Breakthrough Research Finds CFS is An Immune Condition

May 1, 2017  |  Chronic Fatigue

Australian scientists have linked chronic fatigue syndrome (CFS) to a genetic defect in immune cell receptors putting to rest once and for all the pathology of this much-maligned condition.

The research undertaken by the National Centre for Neuroimmunology and Emerging Diseases (Griffiths University) found that an inherited genetic defect means that cells do not work optimally.

These findings have potentially wider implications as many of the patients studied also had fibromyalgia and postural orthostatic tachycardia syndrome.

Mast-cell precursors have also been found in the blood of the patients studied. Whilst CFS patients might well fall under the spectrum of mast-cell activation, the Griffiths University research, by identifying the mechanism of action, provides a much more precise diagnosis.

CFS Genes Studied

Griffiths University is studying a pattern of single nucleotide polymorphisms (SNPs) in the TRP and acetylcholine receptors (AChM3R). If you have done a 23andMe test, you can use livewello.com, to extract the following indicative data.

CFS Genes

Current CFS Research Findings

The receptors being studied by Griffiths University are not well researched.  They are however known to act as part of a primitive “threat” sensing system.

Acetylcholine coordinates the brain’s response to environmental stimuli, either dialing up or dialing down, its response based on the level of perceived threat. It is also highly susceptible to acute psychological stress.

TRPA1 channels, for example, are cellular “threat” sensors that detect cellular oxidative stress and a range of stimuli both within and outside the cell.

It senses temperature, touch, pain, smoke, chemicals, solvents, mold, cold pain, and all manner of stimuli. It also appears to sense some medications.

Once TRPA1 channels are stimulated, TRPM3 moves calcium into the natural killer (NK) cell in order for it to work.

Griffiths University found that the TRPM3 receptors on natural killer (NK) cells are impaired with CFS. They fail to move calcium into the NK cell, which results in decreased cell function and specifically decreased cytotoxic killing ability.

Natural Killer Cells

Natural killer (NK) cells are cells belong to the innate immune system.

This is the part of the immune system that does not require previous exposure to certain types of threats in order to work. NK cells have a primitive ability to recognize stressed cells regardless of previous exposure.

NK cells can be divided into two categories and differentiated by the types of markers on them.

Cytokines – The first type is mainly capable of secreting cytokines, that act as mediators between different cells of the body, mainly cells of the immune system. They disrupt and contain the virus from spreading and facilitate the entry of the NK cells into the affected cell. This process is not necessarily impaired in CFS patients.

Cytotoxic Activity – The second type has cytotoxic activity, meaning that it can kill abnormal body cells, such as virus-infected, or cancerous cells. Griffiths University found that CFS patients have decreased cytotoxic activity of the NK cells.

Preferential Calcium Channel

Both TRPA1 and TRPM3 are parts of the preferential calcium channel which moves calcium into the cell to mount the NK cell’s defense.

Calcium is found in virtually every cell in the body and acts as a biological messenger responsible for carrying signals, through calcium channels, to target activities within cells. NK cells are no exception and require calcium to regulate their cellular functions.

 

CFS Calcium Channel

TRPM3, however, has a secondary pathway distinct from the central pore that can be specifically activated by the combined application of Pregnenolone Sulfate and/or Clotrimazole, a drug used to treat yeast infections. Simplistically, this is a backup system, that can help move calcium into the channel when the primary pore is faulty.

What Does This Mean For CFS Patients?

The impact of altering a gene is not yet known. This is what Griffiths University are diligently working on together with the research into other SNPs that might affect overall function.

Whilst Griffith University believes it has found the primary mechanism of action for CFS there is much that needs to still be done to have a comprehensive solution. This includes screening methods.

If you are in Australia and have CFS then I would encourage you to consult with Professor Pete Smith. 

 

A Functional Approach

The CFS process is triggered by an “activation.” From a functional perspective, the key question is therefore what is the TRP gene sensing? What is the NK cell trying to kill?

Mould (including  Chronic Inflammatory Response Syndrome), bacterial infections, viruses, chemical sensitivities, toxins, and certain medications, are all common “triggers”.

Personally, investigation of these, and resolving them, has been highly significant in my own journey with CFS. I still have CFS, and I still get triggered, but my symptoms have improved.

Improve NK Cell Activity

Improvement of NK cell activity may also help including:

Exercise – gradually increased to no more than capacity.

