All posts tagged NCNED

Finally Found – A Natural Killer Cell Enhancer for ME/CFS?

For several years now, researchers at the National Centre for Neuroimmunology and Emerging Diseases (NCNED) at Griffith University in Australia have been leading the research on natural killer (NK) cells in chronic fatigue syndrome (ME/CFS). In fact, they recently published an overview on NK cells and ME/CFS.

natural killer cell failure ME/CFS

The natural killer cells in ME/CFS are pretty much a failure at killing infected cells.

NK cells play a critical role in the innate immune response which kicks in first to fight off an infection.  NK cells do just what their name implies: after alerting the immune system that trouble is ahead, they jump in and kill as many infected and damaged (cancer) cells as possible. The goal? To keep a pathogen in check long enough for big guns of the adaptive immune system (T and B cells) to rev up and ultimately destroy the invader.

For some time now, the Griffith group has focused on an unusual subject for ME/CFS –  ion channels – the very, very small channels in our neurons and cells – which play a big, big role in nerve and cell activation. Ion channels are getting a lot of interest in pain research but except for the Griffith team – not so much in ME/CFS.

The problem with NK cells in ME/CFS is that they’re just not killing very well. When given the chance to wipe out some infected cells, they pretty much poop out – not good news for anyone wanting to quickly knock down infections or remove cancerous cells.

NK cells, like many cells, require intracellular calcium to function properly, the levels of which are regulated, at least in part, by the ion channels the Griffith group is studying. These TRPM ion  channels are found in a wide variety of cells and tissues, and play a particularly important role in  sensory processing – a big concern in ME/CFS.

The ion channel that the Griffith group has been particularly interested in – TRPM member 3(TRPM3) – appears to be a jack of all trades. The fact that it can be activated by everything from temperature, natural chemicals, and toxins to synthetic compounds suggests it plays a fundamental role in the body, and, indeed, TRPM3 dysfunction has been implicated in inflammatory and neuropathic pain disorders.

Ion Channels and ME/CFS

The Griffith group’s findings in ME/CFS stretch back almost four years. In 2016, they showed that both TRPM3 and intracellular concentrations of calcium were reduced in the NK cells of ME/CFS patients. These findings suggested that in ME/CFS, the signal to kill  the pathogens wasn’t getting through to the NK cells.

That same year, Griffith introduced a potential explanation: the genes that governed TRP ion channel functioning – in particular, TRPM3 ion channel functioning – were loaded with mutations in ME/CFS. That same year, the group reported they’d found similar mutations in the B cells of ME/CFS patients.

ion channel issues

The ion channel / Ca mobilization issues in ME/CFS (From Impaired calcium mobilization in natural killer cells paper_

2017 brought another study validating the TRPM3 channel reductions. Further testing indicated something had gone wrong with the TRPM3 receptors themselves. When stimulation tests found a reduction in Ca2+ mobilization was occurring, the researchers proposed something startling: that TRPM3 channels across the body could be malfunctioning.

“As TRPM3 receptors are expressed throughout the human body, the current findings suggest that impaired TRPM3 function may play a significant role in the multisystemic pathomechanism of CFS/ME.”

Given how ubiquitous TRPM ion channels are, the loss of them body-wide could be responsible for many of the multitudinous symptoms associated with ME/CFS.

2018 and 2019 brought further validation of their previous findings (in small studies).  Just this month, the group published evidence that a related ion channel, TRPM2 – perhaps in a compensatory response – is over-expressed on ME/CFS patients’ NK cells. Despite its increased levels, it too was not functioning well.

Then in October of this year came a potential fix for the NK cell problem in ME/CFS.

Front. Immunol., 31 October 2019 Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients, Helene Cabanas1,2,3*Katsuhiko Muraki3,4,  Donald Staines1,2,3 and  Sonya Marshall-Gradisnik1,2, https://doi.org/10.3389/fimmu.2019.02545

Naltrexone hydrochloride (NTX) is best known in its low dose form in ME/CFS. It was referred to in this paper, though, simply as naltrexone. NTX in its normal dose functions as an opioid antagonist which reverses the effects of opioids. While it’s doing that, it also happens to activate the same TRPM3 channels that have been found inhibited in ME/CFS.

The Australian researchers used something called a whole cell patch clamp technique to assess the functioning of NK cells from people with ME/CFS. This technique, which was developed in the 1970’s/80’s, enabled researchers to assess the functioning of single ion channels on cells for the first time. (It also won its creators the Nobel Prize.)

The study again found that low levels of TPRM3 channels were present in ME/CFS.  It showed that stimulating the NK cells from healthy controls worked – the NK cells sprang into action. The NK cells from the ME/CFS patients responded to the stimulation by remain dead as a door nail. That stimulation test suggested that whatever TPRM3 channels were present simply weren’t working.

ME/CFS patients, then, appeared to have two problems: they were losing TRPM3 ion channels and those that were still present were not working well.

Incubating the healthy controls’ NK cells in naltrexone had no effect on them, but the ME/CFS patients’ NK cells responded dramatically: they now appeared to be acting normally.

