ncned study nk cells, intracellular signalling.

Strike me lucky

Well-Known Member
Another study put out by ncned


http://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-0859-z

Natural Killer (NK) cell effector functions are dependent on phosphorylation of the mitogen-activated protein kinases (MAPK) pathway to produce an effective immune response for the clearance of target cells infected with viruses, bacteria or malignantly transformed cells. Intracellular signals activating NK cell cytokine production and cytotoxic activity are propagated through protein phosphorylation of MAPKs including MEK1/2, ERK1/2, p38 and JNK. Reduced NK cell cytotoxic activity is consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients and intracellular signalling by MAPK in NK cells remains to be investigated. Therefore, the purpose of this paper was to investigate MAPK downstream signalling molecules in NK cell phenotypes from CFS/ME patients.

Methods
Flow cytometric protocols were used to measure phosphorylation of the MAPK pathway in CD56brightCD16dim/− and CD56dimCD16+ NK cells following stimulation with K562 tumour cells or phorbol-12-myristate-13-acetate plus ionomycin. NK cell cytotoxic activity, degranulation, lytic proteins and cytokine production were also measured as markers for CD56brightCD16dim/− and CD56dimCD16+NK cell function using flow cytometric protocols.

Results
CFS/ME patients (n = 14) had a significant decrease in ERK1/2 in CD56dimCD16+ NK cells compared to the non-fatigued controls (n = 11) after incubation with K562 cells. CD56brightCD16dim/− NK cells from CFS/ME patients had a significant increase in MEK1/2 and p38 following incubation with K562 cells.

Conclusions
This is the first study to report significant differences in MAPK intracellular signalling molecules in CD56dimCD16+ and CD56brightCD16dim/− NK cells from CFS/ME patients. The current results highlight the importance of intracellular signalling through the MAPK pathway for synergistic effector function of CD56dimCD16+ and CD56brightCD16dim/− NK cells to ensure efficient clearance of target cells. In CFS/ME patients, dysfunctional MAPK signalling may contribute to reduced NK cell cytotoxic activity.
 

Who Me?

Well-Known Member
The immunologist I just saw said NK cell function meant nothing. But he also said it wasn't viral so who knows?
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
Another study put out by ncned


http://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-0859-z

Natural Killer (NK) cell effector functions are dependent on phosphorylation of the mitogen-activated protein kinases (MAPK) pathway to produce an effective immune response for the clearance of target cells infected with viruses, bacteria or malignantly transformed cells. Intracellular signals activating NK cell cytokine production and cytotoxic activity are propagated through protein phosphorylation of MAPKs including MEK1/2, ERK1/2, p38 and JNK. Reduced NK cell cytotoxic activity is consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients and intracellular signalling by MAPK in NK cells remains to be investigated. Therefore, the purpose of this paper was to investigate MAPK downstream signalling molecules in NK cell phenotypes from CFS/ME patients.

Methods
Flow cytometric protocols were used to measure phosphorylation of the MAPK pathway in CD56brightCD16dim/− and CD56dimCD16+ NK cells following stimulation with K562 tumour cells or phorbol-12-myristate-13-acetate plus ionomycin. NK cell cytotoxic activity, degranulation, lytic proteins and cytokine production were also measured as markers for CD56brightCD16dim/− and CD56dimCD16+NK cell function using flow cytometric protocols.

Results
CFS/ME patients (n = 14) had a significant decrease in ERK1/2 in CD56dimCD16+ NK cells compared to the non-fatigued controls (n = 11) after incubation with K562 cells. CD56brightCD16dim/− NK cells from CFS/ME patients had a significant increase in MEK1/2 and p38 following incubation with K562 cells.

Conclusions
This is the first study to report significant differences in MAPK intracellular signalling molecules in CD56dimCD16+ and CD56brightCD16dim/− NK cells from CFS/ME patients. The current results highlight the importance of intracellular signalling through the MAPK pathway for synergistic effector function of CD56dimCD16+ and CD56brightCD16dim/− NK cells to ensure efficient clearance of target cells. In CFS/ME patients, dysfunctional MAPK signalling may contribute to reduced NK cell cytotoxic activity.
I'll have to look at this more but cause of the NK cell problems in ME/CFS has been a mystery. This study appears to suggest, if I'm reading it correctly, that ME/CFS patients have a significant reduction in a signaling pathway that turns on NK cells compared to healthy controls.
 

bobby

Well-Known Member
NCNED FB page said:
This paper identifies pathological changes in vital signalling pathways in ME/CFS. These pathways exert a major influence over cell functioning suggesting important fundamental steps in the development of the pathomechanism of ME/CFS.
NCNED research team said:
In this group, we see that dysfunctional signalling may contribute to impaired cell activity. These findings are consistent with our previous findings and align with the presentation of symptoms in patients,” says Professor Staines.

The current research findings build upon recent discoveries including novel identification of key genetic changes in cells of the immune system.
https://app.secure.griffith.edu.au/news/2016/05/11/further-clues-in-the-fight-against-chronic-fatigue-syndrome/
 

bobby

Well-Known Member
I tried to decipher this study to the best of my abilities. And yes, I did use an Australian children's encyclopedia for more information about the immune system. :joyful: Comments are very welcome. Not sure if I'll be able to answer any questions. :rolleyes:

NK cells are immune cells that are supposed to help kill the bad stuff. Previous NCNED research has shown that NK cells in ME/CFS are dysfunctional. The job of NK cells is: producing cytokines (aka communicating with other immune cells) and starting cytotoxic activity (aka killing off beasties).

