Ground Zero for Immune Findings
Natural killer (NK) cells are kind of ground zero with regards to immune functioning in chronic fatigue syndrome (ME/CFS). Problems with the ability of NK cells to kill pathogens were identified as early as 1987 and those findings have largely stood the test of time.
Later problems in both stress response systems, the HPA axis and the autonomic nervous system cropped up – both of which regulate immune functioning. Reasoning that activating both stress respone systems would cause the immune system to take a hit in this study the CDC used a stress test called a Trier Social Stress Test (TSST) to push those systems hard and then checked on natural killer cells.
Acute psychosocial stress-mediated changes in the expression and methylation of perforin in chronic fatigue syndrome. Falkenberg VR, Whistler T, Murray JR, Unger ER, Rajeevan MS. Genet Epigenet. 2013 Jan 28;5:1-9. doi: 10.4137/GEG.S10944. eCollection 2013.
The CDC examined natural killer cell levels, the gene expression levels of perforin – a key factor in natural killer cell “killing” – and the methylation sites that affect perforin functioning. Being able to tie activation of a damaged stress response system with poor immune functioning; i.e. natural killer cell functioning – would be a major step forward – particularly given the effects of stress on many people with ME/CFS.
Being able then to tie methylation – a process in the body that turns on and off the expression of genes – to the poor natural killer cell functioning found (via measuring perforin expression) – could be a big step in figuring out what the heck is going with natural killer cells in ME/CFS.
The Trier Social Stress Test consists of a 10-minute public speaking and 10-minute mental arithmetic task in front of three trained staff members (TSST panel. It was guaranteed to raise stress levels.
Another Bizarre Finding
Natural killer cells appear to be exquisitely sensitive to stress and as expected the stress test boosted natural killer levels dramatically in both sets of patients. Perforin expression – a key part of the NK cell killing machinery – increased 60% in both CFS and healthy controls simply by telling them they were about to take a stress test.
During the stress test perforin expression continued to increase in the healthy controls but decreased slightly in the CFS patients. Then perforin expression decreased in the healthy controls after the test but increased later in the CFS patients as time went on. To wit:
- Perforin went up during the test and then decreased in the healthy controls.
- Perforin went down during the test and then increased afterwards in the CFS patients.
During the stress test perforin levels should have increased in the ME/CFS patients but they tanked. That would presumably leave ME/CFS patients more vulnerable to viruses during that stressful period. They normalized immediately after the test but an hour and a half after the stress test was over, however, they shot up dramatically. It was almost as if a delayed reaction was taking place (or it was a spurious finding.)
The take away here is that NK cells appear to have trouble – like so many other parts of the body in ME/CFS – regulating their functioning properly in response to stress. . .
This pattern seems somewhat similar to what happens to autonomic nervous system functioning before and after exercise. The heart rates of ME/CFS patients are increased at rest but then poop out once the system is put under the stress exercise (chronotropic incompetence). Perforin expression was normal during rest in this study (although other studies have found that it was decreased during rest), then declined during stress and then later bizarrely shot up again.
The researchers suggested that reduced perforin expression found in the ME/CFS patients during the social stress test could be due to something as simple as reduced NK cell recruitment – the more NK cells present – the higher the levels of perforin in the blood. (Other studies, however, have found normal natural killer cell levels in ME/CFS)
The big question in the study was methylation. Were perforin levels decreasing because epigenetic processes in the body were turning them off? The CDC tested seven sites involved in the methylation of the perforin gene. The finding that increased methylation was reducing perforin expression (in both groups) was an important one for the field. The main finding, however, was that methylation levels were similar between the two groups.
When the CDC broke the “CFS” group up into patients with low and high methylation rates, however, they found that CFS patients with high methylation rates had significantly lower perforin gene expression just after exercise. The authors noted that these patients had high baseline methylation rates – and therefore reduced perforin levels from the beginning.
The findings were intriguing enough that one wonders what a study with a more select group of ME/CFS patients would have found.
