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The media reports have been sizzling! Griffith University, the home of the NCNED group in Australia that produced the study, called it “groundbreaking”.  IFL Science lead off with a piece called “People With Chronic Fatigue Have A Defective Channel In Immune System Cells” which stated,

“The finding confirms earlier research that CFS is a biological condition, not a psychological one, and opens lines of inquiry for potential treatment options.”

Even a government official got involved telling the Tech Times

“This discovery is great news for all people living with Chronic Fatigue Syndrome (CFS) and the related Myalgic Encephalomyelitis (ME), as it confirms what people with these conditions have long known – that it is a ‘real’ illness – not a psychological issue,” Leeanne Enoch, the Science Minister of Queensland.

Donald Staines, one of the researchers associated with the study, went so far as to say

“This is huge because for the first time we have documented the pathology in this illness. Up until now people have not really understood the illness,” Staines

Natural Killer (NK) Cell Study

The study was putatively on natural killer cells but if the NCNED group in Australia is right NK cells are just the beginning of the story.NK cells are a good place to start, though. Reduced NK cell cytotoxicity is the most consistently found immune aberration found in chronic fatigue syndrome (ME/CFS). Despite several attempts to identify the cause of the NK cell problems in ME/CFS- they haven’t been nailed down yet.

The NCNED group at Griffith University in Queensland, Australia has been digging more deeply into the cause of the NK cell problems in ME/CFS than any other group.

They appear to have had TRP (transient receptor potential) ion channels in their cross-hairs for at least a couple of years. These ion channels allow calcium and magnesium into our cells. Calcium does much more than build strong bones. Inside the cell it plays an essential role in cellular signaling and homeostasis. Changes in calcium concentration also allow our muscles to contract during exercise.Calcium also modulates the activity of many enzymes including mitochondrial enzymes. It affects neurotransmitter release from our nerves. It’s an essential intracellular element; mess with calcium levels and our cells won’t work so well.

But is low calcium the cause of the natural killer cell problems in ME/CFS? In March 2016 the NCNED group looked for and found significantly increased numbers of polymorphisms or mutations in the genes expressing transient receptor potential (TRP) and acetylcholine receptors (AChRs) in people with ME/CFS. That suggested that problems with these ion channels could be limited calcium inflows into our cells.

Crystalline structure of a calcium ion channel

Crystalline structure of a calcium ion channel

Then May 2016, the NCNED team proved that these ion channels exist on natural killer and B-cells(nobody had shown that before), and then showed that fewer than normal of them were present on the NK cells of people with chronic fatigue syndrome (ME/CFS).

The big finding, though, was finding reduced cytoplasmic calcium levels in those cells. That suggested that reduced numbers of ion channels on the NK cells of ME/CFS patients were indeed depriving them of an essential element – and possibly impacting their ability to function

The Study

In the present study  NCNED researchers determined if the reduced numbers of TRPM3 receptors on the NK cells were causing (a) reduced calcium levels in NK cells and more importantly (b) responsible for the reduced NK cell cytotoxicity (killing capacity),

These papers are very difficult to understand. Hopefully most of this is correct.

The Study

The natural killer cells from 15 ME/CFS (Fukuda definition) and 25 healthy controls were labeled with fluorescent antibodies to determine the levels of TRPM3 receptors/ion channels and two other receptors (CD107a, CD69) associated with NK cell activation.

They looked at two kinds of NK cells: the cytotoxic NK cells and NK cells involved in immune surveillance and cytokine production.

They stimulated the cells with various substances (pregnenolone sulphate (PregS), 2-aminoethoxydiphenyl borate (2APB), ionomycin, and thapsigargin (TG)) known to increase intracellular calcium.

The Results

The Gist

  • First the NCNED team found that several mutations trhat were increased in ME/CFS patients affect the ion channels that allow calcium into NK cells
  • Next they determined that the dysfunctional NK cells found in ME/CFS patients were indeed low in calcium – an essential element in cellular functioning
  • Using a series of tests they demonstrated that problems with calcium ion channel functioning exist in two kinds of NK cells in ME/CFS patients
  • Increasing calcium levels returned the NK cells to normal functioning
  • Because the dysfunctional ion channels are found in tissues across the body they could conceivably impact many areas of the body
  • Large studies are needed but the NCNED appears to be confident they’ve uncovered a core pathology in ME/CFS.
  • The next steps are developing a diagnostic test, testing their finding out in larger groups, and looking for pharmaceutical treatments.
  • The NCNED team recently received $4 million to do just that.

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NK Cells Involved in Cytokine Production

At baseline both the number of TRPM3 receptors and the intra-cellular calcium levels were significantly reduced in ME/CFS patients compared to the controls. Given the reduced calcium stores found, the TRPM3 finding was strange. The number of TRPM3 ion channels on the cell should increase when calcium stores are reduced; i.e. ME/CFS patients should have had more ion channel receptors on their NK cells- yet they had less.

Stimulating these cells with a TRPM3 booster to increase cellular calcium levels resulted in increased calcium levels in both groups but reduced calcium levels in the ME/CFS patients relative to the healthy controls; i.e. their calcium levels were up but were still low.

The number of TRPM3 ion channels on the NK cells increased equally in both groups but as noted healthy control NK cells accumulated more calcium. Something was clearly still keeping the calcium levels down in the ME/CFS group.

Cytotoxic NK Cells

The cytotoxic NK cells were different. Stimulating the TRPM3 receptors resulted in increased receptor expression in the healthy controls but not in the ME/CFS patients.