Massage

Micronutrient status: particularly zinc, selenium, vitamin B6, vitamin e, and Co Q10. Pyrroles (which makes an individual vulnerable to zinc and vitamin B6 should also be considered).

Melatonin: particularly liposomal melatonin which I find particularly helpful with a flare-up.

Bravo Probiotics or Suppositories

GcMAF Cream

Digestacure: which I am currently experimenting with.

Calcium and Magnesium

TRPM3 functions as a non-selective calcium channel. It is inhibited by intracellular magnesium – potentially leading to the “work around” secondary TRPM3 channel being activated.

Intracellular levels can be estimated with a hair mineral analysis.

Personally, liposomal magnesium, IV magnesium, and magnesium sulfate baths have been exceptionally helpful in relieving my own CFS symptoms.

Improvement of the calcium channel function, through reducing exposure to electromagnetic fields, can also be helpful to many CFS sufferers.

Pregnenolone Sulfate

Pregnenolone sulfate also activates the secondary TRPM3 channel.

Pregnenolone is synthesized from cholesterol and b vitamins and is considered to be the master hormone of all steroid hormones. Dietary deficiencies or digestive issues can easily compromise pregnenolone levels. When deficient pregnenolone can be supplemented.

However, pregnenolone alone is not sufficient. It needs to be converted to pregnenolone sulfate to activates the secondary TRPM3 channel.

Sulfation is a process that is part of phase II liver detoxification. It can become compromised with inflammation, sulfur deficiency, or glucocorticoid use. Addressing sulphation can, therefore, be helpful to restoring pregnenolone sulfate levels.

Pregnenolone can be roughly estimated with a DUTCH hormone test, and sulfation can be estimated with a Genova Organic Acids Test.

Acetylcholine

Acetylcholine status can be evaluated with the choline marker on a Spectracell Micronutrient Test.

To increase acetylcholine, substances that provide acetylcholine precursors, prevent the breakdown of acetylcholine, or a combination of both can be used. Examples of these combination products are Brain Memory by Douglas Labs, and Acetyl-CH by Apex Energetics.

As acetylcholine is susceptible to acute psychological stress, reduction of psychological stress can be important. Personally, I have used a combination of EFT, mindset, and walking away from stressful situations, with significant benefits.

The Gupta Programme,  the Dynamic Neural Retraining System, and The Lightning Process all claim to help CFS by rebalancing the threat system. I have not tried any of these systems, preferring the use of EFT, but know many people who have benefited from these programs.

Methylation

Methylation is involved in immune cells and natural killer cells. It is also required in the pathway for acetylcholine biosynthesis.

Whether a person is genetically compromised, has impaired digestion and absorption of nutrients, or has a restricted diet devoid of key methylation nutrients, methylation can alter the way cells function.

Whilst this has not been one of my many CFS challenges I have seen simple methylation support make a profound difference in others.

Conclusion

My over-riding approach has been to remove the threats to my body (particularly mold, medications, stress, and dental issues), to create the optimal environment for healing (through lifestyle changes and targeted supplementation), and to support my immune system to calm down.

To a large extent, this has worked. I will always be vulnerable to CFS, and still have flare-ups, but the symptoms have gradually fallen away.

Sources

The articles cited in this article were read by an Associate Professor Of Immunology and summarized for me to ensure that the information above was technically correct.

Marshall-Gradisnik S, Smith P, Nilius B, Staines DR: Examination of Single   Nucleotide Polymorphisms in Acetylcholine Receptors in Chronic Fatigue Syndrome Patients. Immunology and Immunogenetics Insights 2015, 7:7-20.

Marshall-Gradisnik SM, Smith P, Brenu EW, Nilius B, Ramos SB, Staines DR: Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients.Immunology and Immunogenetics Insights 2015, 7:1-6.

Nguyen T, Johnston S, Chacko A, Gibson D, Cepon J, Smith P, Staines D, Marshall-Gradisnik S: Novel characterization of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients. Asian Pacific journal of allergy and immunology 2016.

Huth TK, Brenu EW, Staines DR, Marshall-Gradisnik SM: Killer Cell Immunoglobulin-like Receptor Genotype and Haplotype Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. Gene Regulation and Systems Biology 2016, 10 :43-49.