This potentially quite important study dug deep into NK cell functioning. Being able to link altered methylation rates to stress induced reductions in perforin expression could have identified why natural killer cells are doing so poorly in ME/CFS patients. The authors did find some abnormalities but not the broad abnormalities they clearly expected. The results are a bit murky.
The Achilles Heel
The CDC had a great hypothesis and went to some length to test it – this was probably a quite expensive study – but it’s Achilles heel may have been the participants. The chronic fatigue syndrome patients in this study met the empirical definition of CFS and were gathered up in a population-based study. That presumably means they were gathered up using random sampling and if that’s so that’s problematic.
Using patients from doctor’s practices at least ensures that patients are sick enough to see a doctor. Population-based studies, on the other hand, rely on the veracity of questionnaires to find their patients. (The participants are usually later assessed by a doctor). Lenny Jason’s recent finding that no less than 30% of healthy controls meet the Fukuda criteria (and 15-20% met the CCC and ICC definitions) puts a big question mark on population-based studies like these.
From prior CDC studies we know that many of these patients tend to drift in and out of meeting the criteria for CFS: they’re definitely on the fringes of the CFS population.
It’s hard to know what to do with this study. Does it reflect what’s going in the ME/CFS population at large? It’s simply impossible to know.
Unfortunately, the definition issues in this or other studies are hidden. The limitations of a study are usually provided at the end of the study, and, in fact, the CDC cites several limitations in this study.
The CDC has never, however, acknowledged that I can remember – and does not acknowledge in this paper – the dramatic effects their population sampling approach or the definition they use may be having on the type of participants they’re studying. A CDC study suggesting that using the empirical definition could increase the prevalence of this disorder fourfold means many people who did not formerly fit the criteria for ME/CFS now do. That’s a major possible confounding factor that is never mentioned.
Researchers and doctors who don’t know the history of the illness will assume this group of patients is no different from others. They will probably assume that methylation does not play a major role in the natural killer cell problems in ME/CFS.
It’s otherwise good studies like this that cry out the need for a good research definition. Particularly in population based studies that are already identifying less ill cohorts it’s hard to see the reason to continue using a definition that plucks out less ill patients.
The P2P draft summary suggested the Oxford definition be retired and that a consensus effort identify a temporary definition as work proceeds on a new definition. It’s time for everyone – the CDC, the UK researchers, NIH funded researchers and privately funded researchers to get on the same page. Thirty years into ME/CFS researchers are using no less than five different definitions in their studies: the Fukuda, Oxford, Empirical, CCC and up in Norway – Wyller’s definition.
That’s a recipe for disjointed and slow progress in a field that needs to be as efficient as possible given its low funding.
Wow…I have just been pondering and discussing this very area..thanks!
I also believe the response is instant, like a ruddy alien forcefield….zoom, sorta thing.
My experience as well.
Thanks for the work you do, Cort; I appreciate you and am helped tremendously by Health Rising. You’re a talented writer, and I appreciate all the information you provide.
Many “happy moments” to you all today! (I can’t remember the guest who wrote about happy moments (I do think it was here), but choosing to be aware of all the happy moments I experience through the day has definitely changed my attitude.
It’s taken me awhile to realize that even positive stress has a negative effect on my illness..situations were I find I’m having a delightful, fun time can completely knock me for a loop & it takes days to recover. This illness is INSANE!
I agree – I have a similar problem. I think it’s the autonomic nervous system – I don’t think it handles excitement well and it handles the negative stuff even worse but the point is that it’s not stable – it’s over-reacting to everything.
If the ANS is messed up that means the immune system is messed as well. Note the perforin levels going up when they should have gone down and going down when they were expected to go up…
”I think it’s the autonomic nervous system – I don’t think it handles excitement well and it handles the negative stuff even worse but the point is that it’s not stable – it’s over-reacting to everything. ” This is the hallmark for ME Cort. This reaction is the cause of every problem we have, i think. If we know what causes this abnormal reaction we know the real cause. Maybe the study from Norway will tell us. Abnormal activity of the ANS is the problem 100%.
