NK cells and SNP of specific ion channels and receptor genes in ME/cfs

[Valentijn]

Are you sure they've done that, Val? I can't see it stated anywhere in the paper. But I'm struggling to interpret much of it.

It's the only explanation for the figures, and patient percentage + control percentage in each row adds up to 100%. They did the same thing in a (different) prior letter they published.

 

[adreno]

In the following (in vitro) study, viral infection increased the expression of ion channels. This was mitigated by astragalus and taurine.

http://link.springer.com/chapter/10.1007/978-1-4615-0455-9_28

Astragalus has also been shown to reduce autoantibodies in MG and increase NK cells.

 

[anciendaze]

Here's a quote from an on-line source which probably traces back to Wikipedia:

NK cells are activated in response to interferons or macrophage-derived cytokines.

They serve to contain viral infections while the adaptive immune response is generating antigen-specific cytotoxic T cells that can clear the infection.

Patients deficient in NK cells prove to be highly susceptible to early phases of herpes virus infection.

Please note that the term deficient only talks about numbers of NK cells, not NK cell activity. It is possible to have normal numbers of NK cells which are mysteriously ineffective. Also, the term "herpes virus" applies to far more than HSV. It includes EBV, VZV, CMV and HHV-6.

A defect in ion channels on NK cells could thus be related to other findings common, and commonly controversial, in this disease.

While we're talking controversy, I'm expecting findings about activated HERVs in immune cells to become much more widespread. This would tie in with diseases where rearrangement of genes in immune cells is accelerated.

 

[anciendaze]

Just as an indication that even very specific types of ion channels mentioned in this research have broad biochemical significance beyond NK cells I'm linking this article about them.

 

[adreno]

More on astragalus and calcium channels:

AS-IV induced the shift of L-type Ca(2+) channels from either brief openings (mode 1) or long-lasting openings (mode 2) to no active opening (mode 0). Our results suggest that AS-IV blocks the currents through Ca(2+) channels in guinea-pig ventricular myocytes by affecting the open-closed kinetics of L-type Ca(2+) channels to inhibit the channel activities. This study could provide theoretical basis for the drug exploiting of the monomer of Astragalus membranaceus.

http://www.ncbi.nlm.nih.gov/pubmed/25891370

 

[anciendaze]

It's the only explanation for the figures, and patient percentage + control percentage in each row adds up to 100%. They did the same thing in a (different) prior letter they published.

I'm afraid you are right Valentijn. Unfortunately, the best solution for such statistical false leads is larger data sets. This gets into research politics because it requires more money, not to mention solid diagnostic criteria. From a purely political standpoint an entrenched professional majority opinion has a near perfect defense to change. No really statistically significant results are possible without gaining majority approval in advance.

 

[Valentijn]

No really statistically significant results are possible without gaining majority approval in advance.

If they restrict the number of SNPs they're looking at to the ones with the biggest difference in the current study, statistical power should be attainable in a follow-up study. Or it could have been performed as part of the current study, with one set of patients used to generate the data, and the rest used to confirm it.

 

[anciendaze]

If they restrict the number of SNPs they're looking at to the ones with the biggest difference in the current study, statistical power should be attainable in a follow-up study. Or it could have been performed as part of the current study, with one set of patients used to generate the data, and the rest used to confirm it.

True, as far as it goes, though a follow-up study requires more funding. Which takes us back to my concern that changes in opinion by committees evaluating grants must precede statistically valid evidence.

The problem with the altered version of the current study you propose would then become one of creating new methods of data analysis during a study, which has been misused in some notable examples. Planning this from the start would have avoided criticism, but was not proposed. This is pretty standard in research.

If you keep analyzing data long enough I'm sure you can show that both Barack Obama and Donald Trump are The Beast (Θηρίον) described in The Apocalypse of John.

 

[anciendaze]

This may be off-topic, but it has considerable relevance. I've started discussing these results with private correspondents who are not on this forum. Part of the dialogue sounds like "Calcium channels? Acetylcholine? These things have been studied for ages. How did such associations with any disease get overlooked?"

One correspondent who had previously been hit with a tirade of mine about neurotransmitters and their effect on immune cells and functions remarked that the words "humility" and "medicine" should not be used in the same sentence unless interactions are mediated by the "lack" verb or modifier. This correspondent has an M.D.

 

[jimells]

Perhaps, like everything else associated with this illness, it's more complicated than we've ever previously imagined.

I recall Professor Edwards stating that the process that results in RA involves 50 steps. It's truly a miracle anything that complicated can be sorted out.

 

[Comet]

I recall Professor Edwards stating that the process that results in RA involves 50 steps. It's truly a miracle anything that complicated can be sorted out.

Which is why the Medicals (docs, etc) shouldn't jump to conclusions. Sorry for OT. Just throwing in a snark.

 

[wastwater]

I have seen the fruit fly drosophila mentioned in my book on Axenfeld Riegers syndrome.
And have seen calcium channels mentioned in autism before

 

[Jonathan Edwards]

I totally don't understand the abstract. Does anyone understand any of it?