Besides presenting a possible treatment for the NK dysfunction in ME/CFS, the finding suggested the Griffith researchers’ original hypothesis could be correct: the mysterious NK cell dysfunction problem could derive from problems with the TPRM3 ions.

Sonya Marshall-Gradisnuk was enthusiastic about her team’s results

This was a laboratory study – a proof of concept study. It’s a long way from testing naltrexone in humans but it did hold out the potential of a treatment for the low NK functioning in ME/CFS.

Given that NK cells ferret out infected and cancerous cells and remove them, getting the NK cells functioning properly again in ME/CFS would be a big step forward.

The leader of the group, Sonya Marshall-Gradisnik, was clearly enthusiastic:

“This world-first discovery suggests new potential pharmaco-therapeutic interventions in ME/CFS.”  Professor Sonya Marshall-Gradisnik

Opioid Drugs and Immunosuppression

The study also raised the question of what effects opioid drugs could be having on the immune systems of people with ME/CFS. No studies have attempted to assess that issue, but this study and others suggests it could be negative.

Opioid drugs have been found to impair the functioning of macrophages, natural killer cells and T‐cells and weaken the gut barrier.  A 2013 review asserted that, given the prevalence of opioid use, “opioid-mediated immune suppression presents a serious concern in our society today”.

The effects of opioids are complex, however. Immune cells also secrete endogenous opioid peptides which relieve inflammatory and neuropathic pain.

Conclusion

 

breakthrough

A breakthrough for ME/CFS? Time will tell.

The studies have generally been small, but the results have been consistently positive. They suggest that poorly functioning TRPM3 and perhaps related ion channels could be causing the reduced NK cell cytotoxicity commonly found in ME/CFS. This study found that the opioid antagonist Naltrexone was able to reverse the TRPM3 and calcium mobilization problems in ME/CFS patients’ NK cells.

Reversing the poor NK cell cytotoxicity functioning to normal would be a major step forward. Further studies will be needed, however, to determine if the results seen in the laboratory apply to people with ME/CFS – which is often a perilous step. I couldn’t find any clue as to what the effective dose would be or whether the low dose form of naltrexone might help.

It bears mentioning that the Griffith group has evidence that another ion channel may not be working properly in ME/CFS, that these channels are widespread throughout the body, and a systemic dysfunction with them, if present, could cause many problems.

 

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Aussie Immune Study Raises Questions About Chronic Fatigue Syndrome Research Definition

December 12, 2013

The more specific requirements of the ICC however, may select patients that are less clinically diverse. This could improve detection of immunological findings in CFS/ME.      

Study authors.

How much of a difference the International Consensus Criteria (or any definition) makes is a major question in chronic fatigue sDr. Marshall-Gradisnikyndrome.

Dr. Sonya Marshall-Gradisnik’s team in Australia, who just celebrated the grand opening of the National Centre for Neuroimmune and Emerging Diseases at Griffith Univeristy, examines this question in a recent study. Dr. Marshall is a leading ME/CFS researcher, as well as a member of Simmaron’s Scientific Advisory Board.

Proponents of using a more restrictive definition such as the CCC/ICC believe that winnowing out a homogeneous group in research studies  could be the key to figuring out ME/CFS.  Once ‘non-ME/CFS patients are eliminated, core factor will pop out and be quickly replicated.  It’s an enticing vision.

netOthers worry that a more narrowly focused group might miss some legitimate ME/CFS patients. The ‘wider net’ approach, may have been embodied in the ’empirical definition’, which grabbed a large set of ‘CFS’ patients, from which subsets could conceivably have been winnowed.

This strategy would have the benefit of applying to a larger population (up to 4 million in the US), and might work well if the funds and will had been available. Without that commitment that  strategy runs the risk of producing almost meaningless results.

A recent publication by Dr. Sonya Marshall-Gradisnik’s team compares the immune functioning of ME/CFS patients meeting the International Consensus Criteria vs. those meeting the Fukuda/1994 CDC definition, giving us a start on determining the pros and cons of a more narrow vs. a broader approach to ME/CFS research.

Fukuda/1994 CDC Definition

The fact that few research papers in the last twenty years used something other than the 1994 Fukuda definition to define their participants means that virtually all the findings in ME/CFS from the natural killer cell dysfunctions to low blood volume to exercise intolerance, etc., have all been found using the Fukuda definition. By putting all researchers on the same playing field, the Fukuda definition has played an important place in the history of ME/CFS research, but its vagueness and its inability to highlight what many believe to be the key symptom in ME/CFS means it almost certainly allows several questionable subsets into research studies.

The Study

Sixty-three participants including 41 people with ME/CFS and 22 controls answered questionnaires and gave blood samples. The blood samples were assessed for immune functioning. All patients had been previously diagnosed with chronic fatigue syndrome at the National Centre for Neuroimmunology and Emerging Diseases, a top ME/CFS research lab (and soon to be clinic) led by Dr. Sonya Marshall-Gradisnik in Australia. (Dr. Marshall-Gradisnik serves on the Simmaron Research Foundation’s Board).

