularly high in the group of patients whose illness began without evidence of an infection. The Spanish group suggested that activation of the stress response via the HPA axis and raised levels of catecholamines such as norepinephrine (adrenaline) could have triggered the expansion of this potentially autoimmune affecting natural killer cell subset.

No differences were found, however, in the levels of several receptors (NKp46, NKp30, NKp44) that have been found elevated in some autoimmune/inflammatory conditions (Sjogren’s Syndrome, Crohn’s disease) or reduced in chronic infections (HIV, tuberculosis, influenza, etc.).

CD 69

Increased levels of the CD 69 marker suggested autoimmunity may be present in ME/CFS

Reduced levels of a receptor (NKG2C) were very common (p<0.0001) in ME/CFS. When this receptor, which is only found in NK cells, is activated by the presence of virally infected cells, it triggers an expansion of NK cells. Not surprisingly, NK cells become dotted with this receptor in people with chronic herpesvirus and other infections (HCMV, EBV) but ME/CFS patients’ NK cells had consistently lower levels of this receptor than did the healthy controls.  The authors didn’t speculate why this occurred, but it could involve lower levels of infection in ME/CFS – something Ron Davis is finding in his severely ill cohort – or a problem responding to infections that are present.

That second possibility was buttressed by an inverse correlation found between a marker of infection (CD 57+) and the lower expression of a marker (NKp46) which is often reduced in herpesvirus infections. The authors suggested that the scenario found in ME/CFS (increased cd57+, lower NKp46, high NKG2C) could reflect HCMV (cytomegalovirus) reactivation.

Watch Natural Killer T-cells (red) Swallow Up Antigen Presenting Dendritic Cells (green)


Increased levels of the CD69 marker (p= 0.011) provided another suggestion that ME/CFS may be an autoimmune/inflammatory disease. This important marker, which is found on many immune cells, stimulates NK cell cytotoxic activity. More importantly, CD69 has been described as a master regulator for autoimmunity in rheumatoid arthritis (RA) through its upregulation of TGF-B – one of the very few cytokines that has usually been found increased in ME/CFS.

A “descent” in T regulatory cells similar to that found in autoimmune conditions such as lupus and RA was also found. Finally, an inverted Th17/T regulatory cell ratio, which is also found in autoimmune conditions like lupus, wrapped up the autoimmune connections found in this study.

Using a mathematical classification model, the group was able to correctly diagnose 70% of ME/CFS patients and healthy controls simply by using the findings from this in depth study of natural killer cell populations.


This large Spanish study of NK cell subpopulations found numerous irregularities in NK cell types in ME/CFS, several of which pointed to issues with autoimmunity and/or inflammation. As in other studies, this study indicates that larger is indeed better when it comes to studying ME/CFS.

The study validated prior findings of an unusually large set of NK cells which produce more cytokines – conceivably causing more symptoms and immune activation – but which are less effective at killing infected cells.  That finding seemed to jive with a picture of highly symptomatic ME/CFS patients who may have trouble fighting off infections.

While no differences were found in the levels of receptors which can be elevated in autoimmune conditions, several other findings suggested that NK cells may be fighting off herpesvirus infections or may be involved in autoimmune/inflammatory processes in ME/CFS.

Finally, using just NK cell subpopulation data, the authors were able to correctly identify 70% of patients and healthy controls, indicating that significant NK cell differences exist. All told, the study identified several natural killer irregularities that could participate in autoimmunity and dysregulate other parts of the immune system.

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  • Merry Speece

    June 14, 2018 at 12:50 pm - Reply

    Great article. Thank you, Cort.

    • Cort Johnson

      June 14, 2018 at 1:22 pm - Reply

      Thanks! Interesting stuff! Nice to see issues showing up in other than killing ability.

  • Nila Williams

    June 14, 2018 at 2:44 pm - Reply

    This is good to know. I do believe that the doctor that died, can’t remember his name ,mentioned low dose Naltrexone 4.5 helps this condition. I hope the Rheumatologists in out nation are notified.

    • SandyB

      July 7, 2018 at 10:07 am - Reply

      Low Dose Naltrexone does help with Chronic Fatigue Syndrome and it helps with pain from Fibromyalgia. It was a game changer for me.