I am afraid I am with you there Bob. Someone may explain but I see no point in looking for SNPs in NK cells since they are in the genome and in all cells. Their presence says nothing about them being relevant to NK function I would have thought. You can get somatic mutations at single sites producing dominant haemopoietic precursor clones with a novel deletion. The best example is paroxysmal nocturnal haemoglobinuria if I remember rightly, with stem cells that fail to express CD55. But I cannot see that being in any way relevant to a statistical analysis of SNPs across a population. I just don't follow the logic of the paper. But I may be missing something.

I am also puzzled by the statement that NK cytotoxicity was tested by flow cytometry. OK you might use flow cytometry to look for the dead or not dead cells I suppose but the basic technique will surely be something like K562 lysis.

I hope we are just muddled, Bob!

 

[Bob]

I am also puzzled by the statement that NK cytotoxicity was tested by flow cytometry. OK you might use flow cytometry to look for the dead or not dead cells I suppose but the basic technique will surely be something like K562 lysis.

The technique is explained on the third page of the PDF, and I think the basic technique was indeed K562 lysis.

 

[Bob]

Someone may explain but I see no point in looking for SNPs in NK cells since they are in the genome and in all cells. Their presence says nothing about them being relevant to NK function I would have thought.

Are NK cells not one of the type of immune cells that regularly mutate?

 

[Jonathan Edwards]

Are NK cells not one of the type of immune cells that regularly mutate?

No, they do not rearrange Ig or TCR genes, or any genes as far as I know. And the SNPs here are not adaptive immune genes anyway. Paroxysmal nocturnal haemoglobinuria is a rare disorder - I never saw a case. It is just conceivable that ME is due to a much commoner clonal mutation but then this would have zero prevalence in the controls presumably. By and large stem cell genomes have to be very very stable - so that you go on making healthy cells for 90 years. I simply cannot see any reason why one might think finding these SNPs in NK cells was relevant. And presumably if one did think it was special to NK cells it would be necessary to do some other cels as well - like a buccal smear or something.

 

[alicec]

Does anyone understand any of it?

Well I think I understand what they are saying but I don't understand why they would do such a study or why they think it means anything, or why the journal published it.

Earlier in this thread people seemed to think the authors were saying that these SNPs were peculiar to NK cells but that is not so. They just chose to look in NK cells for this particular study.

Previously they had looked at similar SNPs in mononuclear cells (PBMNCs; the study referred to by @Valentijn). That study is discussed, along with claims by the group to be developing a diagnostic test for CFS/ME, in this thread.

In the NK study they have analysed a broader range of SNPs and have added an assay of NK cell function, but essentially it is just a repeat of the PBMNC study - very small number of subjects and the same dodgy statistics.

The expansion has enabled them to claim a publication rather than a letter to the editor which was all they could manage for the previous very thin study. This seems like an attempt to boost publication numbers.

Even if the numbers and statistics gave one more confidence in the study, it makes no sense to study SNPs in different cell populations and imply that their presence their has some implication for function.

The SNPs are genome-wide and would be found in any cell examined.

SNPs in ion-channels could well be a fruitful avenue of research in CFS/ME but the SNP studies by this group so far are abysmal.

 

[Bob]

No, they do not rearrange Ig or TCR genes, or any genes as far as I know. And the SNPs here are not adaptive immune genes anyway. Paroxysmal nocturnal haemoglobinuria is a rare disorder - I never saw a case. It is just conceivable that ME is due to a much commoner clonal mutation but then this would have zero prevalence in the controls presumably. By and large stem cell genomes have to be very very stable - so that you go on making healthy cells for 90 years. I simply cannot see any reason why one might think finding these SNPs in NK cells was relevant. And presumably if one did think it was special to NK cells it would be necessary to do some other cels as well - like a buccal smear or something.

They say they've previously found similar SNPs (specifically TRPM3) in peripheral blood mononuclear cells, so I'm not sure why they carried out the same study on NK cells. See details of the earlier study in an earlier comment in this thread, here. I haven't read the other study and don't know exactly what similarities they found.

Edit. I see there's a thread on the other study...

That study is discussed, along with claims by the group to be developing a diagnostic test for CFS/ME, in this thread.

 

[Jonathan Edwards]

They say they've previously found similar SNPs (specifically TRPM3) in peripheral blood mononuclear cells, so I'm not sure why they carried out the same study on NK cells. See details of the earlier study in an earlier comment in this thread, here. I haven't read the other study and don't know exactly what similarities they found.

Edit. I see there's a thread on the other study...

@alicec makes sense to me. I think we all have the same problem.

 

[Kati]

Personally I think it matters a lot to know what is happening in the NK cells considering that they are not working well for us. This group decided to look at genes and found gene mutation affecting the calcium channels. It is relevant because it's been shown many times that our NK cells are dysfunctional. Dr Marshall-Gradisnik and team are researching into this further, and I am so ever thankful. Genes in a group of cells turn on or turn off depending whether they wre needed or not. So (and again i may make a fool of myself) it is important to know whether some genes that are supposed to be important for important functions are functioning as they should or have mutated.

I prefer this kind of research, to get to the bottom of things, instead of having a clinician telling me that my brain is freaking out, and the treatment is CBT and GET. This is what is happening currently in many parts of the world. Science, please! We need more of that.

@Jonathan Edwards I believe the Australian team will be present at Invest in ME, so it would be a great opportunity to find out more.