I think the ANS plays a big role but I don’t think framing it as the ANS over reacts to everything is the best way to frame it. I think it’s more accurate to say that the ANS is dysfunctional. As has been discussed before think about temp control issues (both high and low temps) and breathing. I do not hyperventilate but actually have to think about inhaling and exhaling. And at least in my case I think the ANS is contributory to exercise dysfunction.
I think you’re right and Staci Stevens would agree – it’s more like it’s set wrong or broken and can’t find home base…
I agree with the positive stress thing. The moment I start to pack to go away for a holiday, I feel uneasy with a reaction that is like anxiety. I’ve tried packing the day I leave. I’ve tried packing four days before leaving. No matter when I do it, I get that reaction. I’ve finally come to the conclusion that it’s anticipation and excitement but my body can’t cope with that positive stress. Now I tend to do the packing a few days beforehand and then I have time to relax and recover before going away.
Other friends talk about how excited they are before going away on a cruise. I don’t feel that excitement. I just quietly look forward to being on the ship. I think I don’t allow myself to get excited because I know that I will pay for it.
Before a trip I am more wired than ever and often cannot sleep.
Same thing happens when something big — good or bad — happens. I could stay up until 3 AM easily.
It continues to be a very rocky road to success with this illness. It is insidious and illusive. Hipjaven@gmail.com
Such a clear critique Cort. You do a wonderful job on behalf of all of us. I feel I understand both the content and its limitations. You do us a great service in sorting out this incoming rush of information.
Kia Kaha, Cort.
(Kia Kaha = ‘take courage’ or ‘be strong’ in Maori and is an expression of recognition of fortitude down here in the Southern hemisphere)
Thanks Phillida 🙂 and for teaching me some Maori….
I was just reading a Jack London biography – he visited the Maori – was very impressed by them.
As a newcomer to this site, could you please define the four different criteria for diagnoses? I find this site to be the absolute best on information of ME/CFS.
If i LAUGH or SNEEZE, i get so ILL, not tired but awfully ILL then maybe the SEVERE fatigue sets in!
laughter is NOT the best medicine with this illness! thats why i cannot understand WHY they keep talking about EXERCISE when it emcompasses almost any MOVEMENT like laughter, sneezing, moving a hand, holding ones head up, any MOVEMENT at all like just waking up can be a horrible experience! TOO ILL TO LIVE WITH!
WHY don’t they know this yet?
If left up entirely to the CDC, they would drag this on for another thirty years.
I think they were on the hundred year plan with Reeves…
Just want to ‘ditto’ (having brain fog right now, words not coming) what Phillida said. You do a fantastic job Cort and those of us suffering are extremely grateful. Thank You!!
Thanks Kira – I appreciate it!
Definitions of ME are such a huge issue as you point out. Could differentiating subgroups according to symptom severity help to some degree in this type of study unttil some agreed definition or biomarker (pie in the sky variety) emerge?
By definition (:)) if you start using the CCC you would start to do that because it plucks out a more severe set of patients.
How nice it would have been if the CDC has stratified it’s patients by CCC vs Empirical definition instead of by the median values…Using median methylation values they did find more evidence of altered perforin status (eg natural killer cell dysfunction.) We can probably assume that those folks would have been more likely to fit the CCC…
So they did kind of do what you suggested indirectly – and it did work.
These illnesses sure lead the way for paradoxical reactions. My experience with FM is that while I have symptoms, I never catch viruses but if I have several days of feeling really well ( which doesn’t happen very often unfortunately), I am much more likely to come down with something.
I have a sister! :)…When I do something that increases my energy – the almost inevitable outcome – if I keep taking it is that I will end up in a fluey – I imagine virally reactiivated state..
