Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multip

IrisRV

Well-Known Member
@IrisRV What is IIRC?
If I recall correctly. Which I often don't. ;)

I haven't had NK cells measured. I saw one site for measuring them, it looks expensive. Maybe insurance pays for it???
Mine are paid for, but I don't know what hoops my ME specialist had to jump through to make that happen. It probably helps that she's a highly respected academic immunologist, so the insurance company weenie know-nothing so-called medical specialist didn't dare claim he or she know more about the matter than my doc. And I have really good insurance.

It is apparently well established in the literature that psychological stress can cause reduced NK cell function.
Not to the extent ours is reduced, I believe. The magnitude of the drop in function does matter.
Cytokine disturbances and NK cell dysfunction has been documented in PTSD for example.
Again, details matter. There are a lot of cytokines, two directions they can be disturbed, and a large range in which the magnitude can vary. Vague minor similarities in lab results occur across all kinds of diseases. It's more the complex patterns that matter. Vague similarities like some cytokines change in some way in different diseases don't mean much. Probably hundreds of diseases have some cytokine disturbance. That doesn't mean the diseases are related. Now if the patterns (which cytokines changed in which direction and how much) are very similar, that's another matter.

"NK cell dysfunction" may or may not mean the far below normal range NK cell function seen in ME. Details matter.

The study I found about NK cells and psychological stress studied NK cell function immediately after (<2 hrs) acute stress (novice skydivers on their first jumps). They found significant decreases from their normal baseline levels. Significant decrease doesn't mean a plummet far below normal range. Significant means it's noticeable enough that it's not likely to be random. That's not anywhere near the same thing as persistently very low NK cell function, far below normal ranges, for years on end. We are not experiencing acute stress anywhere near that level and yet our NK cell dysfunction tends to be severe. The situations are hardly comparable.

I did not see any papers correlating severe, persistent very low NK cell function with PTSD. That doesn't mean they don't exist of course. :) If you can point to reliable research (done by immunologists, not psychologists) that the cytokine and NK cell function disturbances in psychological stress, PTSD, and ME are very similar in detail, I'd love to see them. It would be interesting to see in what ways the disturbances are alike and in which ways different.

Just so's ya know, I'm not one of the ME patients with persistently very low NK cell function, so I don't have a dog in this fight. I just think we need to look at these issues as the complex issues they are and not grossly oversimplify them.

When highly knowledgeable immunologists who also study ME think these immune disturbances mean something, I'm inclined to listen.
 
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IrisRV

Well-Known Member
I think its perforin thats used by nk cells to kill viruses and these nk researchers are finding that perforin is the reason why nk function is low. As for why this is so ??
I think in ME patients it could be a consequence of dysautonomia. NK cells express beta-adrenergic receptors, the activation of which suppresses their activity, so excess sympathetic nervous system tone could be one possible explanation.
Sorry, I didn't catch what perforin has to do with dysautonomia. Or are you disagreeing with the research immunologists' finding that perforin is the reason why NK cell function is low and suggesting your own hypothesis as an alternative reason? I'm not really up on the details of this stuff.
 

Strike me lucky

Well-Known Member
I'm not sure that studying this particular aspect of the disease is ever going to get us far. It is apparently well established in the literature that psychological stress can cause reduced NK cell function. Cytokine disturbances and NK cell dysfunction has been documented in PTSD for example.


Griffith university nk research aretrying to develop a biomarker for cfs by trying to distinguish the different parts of the nk cell. They have found the cfsers generally have lower nk bright cell function compared to dim cells.

I know they are trying to compare their results with other illnesses to help refine a cfs diagnosis. It could be a matter of how low ones nk function is or for how long, as they have done immune testing over long periods of time as well as researching severely affected bedridden patients. Bedridden patients one would think should be able find a difference compared to depression, i hope.

But also i dont think nk function should be used or would be used in isolation but along with the Canadian criteria and other tests eg cytokine studies, rnasel, 2 day cpet test, to help come to a diagnosis of cfsme.

Having low nk function no matter what condition someone has could make them more prone to viruses and cancers.
 

weyland

Well-Known Member
Sorry, I didn't catch what perforin has to do with dysautonomia. Or are you disagreeing with the research immunologists' finding that perforin is the reason why NK cell function is low and suggesting your own hypothesis as an alternative reason? I'm not really up on the details of this stuff.
Immune function is partially regulated by both branches of the autonomic nervous system. NK cells have adrenergic receptors on them. When these receptors are activated, this seems to reduce NK cell cytotoxicity.
 

weyland

Well-Known Member
I did not see any papers correlating severe, persistent very low NK cell function with PTSD. That doesn't mean they don't exist of course. :) If you can point to reliable research (done by immunologists, not psychologists) that the cytokine and NK cell function disturbances in psychological stress, PTSD, and ME are very similar in detail, I'd love to see them.
I'm not that familiar with the psych literature (nor do I want to be) so I can't point to any specific studies. I have just seen it stated that a th2 shift and low NK function is seen in PTSD.