Ionomycin increased TRPM3 expression on the ME/CFS patients’ NK cells compared to the controls, but not enough to increase cytotoxic T-cell activity. That may be because another enzyme (extracellular-regulated kinase (ERK)) needed for that process is depleted in ME/CFS.

The only way the researchers were able to increase cytotoxic T-cell activity in the ME/CFS patients was by whacking their NK cells with a calcium depleter first and then activating them with a ion channel (TRPM3) enhancer.  It appears that the first part of that process – the calcium depleting process – stimulates the enzyme ME/CFS patients are low in.  Once that enzyme is present calcium levels could be increased.

Putting those substances together had no effect on healthy controls who presumably have functioning NK cells.

It’s clearly a complex situation but the takeaway message I got was that both types of NK cells had problems with ion channel (TPRM3) expression and calcium levels.

The TRPM3 Ion Channels

calcium

Is an essential intracellular element – calcium – low in many ME/CFS patients cells?

Because these ion channels allow calcium into the cell, a deficit of these channels could result in reduced intracellular levels of calcium – an essential element. (TRPM3 also controls levels of magnesium in the cell.)  As we’ve seen, deficits in these ion channels were found in both types of NK cells.

The NCNED’s earlier research suggests that ME/CFS patients may have increased levels of mutations in the genes that produce these ion channels. They’ve also found  low intracellular calcium levels in ME/CFS patients NK cell Increasing those levels may help with the NK cell killing problems. The studies are small but the evidence seems to be adding up.

 The Big Picture

The big news, though, is not the NK cells but the possibility that the same gene mutations have impaired the activity of these ion channels in cells across the body.

A review of these ion channels suggests they may in particular affect the sensory neurons – an intriguing finding given the many weird sensations ME/CFS patients experience. These ion channels, interestingly enough, given the feelings of heat or burning experienced by some patients, appear to play a role in the sensation of heat and could induce a hypersensitivity to heat.  They are also found in the brain, spinal cord, sensory neurons, pituitary, kidney, eye, testis and fatty tissue, plus they’re also expressed in sperm cells, ovaries, pancreas, heart, blood vessels and bladder.   That could make them a perfect fit for a disease that affects so many areas.

Donald Staines of the NCNED explained ME/CFS like this:

“This dysfunction affects the brain, the spinal cord, the pancreas, which is why there are so many different manifestations of the illness – sometimes patients will suffer from cardiac symptoms, sometimes it will be symptoms in the gut.”

key to chronic fatigue syndrome

Has a key to chronic fatigue syndrome been found? Bigger studies await.

Other kinds of stress have not yet been associated with these still poorly researched ion channels, but Staines noted that similar ion channels are known as “threat receptors”. That fits in with the increased sense of threat or wiredness that seems almost ubiquitous in this disease.

Sonya Marshall-Gradisnuk – the leader of the group – told IFL Science that these receptors are so primitive virtually any stressor – from an infection to a toxin to perfume – could set them off. According to Science Alert Staines suggested that these stressors cause calcium receptors to ramp up – exposing the genetic problems present – and causing chaotic calcium conditions in the cells. 

Regarding treatments, Staines was optimistic stating that potential treatments for malfunctioning ion channels “are already being used for other conditions.” Because we already have “good safety data” on them and know how well they are tolerated, etc. “if they are found to work in the lab, clinical trials should be smoother sailing.”

Staines wasn’t willing to talk about a cure, but hey, a normal life would be a huge step up:  “We don’t know that we can necessarily cure the illness but we can help people lead a normal life.”

Dr, Gradisnuk-Marshall was willing to answer the following questions:

Can you say what the putative biomarker would consist of? All the polymorphisms associated with TRPM3 or some of them or the polymorphisms plus other factors?

We are exploring a number of potential biomarkers. We are not limiting ourselves here because of the extraordinary complexity of this illness.

Have you been able to check out other cells yet to see if the TRPM3 problems are present in them?

Our investigation of other cell types is ongoing.

Are you satisfied that the TRPM3 problems are causing the NK cell killing problems?

Still a long way to go as these ion channels behave in complex ways with many additional interactions which may have a role in the pathology.

Will you be examining the polymorphism in other disease groups?

We are totally focused on CFS/ME at this stage.

Take care and best wishes

Sonya and Don

Conclusions

The studies have been quite small but the NCNED is clearly confident that they’re onto something important. A diagnostic test is a top priority and has been for a year or so. Last year a news report stated the team was searching for partners to produce an  ME/CFS diagnostic test involving these genetic polymorphisms. Last December they scored $4 million (@ $3 million U.S.) in funding to develop this diagnostic test and explore drug treatments. That’s on top of the $2.5 million  (@ $1.9 million U.S.) they received earlier to do likewise.

It’ll be fascinating to find out what percentage of patients have these SNP’s or mutations.The NCNED identified a range of TPMR3 polymorphisms (as well as other polymorphisms) in an earlier study. Does the potential biomarker consist of all of those polymorphisms (in combination with others?) or?

If the group is correct that the TRPM3 problem is body-wide in ME/CFS, it could help explain the huge range of symptoms found in ME/CFS. No study evidence indicates that these problems exist in other cells, but the NCNED group’s willingness to assert that that’s probably the case suggests they may already have evidence of that in their lab. Bigger studies involving other disease groups as well as studies that establish symptom relevance are needed and it appears are coming.




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