My ME is very much the same. I RARELY catch even a cold but feel fluish all the time. If I get a short reprieve from my crushing symptoms I will invariably catch a cold & still feel better than my usual- that’s whacked. In fact if I catch a cold I say “I must be on an upswing”…
My ME is similar: if the depths of crushing fatigue, muscle weakness, unrelenting pain, wired/tired phenomena, severe headaches & brain fog begin to lighten ever so slightly I will catch a cold & feel much better than normally, more energy, less pain, less fog. It is short lived & I return to much sicker. And it is a long time before I am “well enough to catch something” again. Whacked out indeed!
When I became very sick two weeks after the flu shot of 93 I had many tests. One was a thallium graded stress test. I passed the graded treadmill with flying colors. I had been knocking off 3-5 miles 5 times a week but beginning to be very tired after and pushed harder thinking that I needed to do more. I was skipping it more and more.
I had to leave the hospital for two hours, go back and get under a machine (for lack of better word ) to see how the blood was flowing though my heart. I could hardly lie there I had gotten so sick while I was out killing time. I was in a panic attack and felt so sick. I don’t know how I stayed under that machine. I can see now I was pushed to the max. Something was activated..could it have been HHV6 or EBV? I bet it was. The test results were fine and I was asked if I was having trouble at home. There is no doubt in my mind that the flu shot kicked it all off.
Same. Flu shot in 2011 — ME 10 days later. Although do you think that any next infection or stressor could have set it off? I wonder that question all the time!
That year 1093, was the most stressful of my life but that year things bothered me more for some reason. I think the flu shot was probably the last straw.
James, I agree that even vacations can be stressful can be stressful, all the arrangements and the packing and on and on. It is the way we are we cannot deal with stress of any kind.
I do have some tricks, plan way ahead. I have to do that with company and holidays. People think I am very organized and even laugh about it.. LOL No need to explain they would not understand anyway.
Marg, Would you be willing to share any of your organization tips with me when you’re up to it? Or anyone else who is “organized.”
Pre-ME I had no problems with organization, but now…
I’m moderately ill, housebound approx. 80%. I keep telling myself there must be some way to stay organized, but after eighteen years I still don’t have it figured out.
My email is email@example.com
The trick that helps me the most is getting things done way ahead of time and not having to worry about any of them. I cook when I feel like it and freeze. I love to entertain and I can now but not without the freezing of most everything and doing one thing in a day. Getting the house ready 1 room at a time in a day or a few. I have found that that takes the stress away.
My husband was in the military and we have friends all over the place and relatives as well. I keep in touch for Xmas and do the cards as I feel like it starting in October. I write a short note on each not a news type letter. I sometimes think I will give that up but I love hearing just a little something from each.
Most of them know I have been very sick but do not understand any of it.
I schedule appointments ahead as well and sometimes I have to cancel but oh well!
Is anyone on this list getting a lot of snow. We are originally from near Buffalo NY but I don’t think they will be hit hard. Myself I would love to see a few flakes. We once had two inches.. LOL
Stress comes in many forms (good and bad) and sends my immune system into complete overdrive. As a long-time ME/CFS sufferer, I don’t believe my immune system has any trouble killing off pathogens. The role pathogens play in chronic fatigue syndrome (ME/CFS) is controversial. Although the disease is often triggered by an infection, I believe the triggering infection is simply the last stressor that tipped the vulnerable patient over into an autoimmune illness. The fact that women have enhanced immune systems compared to men increases women’s resistance to many types of infection, but also makes them more susceptible to autoimmune illnesses including ME/CFS. As far as I’m concerned, there is absolutely nothing down-regulated regarding my natural killer cells; my NK cells are always performing at a frenzied rate.
One theory, Rachel, is that the NK cells are actually burnt out – that they are so overactivated that they’re burning themselves out and that’s what’s causing the dysfunction…
I know that’s not what’s happening in my case of ME/CFS Cort; not sure about others with this illness. I’m actually amazed that my immune response is not dampening with age (closing in on 60 years of age). I never get colds, flues or infections, but I do over-react to to common environmental molecules such as some foods, airborne particles and chemicals. I am allergic, up-regulated and always immune-activated..