I'm just pointing out the difficulty in using things like NK cell dysfunction, herpes reactivations, cytokine changes, etc. as proof of organicity in ME when the psych literature has already claimed a lot of these things under the banner of psychological stress. So you're right, details matter. Research in these areas has to be in depth and has to prove that the reasons why they are occurring in ME is different from chronic psychological conditions. To be clear I don't think these things have anything to do with psychological causes in ME, but you can bet the BPS crew think they do.
 

IrisRV

Well-Known Member
Immune function is partially regulated by both branches of the autonomic nervous system. NK cells have adrenergic receptors on them. When these receptors are activated, this seems to reduce NK cell cytotoxicity.
I get that part. Unfortunately, it doesn't answer my question.
sorry, I didn't catch what perforin has to do with dysautonomia. Or are you disagreeing with the research immunologists' finding that perforin is the reason why NK cell function is low and suggesting your own hypothesis as an alternative reason?
I'm not that familiar with the psych literature (nor do I want to be)
I can certainly understand that! I don't either.

I don't trust immunology studies done by psychologists. Immunology is way too complex for someone without any medical training to dabble in with any credibility. I also wouldn't trust podiatrists to do neurology research or immunologists to represent me in court. ;)
I'm just pointing out the difficulty in using things like NK cell dysfunction, herpes reactivations, cytokine changes, etc. as proof of organicity in ME when the psych literature has already claimed a lot of these things under the banner of psychological stress.
Heck, they claim everything. Basically they've been claiming anything related to poorly understood illnesses under psychological conditions for decades. All the symptoms of MS, including paralysis, were claimed to be the result of hysteria. Ulcers were caused by to stress. Autism was caused by emotional damage from poor parenting.

We can't refuse to acknowledge or research very real ME symptoms and findings because psychologists claim them. Anything we come up with they'll claim is related to stress, so it doesn't matter. They don't need real substantive evidence because they don't distinguish a hypothesis from a conclusion, nor do they understand that correlation is not causation. We just need to keep on supporting good science wherever it leads and ignore the idiocy of the psychobabblers. They are always proved wrong eventually when the mountain of biological evidence completely overwhelms them. They'll just keep moving on to the next poor sods.

At some point they'll be reduced to "proving" that sprained ankles and broken fingernails are caused by stress. A much higher percentage of people working long hours at hard physical labor (under stress) sprain their ankles and break their nails compared to people relaxing on the beach (not under stress). Ergo, sprained ankles and broken nails are caused by stress. Stress-related conditions can be treated with CBT, therefore sprained ankles and broken nails can be cured by CBT. Nice heaping plates of logical fallacies all around!
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
One thing I would like to point out about NK cells that often doesn't get mentioned - the Broderick/Klimas Miami group believes something in the blood is responsible for deactivating them. They realized that when one study which tested cytotoxicity in NK cells in isolation found that they functioned just fine.

One of the things Ron Davis wants to do in his study is find what's turning them off. I can think of two alternatives: there could have receptors on their surface that allows something in the blood to turn them off or there could be an increased abundance of a substance in the blood that naturally turns them off. Every immune cell must have an on/off switch so to speak.
 

RuthAnn

Well-Known Member
I saw one study where perforin is provided by CD8 T cells, not only NK. So if one has a deficiency in CD8 T cells, it could affect NK activity.

I would go get the links (and double check myself) but I am trying to do several things at the same time this morning. Before I get tired.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
That's right - and T-cell killing is apparently down in ME/CFS as well. That's a pretty darn big hit to the immune system..
I saw one study where perforin is provided by CD8 T cells, not only NK. So if one has a deficiency in CD8 T cells, it could affect NK activity.

I would go get the links (and double check myself) but I am trying to do several things at the same time this morning. Before I get tired.
 

RuthAnn

Well-Known Member
One thing I would like to point out about NK cells that often doesn't get mentioned - the Broderick/Klimas Miami group believes something in the blood is responsible for deactivating them. They realized that when one study which tested cytotoxicity in NK cells in isolation found that they functioned just fine.

One of the things Ron Davis wants to do in his study is find what's turning them off. I can think of two alternatives: there could have receptors on their surface that allows something in the blood to turn them off or there could be an increased abundance of a substance in the blood that naturally turns them off. Every immune cell must have an on/off switch so to speak.
Although for this I would put my money on the calcium channel.

"
Signaling through CD38 induces NK cell activation.

Mallone R1, Funaro A, Zubiaur M, Baj G, Ausiello CM, Tacchetti C, Sancho J, Grossi C, Malavasi F.
Author information