In order to start their job, NK cells need some sort of alarm signal. This alarm signal happens through a pathway called MAPK. This MAPK pathway had not been researched yet in ME/CFS patients. Dysfunctional MAPK signalling has previously been linked to illnesses like leukaemia, diabetes, Alzheimer’s and Parkinson’s disease, atherosclerosis, arthritis and airway inflammation. So that is why they thought it would be interesting to study it in ME/CFS as well.

So basically the researchers found that this alarm signal (MAPK) in ME/CFS patients is dysfunctional, which leads them to believe that this is what is making the NK cells dysfunctional as well. (The reason behind the dysfunctional MAPK would be an interesting next step to investigate, they say.)

A whole range of subsets of NK cells were looked at. Abnormalities were only found in two subsets of NK cells: CD56dimCD16+ (we’ll call it (+) ) and CD56brightCD16dim/− (we’ll call it (-) ).

In (+) they found a REDUCTION of ERK1/2. Reduced ERK1/2 is linked to reduced cytotoxicity (aka inability to kill off beasties).

In (-) they found an INCREASE in MEK1/2 and p38. Increased p38 and MEK1/2 is linked to increased cytokine production (aka inflammatory response).

The hypothesis of the researchers seems to be this: because of continual contact with target cells (aka beasties), our NK cells become desensitized. The NK cells somehow go into a dysfunctional mode where they keep secreting cytokines (aka inflammation), without increasing cytotoxic activity (aka not killing off anything).

This echoes previous findings of our immune system being both underactive and overly active at the same time.

As usual, this was a small study, so results are not yet 100% conclusive.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
I tried to decipher this study to the best of my abilities. And yes, I did use an Australian children's encyclopedia for more information about the immune system. :joyful: Comments are very welcome. Not sure if I'll be able to answer any questions. :rolleyes:

NK cells are immune cells that are supposed to help kill the bad stuff. Previous NCNED research has shown that NK cells in ME/CFS are dysfunctional. The job of NK cells is: producing cytokines (aka communicating with other immune cells) and starting cytotoxic activity (aka killing off beasties).

In order to start their job, NK cells need some sort of alarm signal. This alarm signal happens through a pathway called MAPK. This MAPK pathway had not been researched yet in ME/CFS patients. Dysfunctional MAPK signalling has previously been linked to illnesses like leukaemia, diabetes, Alzheimer’s and Parkinson’s disease, atherosclerosis, arthritis and airway inflammation. So that is why they thought it would be interesting to study it in ME/CFS as well.

So basically the researchers found that this alarm signal (MAPK) in ME/CFS patients is dysfunctional, which leads them to believe that this is what is making the NK cells dysfunctional as well. (The reason behind the dysfunctional MAPK would be an interesting next step to investigate, they say.)

A whole range of subsets of NK cells were looked at. Abnormalities were only found in two subsets of NK cells: CD56dimCD16+ (we’ll call it (+) ) and CD56brightCD16dim/− (we’ll call it (-) ).

In (+) they found a REDUCTION of ERK1/2. Reduced ERK1/2 is linked to reduced cytotoxicity (aka inability to kill off beasties).

In (-) they found an INCREASE in MEK1/2 and p38. Increased p38 and MEK1/2 is linked to increased cytokine production (aka inflammatory response).

The hypothesis of the researchers seems to be this: because of continual contact with target cells (aka beasties), our NK cells become desensitized. The NK cells somehow go into a dysfunctional mode where they keep secreting cytokines (aka inflammation), without increasing cytotoxic activity (aka not killing off anything).

This echoes previous findings of our immune system being both underactive and overly active at the same time.

As usual, this was a small study, so results are not yet 100% conclusive.
Darn that's a great explanation! It cleared up some stuff for me about NK cells - thanks a lot :) Such a difficult paper. That MAPK finding sounds real interesting.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
The immunologist I just saw said NK cell function meant nothing. But he also said it wasn't viral so who knows?
That's probably because NK cell numbers fluctuate wildly - they are the most variable of immune cells. We definitely didn't luck out with the immune cell we got associated with.

That doesn't mean though that reduced NK cytotoxicity is not a factor.

You might ask him if NK cells do don't diddly why are many clinical trials are trying to manipulate them to stop cancer - and give him the below link. NK cells are the product of a lot of research.

https://clinicaltrials.gov/ct2/results?term=natural+killer+cancer&recr=Open
 

Who Me?

Well-Known Member
No @Cort He specifically said NK cells were irrelevant. He also said that IF I felt better after taking ABX for a mycoplasma infection it was a coincidence and probably treating some unknown thing yet to be found. He said the thing about Viruses. I asked him then why is Montoya giving people valtrex? He referred back to Montoya's study with Valcyte and he said he cherry picked the candidates (I forgot what he said about the criteria). And I said I know people right now who he is rx'ing Valtrex to (not Valcyte) and he refused to accept it.

I have zero interest in pursuing this with him. He was very clear about how he thought and why. I have my notes from them but I have not looked at them. He did say it had something to do with us not having active viruses or infections that our body had memory of those infections and so acted like it still had the infection. Or something like that. It was the total opposite of what many think now.

I will say during the appointment he clearly thought I was not a candidate for immunoglobulin since I have not had 2 or more document with a CT bacterial infections. I also had a pneuovax 13 challenge which he said I had a good response to. But he also said a strong response isn't the entire picture. You have to look at the quality of the response. Then he got my labs back and I believe he was shocked to find I met the DX criteria for CVID.

Now he is testing for ANA, lymphocyte Subsets and pre and post vaccine challenge. He's looking for autoimmune diseases and other rare primary immune diffitiencies
 

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