I’m surprised when some posters with ME/CFS state that they are also suffering from cancer. Cancer is more likely to develop in people with poor immune function. Perhaps, in this group of ME/CFS sufferers NK cells are burnt out lending them vulnerable to illnesses of a depleted or weak immune system. They are also probably less able to fight off viruses and infections.
I read somewhere, Nightingale site maybe, there was an increased incidence of Thyroid cancer with M.E.
My NK cell count is very low. I had a thyroidectomy and radiation for thyroid cancer five years into the illness. Seven years later I had the upper L. lobe of my lung removed due to lung cancer. However…I rarely “catch” any contagious illnesses going around.
Does anyone know if there’s a way to boost NK cells?
I don’t have an easy answer, but your question about boosting NK cells, led me to consider, that while cortisol suppresses the immune system and directly inhibits natural killer NK cell activity. Conversely, prolactin, a hormone secreted by the anterior pituitary is an immunostimulatory cytokine, that directly increases NK cell function. Dopamine is sometimes called the prolactin-inhibiting factor or PIF. Dopamine inhibits the secretion of prolactin produced by your anterior pituitary gland. So, lowering dopamine levels may stimulate prolactin secretion, thus stimulating NK cells.
When I was first tested for NK cells they were only working at 5%. Imunivor and LDN brought them to high normal. I have not had Imunivor for a while and I am due for a test.
I have been doing quite well but pace. I have recently done a little painting.the of the sides of an island in my kitchen. It took three days. The first day with the primer I was very tired and decided to wait two days by afternoon I was ready to go again. I finished the next morning surprising myself.
Paint has changed a lot since I last painted. There was no smell at all to the primer and very little to the paint. I was worried about the smell.
That is the thing I was never sick when I was very sick. The last few days I have been having a problem with sinuses like I used to. I used to have a terrible time but not when I was very sick. It is I was never sick when I was sick. I hope this is a good sign.
Could the dysfunctional NK cells account for higher rates of cancer among ME/CFS folk?
What confuses me is that I have cancer, yet I never get viral illnesses. Something is obviously screwed up.
WHY does the CDC do research using the way-too-broad Empricial criteria, which – as you say, Cort – increased the “prevalence” 4x and clearly isn’t the narrow criteria we need for meaningful ME/CFS research?
Why spend money on research and do it in such a sloppy way?
It looks like more of the same since the decision they made to not include the 2-day CPET test in their multisite study, but just a 1-day test, which research already has demonstrated will show noting in ME/CFS patients. The 2-day test in their study could really have made a difference. An NK cell study with a narrowly defined patient group with mandatory PEM could have made a difference.
Why don’t they want meaningful progress??
The CDC does believe in the Empirical definition – they think it accurately parses out ME/CFS patients. Unfortunately nobody else does.
With their new emphasis on patients seeing ME/CFS experts the problems with the Empirical definition and random population sampling are essentially gone – at least for now…
My eldest dtr. had a lumpectomy in her breast. (I’ve had breast cancer), the stress of worrying about her, while she lives on the other coast from me, caused my mouth to break out in cold sores all over my mouth and lips! I’ve already lost one adult son to illness, and couldn’t imagine going through this grief again.
It’s really good to know that other people are also experiencing getting sick when their symptoms have gone away, I wondered what was going on. Since developing ME/CFS symptoms I haven’t caught as much as a cold but put it down to my healthy living regime. I’ve noticed I keep catching stomach bugs though which lay me out for 24 hours. It’s so annoying when you actually have a stretch of a few symptom-free days and then get sick just when you wanted to clean the house, catch up with friends, etc! The thing that always gets me is how much sympathy you get when you’re “sick” when actually those days are like a holiday from the real illness.
Exactly. What is usually called sick is like a holiday to what we go through every day.
Not to dismiss the ending part regarding the many definitions used by those doing these studies, but the finding makes sense to me. I always note a delayed reaction.