  • Maschelle

    June 14, 2018 at 4:24 pm - Reply

    I’ve mentioned many times before that I had a positive Ana when I was first getting diagnostic testing and also the rheumatoid Factor was what they expected to find based on my family history of rheumatoid arthritis. I also have that herpes virus constantly breaking through and since getting ill antibiotics just don’t seem to work like they used to. I’ve been on antibiotics for 3 months at a time for the simplest things and I’ve been fighting skin lesions they keep getting infected with normal bacteria that lives on our skin which healthy people fight off if there’s a break in the skin.

    What I’ve never mentioned before is when the rheumatologist dropped me as a patient his reasoning was “you have nothing that is autoimmune or inflammatory in nature. There is nothing I can do for you.” He would on to add that he did not believe any CFS was a biological disease and that I was just a very nervous anxious person. And when I told him that what I’m feeling is very real and it is a real disease, and that technology just hadn’t developed to the point where they’re able to find what’s going on. But I know that one day science will figure it out. To that he said “well, then maybe someday you’ll be able to come back to me and say “I told you so.”.. but I find it highly unlikely.”
    I honestly thought this doctor had my back. He was one of the 3 doctors that diagnosed me with ME/CFS using the CCC in the first place, and he had helped me. When I pointed that out he said” that doesn’t mean I have an inflammatory illness, low-dose short-term steroids can make almost anybody feel better it helps so many things not just autoimmune or inflammatory diseases.”
    And Along Comes This study. Fascinating and it’s only been 10 years since he said that to me. Things are looking up as far as validation goes for us. I found this article to be very interesting and it made a lot of sense. Hills like finally researchers are starting to find these things that explain why we feel the way we feel and what happens to us. It gives a lot of Hope for an earlier diagnosis, and maybe even a treatment!

    • Kat

      June 14, 2018 at 11:32 pm - Reply

      I had a similar experience with positive ANA and RH and getting dismissed by a rheumatologist. I hope you are able to get this study to the one you saw and say, I told you so!

    • Rob

      June 16, 2018 at 12:47 pm - Reply

      Please find a Lyme literate physician and have yourself checked for Lyme disease.

  • dejurgen

    June 14, 2018 at 7:27 pm - Reply

    Those NKC seem to be able to dampen an auto-immune response and convert it to a combined inflammatory/CDR reaction. They play a major role in reducing immunity reactions to a “foreign” entity during pregnancy. See “NK cell function in pregnancy” in And they can reduce theirs and other immune cells aggressiveness and increase inflammation at the same time. Inflammation and increased ROS production go hand in hand. And dr. Naviaux showed Dauer is strongly linked to convert mitochodria from energy producing machines to peroxide producing machines. The resulting peroxide further encourages neighboring cells mitochondria to convert to peroxide producing machines too.

    If they would “transform” auto-immunity problems to high levels of inflammation, CDR and ROS, what could this auto-immunity be targeted at? Maybe no cells at all. That might be a reason why researchers can’t find a single specific type of cell (identical clear response in all cases) that is targeted by auto-immunity in ME. So what could it be targeted at?

    Since I learned about misfolded and faulty proteins, I’d put a bet on those. They can reside inside and outside near all cells. So going the classic immune route would cause massive damage. I’ll bet the neutrophils are not damped but maybe even increased in action. They can form NETs that are ideal to catch rouge proteins with minimal damage. Massive ROS bombardments can damage and destroy many of them and reduce them sticking together (like in Alzheimers anc co blocking blood flow) and going to CDR gives the double benefit of decreased need of protein synthesis (less production of misfolded proteins) and more time for refolding misfolded proteins (in the hope redoing it several times will get it wright at least once).

    BTW: I’m a bit confused by the video on NKC-T cells in an blog about NKC cells. We’re talking about the latter don’t we?

    • Cort Johnson

      June 15, 2018 at 11:06 am - Reply

      Very interesting! It’ll be interesting to see if those misfolded proteins show up. Baraniuk’s early proteome study suggested that. I imagine that Ron Davis’s work would find them but don’t know and you could be very right – no specific target at all. Some study somewhere suggested that. A good way to lead to exhaustion.