Abstract

Human CD38 is a signal transduction molecule, and, concurrently, an ectoenzyme catalyzing the synthesis and degradation of cyclic ADP-ribose (cADPR), a potent Ca2+ mobilizer. One facet of CD38 that has not yet been addressed is its role in NK cells. To this end, the events triggered by CD38 ligation with agonistic mAb were analyzed on freshly purified human NK cells. Ligation was followed by (i) a significant rise in the intracellular level of Ca2+, (ii) increased expression of HLA class II and CD25, and (iii) tyrosine phosphorylation of discrete cytoplasmic substrates. The phosphorylation cascade involved CD3-zeta and FcepsilonRIgamma chains, zeta-associated protein (ZAP)-70 and the proto-oncogene product c-Cbl. NK effector functions were then analyzed: CD38 signaling was able (iv) to induce release of IFN-gamma and, more prominently, of granulocyte macrophage colony stimulating factor, as assessed by measuring both mRNA and protein products; and, lastly, (v) to induce cytolytic effector functions on target cells after IL-2 activation, as shown both by cytotoxicity assays and ultrastructural changes. The tyrosine-phosphorylated substrates and all the effects mediated by CD38 were similar to those observed following triggering via CD16 (FcgammaRIIIA); moreover, Ca2+ mobilization via CD38 no longer operated in NK-derived cell lines lacking CD16. These results suggest that the activation signals transduced by CD38 in NK cells elicit relevant cellular events. The effects are similar to those elicited via CD16 and possibly rely on common signaling pathways."
 

IrisRV

Well-Known Member
I saw one study where perforin is provided by CD8 T cells, not only NK. So if one has a deficiency in CD8 T cells, it could affect NK activity.

I would go get the links (and double check myself) but I am trying to do several things at the same time this morning. Before I get tired.
Well now, that's interesting. Over the past few years (as long as I've been tested), I've had very low (and continuously dropping) CD8+ cell numbers, but high-normal to slightly high NK cell function. My latest test shows a small increase in CD8+ cells (I'm pretty sure, need to dig out the old tests), but for the first time, low N cell function. It's not severely low like in many PWME, but a big drop.

IIRC, Griffith has been saying that PWME typically have low NK cell function or low CD8 cell count (although that part usually gets ignored by the patient population). I've been wondering what the connection is. Maybe perforin is behind something big.

@RuthAnn, any hope of a very brief translation of that abstract for the cognitively impaired, preferably with words of few syllables? :p
 

RuthAnn

Well-Known Member
Ca2+ mobilization via CD38 no longer operated in NK-derived cell lines lacking CD16
NK cells need an influx of calcium in order to operate.

When they are lacking CD16 the CD38 no longer will make the calcium go into the NK cells.

"CD16 :

It is a cluster of differentiation molecule found on the surface of natural killer cells,neutrophil polymorphonuclear leukocytes, monocytes and macrophages.[1]These receptors bind to the Fc portion of IgG antibodies which then activates the NK cell forantibody-dependent cell-mediated cytotoxicity. A lack of CD16 in a given population of neutrophils may indicate prematurity, as could be caused by a left shift due to neutrophilic leukocytosis induced by tissue necrosis or bacterial infection.[2]"

So I don't know what would cause a lack of CD16 in NK cells, but as in the above paragraph, lack of CD16 in neutrophils has a listed cause. Although this paragraph may give another clue, lack of IgG antibodies on the NK cells.
 

RuthAnn

Well-Known Member
This might be a strange tangent, but I've been wondering about why rituximab might cause increase in NK cells, and then if we could just find out why, it might have some clues.

I just looked up rituximab with CD16 and found this:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1988936/
Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the FcγRIIIa-158 V/V and V/F polymorphism

I'm not sure what it means yet. Maybe I can find something on the subject that is easier to understand.
 

RuthAnn

Well-Known Member
This is easier to understand, but I'm still not sure what it means. I know that someone who has GWI, which involves high NK cell counts does not do well with rituximab, and that rituximab raises NK cell levels.

"
Rituximab infusion induces NK activation in lymphoma patients with the high-affinity CD16 polymorphism.

Veeramani S1, Wang SY, Dahle C, Blackwell S, Jacobus L, Knutson T, Button A, Link BK, Weiner GJ.
Author information


Abstract

Natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity involving FcγRIIIa (CD16) likely contributes to the clinical efficacy of rituximab. To assess the in vivo effects of CD16 polymorphisms on rituximab-induced NK activation, blood was evaluated before and 4 hours after initiation of the initial dose of rituximab in 21 lymphoma subjects. Rituximab induced NK activation and a drop in circulating NK-cell percentage in subjects with the high-affinity [158(VF/VV)] but not the low-affinity [158(FF)] CD16 polymorphism. There was no correlation between NK-cell activation or NK-cell percentage and polymorphisms in CD32A, C1q, or CH50. We conclude that NK activation occurs within 4 hours of rituximab infusion in subjects with the high-affinity CD16 polymorphism but not those with the low-affinity CD16 polymorphism. This finding may help explain the superior clinical outcome seen in the subset of high-affinity CD16 polymorphism lymphoma patients treated with single-agent rituximab."

I don't know if I will ever understand it because I don't understand polymorphism.
 

weyland

Well-Known Member
I get that part. Unfortunately, it doesn't answer my question.
I'm saying that perforin production or release may be diminished by activation of beta adrenergic receptors on NK cells. Hyperadrenergic states are known to occur in dysautonomia.
 

IrisRV

Well-Known Member
I'm saying that perforin production or release may be diminished by activation of beta adrenergic receptors on NK cells. Hyperadrenergic states are known to occur in dysautonomia.
Finally got it! Thanks for your help!
 

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