Results

The breakdown was fascinating. Seventeen people met the Fukuda criteria but not the ICC, and 18 people met both the ICC and the Fukuda criteria. Five people — over 10 percent — of the ME/CFS patients met neither criteria. This was one small study, but it did suggest that a large percentage of people that doctors identify with ‘chronic fatigue syndrome’ may not meet the ICC, and another substantial subset may not meet either criteria. It does not bode well for a more restrictive approach to ME/CFS.

Natural Killer Cells

It was no surprise to see reduced NK cell functioning show up in both the ICC and Fukuda groups. This reduced natural killer cell functioning is believed to inhibit the ME/CFS patient’s ability to clear new infections and/or stop recurring infections. (Interestingly, reduced NK cell function was not associated with alterations in the cytotoxic factors – granzymes and perforin – that NK cells use to kill cells, as has been seen in the past. The authors suggested, however, that this might have been due to the small sample size.)

Immune Suppression Enhanced in the ICC Group

Both groups demonstrated immune suppression, but the immune suppression was significantly increased in the ICC patients. The increased prevalence of two inhibitory or suppressive immune factors in the ICC group suggested a) they were a distinct group, (b) the promise of more abnormalities showing up when a more restrictive definition was used was fulfilled and c) that their immune system was having more trouble than the Fukuda group’s in becoming properly activated. Treg or T regulatory cells or ‘suppressor’ T-cells are rather new to the scene in ME/CFS, but this is the third study showing significant increases in these cells. That suggests they may play an important role in chronic fatigue syndrome. High levels of Treg cells could be suppressing natural killer cell functioning in ME/CFS.

the word reduced

Both groups exhibited reduced immune activity, but more immune suppression was found in the ICC group

KIR Receptors – High levels of ‘KIR’ receptors on the NK cells of the ICC group (but not the CDC group) could further suppress NK cell function. The presence of two ‘profoundly’ inhibiting factors suggested the ICC group’s immune systems were getting particularly hammered. (Increased levels of an ‘activating’ NK cell receptor were also found. The authors felt this resulted from an attempt to balance the ‘overwhelming’ inhibitory signals from the two inhibitory receptors.) (Receptors on the surface of a cell greatly influence what the cell does. NK cells that are dotted with inhibitory receptors, for instance, can be easily turned off. Conversely, NK cells with few inhibitory receptors will be difficult to turn off.) The authors suggested, but could not prove, that the ICC group carried genes that promoted a tendency towards NK inhibition.

Hitting Home – Physical Functioning Affected

One of the vital questions regarding the abnormalities in ME/CFS is how much they matter. Ironically, THE immune finding in ME/CFS, poor NK cell functioning, didn’t pan out in this regard. While low NK cell functioning was associated with poorer health in the healthy controls, it didn’t appear, at least in this small study, to be correlated with poorer health in the ME/CFS groups. Decreased CD39+ and altered KIR receptors were, however, ‘strongly’ associated with poorer health in the ICC (but not the Fukuda delineated patients). This  suggested that immune suppression was having an impact in the ICC delineated patients.

Touchy Situation Ahead

The increased  amount of immune suppression in the ICC group suggested that the ICC criteria did select a more immune-challenged set of patients and that group should be set apart for separate study. The immune findings in the Fukuda group (low NK cell functioning/increased Tregs) were nothing to sneeze at, however. Plus, the high percentage (almost 50%) of patients meeting the Fukuda criteria, but not the ICC criteria indicated that group cannot be ignored. The ten percent of people with ME/CFS that met neither criteria suggested an important subset of people who are sick, but don’t meet either criteria, may be present. The fact that all the study participants were identified by ME/CFS researchers/doctors working at an ME/CFS lab suggested they were indeed ME/CFS patients. These researchers proposed that both groups should be included in studies. Since all the people that met the ICC also met the Fukuda/1994 CDC criteria, starting off with the Fukuda criteria and then examining the ICC criteria patients could achieve this.

Conclusion

“These findings are highly suggestive of a need to incorporate both the 1994 CDC and the ICC in future clinical research”

Study authors

With a new research definition coming up on the docket, it was good a see a study examining a prominent candidate — the International Consensus Criteria.

casting a net

With this study suggesting both definitions have merit, determining how wide or narrow of a net to cast in the research definition will not be easy.

The IOM contract for a clinical definition was really just a prelude to the big problem looming ahead, which is creating an appropriate research definition.

Since the research definition defines what types of patients participate in a study, its use can fundamentally alter how a disorder is viewed or researched.

The suppressive nature of the immune dysfunctions found in the ICC group suggested, to my mind, that they might be ‘Fukuda plus’ patients dogged by increased levels of immune suppression.

This study gave no clear answers. It suggested that patients that meet the Fukuda criteria but not the ICC criteria are an important subset of ME/CFS, but it also suggested that segregating patients meeting the ICC criteria could help uncover more immune abnormalities.