      The NKC-T are considered a kind of blend of NK and T cells and NKT-like cells included in the study. From the abstract: “The ME/CFS patients showed significantly lower values of T regulatory cells (CD4+CD25++(high)FOXP3+) and higher NKT-like cells (CD3+CD16+/-CD56+) than the healthy individuals.”

  • David

    June 14, 2018 at 9:29 pm - Reply

    So is ME/CFS an immunological disease or a metabolic disease….is that the crossroads we are at? It seems to keep coming back to the immune system.

    • Cort Johnson

      June 15, 2018 at 10:59 am - Reply

      I think its possibly an immunological metabolic disease! Autoimmune disease that effects the metabolism. The SMCI has several studies going assessing the metabolism of immune cells or how pathogens effect metabolism.

      • sick and tired

        June 16, 2018 at 2:28 am - Reply

        are there immuno-metabolic diseases that have already been identified? hope we arent the first.

        • Cort Johnson

          June 16, 2018 at 1:02 pm - Reply

          I wonder if diabetes fits into that mix. Sepsis and post=trauma burn does – a blog is upcoming on that.

  • Michelle L

    June 14, 2018 at 10:13 pm - Reply

    Thanks heaps Cort :)) Just wondering re the impaired natural killer cells, would this mean they were impaired also fighting any infections a person with ME/CFS was exposed to? I personally am not at all prone to getting sick (touch wood) apart from having ME/CFS.

    • Cort Johnson

      June 15, 2018 at 2:18 am - Reply

      One would think so. On the other hand other parts of the immune system could be compensating or over compensating for the NK cell problems I suppose.

  • Kat

    June 14, 2018 at 11:29 pm - Reply

    Wow, this seems spot on. Have had both EBV and MCV, as well as positive ANA and positive.RH bloodwork. When I do get sick, I get sick hard. The rheumatologist I saw to follow up on the. ANA & RH tests dismissed the idea I could have a connective tissue autoimmune disease, diagnosed me with hypermobility and told me there was nothing she could do for me, bye bye.

  • Rebecca Cook

    June 15, 2018 at 2:42 pm - Reply

    Cort, is there a link to the original technical paper? My husband the scientist would be interested in reading it. In addition to ME and other subsets, I have MCAS and think this all interrelates.
    Thanks, Rebecca

    • Cort Johnson

      June 16, 2018 at 1:09 pm - Reply

      Yes, if you click on the name of the paper in the blog it will take you to the original paper.

  • cbbrooks

    June 15, 2018 at 10:41 pm - Reply

    the first cfs dr i saw recommend i take Immpower which is a mushroom .
    wonder if it has helped anyone or would it help in this situation? thanks

    Maintains Peak Natural Killer Cell Function
    Size: 30 capsules/bottle
    Active Ingredients: 500 mg AHCC proprietary blend.

    Maintains peak Natural Killer cell function.
    Supports enhances cytokine production.
    Supports optimal T-cell and macrophage activity.

    • Cort Johnson

      June 16, 2018 at 12:59 pm - Reply

      Thanks for passing that on. I’ve had some help with REISHI mushroom tea.

      • cbbrooks

        July 8, 2018 at 9:19 pm - Reply

        Thank you for sharing about your help with Reish tea.. do you get a tincture and just add it to hot water? and take it like 3 times a day? what benefits have you noticed? thank you

  • cbbrooks

    June 15, 2018 at 11:50 pm - Reply

    The first cfs dr I saw recommend i take Immpower which is a mushroom .
    Wonder if it has helped anyone or would it help in this situation? Thanks

    Maintains Peak Natural Killer Cell Function
    Size: 30 capsules/bottle
    Active Ingredients: 500 mg AHCC proprietary blend.

    Maintains peak Natural Killer cell function.
    Supports enhances cytokine production.
    Supports optimal T-cell and macrophage activity

  • sick and tired

    June 16, 2018 at 2:22 am - Reply

    i don’t have herpes though and don’t seem to have trouble with infections. the only kind of herpes i ever had was chicken pox as a child. dont even have cold sores or genital sores. i believe chickenpox caused my guttate psoriasis. ive been sick since my late teens, now i am in 23. i had to drop out of school due to cfs and an LD that i was not getting the right accommodations for. i wish my family especially extended family could understand what i go through instead of judging me for not going to school and/or having a job. dr. diagnosed me with cfs but i have also suffered hypersomnia or delayed sleep phase syndrome which i was never able to figure out or get a diagnosis because i messed up the sleep logs and tracking because of my ld. i worry that i have slowly gained weight over the years due to inactivity. even lifting my arms hurts. its like there’s lead in my bones. im probably going to get an elliptical or recumbent bike and force myself to exercise because i cant bear to be obese on top having no accomplishments. i live in canada which has legal assisted suicide. do u think there will be a treatment in my lifetime that would make me able to function like normal like how a person with arthritis or diabetes can live a long, functional life? would anyone here try to get assisted suicide because of cfs? how likely do u think they would grant it? one guy my age was allowed to do it because of ocd which i also have. it rly sucks have a disorder like ocd with cfs because its even more likely u will be seen as a hypocondriac or malinger.

    • Rose

      June 18, 2018 at 4:08 pm - Reply

      No wonder you are in such a dark and lonely place – when no one believes you or helps you, life can seem not worth it. I have children with LD’s who had varied responses and help/hindrance during their schooling. It’s pants. However, there is hope, I’ve had this illness for many, many years with many ups and downs – sometimes going very deep and dark indeed. One thing that gives me hope is that the research being done now is a million times more detailed and organised than it used to be. There is also much more research than there used to be. Also more people are involved in research who are personally affected and determined to discover some help for us. So I hope you can grasp this hope – along with me and millions of other sufferers. Hang in there! If I may, I will pray for you as I know having others pray for me has helped enormously, especially when things were very bad. Let’s sit or lie down (as we can’t stand!) in solidarity together until this illness is beaten!

  • sick and tired

    June 16, 2018 at 2:31 am - Reply

    r cfs ppl more likely to get cancer if our cells are messed up?

    • Cort Johnson

      June 16, 2018 at 1:01 pm - Reply

      There is a study or two which suggests the risk of a certain kind of lymphoma is increased but the incidence of that cancer is very low – which translates into a very, very low risk for any one of us. Other than that no. I believe another lymphoma risk study is underway.

      • jimmy

        June 17, 2018 at 3:10 am - Reply

        Cort thanks for all your work. You have said several times that cfs does not cause cancer? you state some studies that are not done correctly. People are dying from cfs . Cancers heart failure ect. they are not being labled as cfs diseases but cancer ect. You have to be careful with your statements in this regard. It is happening to me and I know it happened to others. there is reserch showing we die at least 20 years younger from these diseases. I think you need to be more open in this area as there may be much more funding if what Im saying is true. It may be that a mild version of this disease does not cause cancer,. doctor kaufman and klimas have said Low nk caell ebv resctivation and oxidation can be just some reasons for cancer. imflamation ect. The body has cancer cells in it all the time if the immune systej is not doing its job yiou can get cancer. best jimmy

  • Michiel Tack

    June 16, 2018 at 9:37 am - Reply

    What about the remark in the IOM-report:

    “Low NK cytotoxicity is not specific to ME/CFS. It is also reported to be present in patients with rheumatoid arthritis, cancer, and endometriosis
    (Meeus et al., 2009; Oosterlynck et al., 1991; Richter et al., 2010). It is
    present as well in healthy individuals who are older, smokers, psychologically
    stressed, depressed, physically deconditioned, or sleep deprived
    (Fondell et al., 2011; Whiteside and Friberg, 1998; Zeidel et al., 2002).”

    Do NK cells really have the potential to become a biomarker for ME/CFS? Are these reported findings somehow more specific to ME/CFS? As far as I can see only healthy controls were used in this study…

    • Cort Johnson

      June 16, 2018 at 1:04 pm - Reply

      Interesting. It doesn’t look like it. I didn’t know about that. Maybe that is why NK cell cytotoxicity has never become a biomarker for ME/CFS. (Another reason could be the difficulty of the testing procedure.) Perhaps a combination of NK cell phenotypes and poor functioning could be but it looks like a long shot.

  • Donna

    June 26, 2018 at 10:41 am - Reply

    What about here in Australia, Griffith Univ, Researches Don
    Staines and team, have found a bio maker in the cell receptor TRPM3, messing up the calcium transfer in a range of cells, causing inflammation.