Oberwinkler J, Lis A, Giehl KM, Flockerzi V, Philipp SE: Alternative splicing switches the divalent cation selectivity of TRPM3 channels. J Biol Chem 2005; 280:22540-8; PMID:15824111;

Wagner TF, Drews A, Loch S, Mohr F, Philipp SE, Lambert S, Oberwinkler J. TRPM3 channels provide a regulated influx pathway for zinc in pancreatic beta cells. Pflugers Arch 2010; 460:755-65; PMID:20401728;

Clapham, David E. “TRP channels as cellular sensorsNature 426.6966 (2003): 517-524.

Nilius, Bernd, and Thomas Voets. “A TRP channel-steroid marriage.Nature cell biology 10.12 (2008): 1383-1384.

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  • Erik Johnson

    https://uploads.disquscdn.com/images/3f4fb86350cf44233cf3c82d4a07b7c43bf35e071c964b345e5e106db79ddc07.jpg

    North Lake Tahoe Bonanza

    Nov
    16 1987

    “Incline Victims Show Cell Abnormalities”

    Tests Reveal New Clue in Fatiguing Illness

    by Chris Fotheringham

    NLTB Managing Editor

    Laboratory results published this week
    in a prestigious medical journal confirm that over 50% of Incline Village
    chronic fatigue patients tested have suffered “dramatic”
    abnormalities in their immune systems.

    Calling it the “most significant
    finding yet” in efforts to unravel the mystery of the widespread fatigue
    illness, Harvard researcher Dr. Anthony Komaroff said Monday the report
    published Sunday in the Journal of Immunology is the first scientific study
    that confirms “something is wrong with these people.”

    “it is really dramatic.” said
    Komaroff, who is chief of general medicine at a Harvard teaching hospital in
    Boston.

    The article, which underwent nearly 11
    months of peer review before being published, was authored by Komaroff, Incline
    Village internist Dr.Daniel Peterson, and former Incline internist Dr Paul
    Cheney.

    Dr Michael Caligiuri, an immunologist with the Dana-Farber Cancer institute of
    the Harvard Medical Center, was the lead author for the article which was
    originally submitted for review in January.

    Komaroff says test results reveal an
    attack on the immune system’s “natural killer cell” which is the
    body’s primary means of killing virus-infected cells or cells that become
    cancerous.

    Komaroff said “There is a
    substantial reduction in the number of natural killer cells in patients
    tested.” He said the study has
    determined that this “major defense against virus infection and
    cancer” is damaged in over half of the test cases involving Incline
    Village patients.

    Komaroff first broght his team of
    researchers to Incline Village in February of 1986 after Incline doctors Cheney
    and Peterson had documented an outbreak of approximately 200 cases of
    mononucleosis-type illnesses in the North Tahoe and Truckee area beginning in
    the fall of 1985.

    While the Incline Village cluster of
    fatigue cases has drawn primary attention in the national media, researchers
    have found widespread occurrence of the illness throughout the country.

    See TESTS on page 9.

    http://www.ncbi.nlm.nih.gov/pubmed/2824604

    • Super interesting Erik. Thankyou! So basically they have known this since the 1980s! How crazy it has taken them 30 years to do something about it. Also thanks for the link to the study. As I understand the NCBI study (which I could only read the summary of – cause it was a pay per view) they are suggesting that it is the viral component (and ? EBV) that is impaired. So no doubt this is the link to the high nagalese tests – but I am curious now to see if in addition I have high EBV as well as high nagalase. Is this your understanding? Thanks for being so generous with your info erik.

      • Erik Johnson

        This Komaroff study was privately funded by advocates in order to find some immune abnormalities to ‘impress’ the CDC, and embarrass them out of their concerted indifference.

        The plan was a spectacular success, as this did cause abandonment of CEBV Syndrome and compel a replacement medical research entity.

        What we did not anticipate was that by giving the new one a laughable name and omitting the immune findings, that the CDC would succeed in making the new syndrome even more trivial than its predecessor.

        • That would be right. Hopefully, there will be some long overdue change in attitude. Griffith Uni is getting a lot of attention and funding including from the Government, so hopefully, in another 30 years, CFS will be taken seriously. I don’t know why health needs to be so political. Well, I do but it is so wrong.

  • Tamara Romanuk

    Hi all, I am new to this site but not to CFS/ME/Fibro. As a PhD biologist by trade (tenured prof) now on 100% disability I have a heap of experience evaluating the scientific literature so I just wanted to add a few points and caveats. First, the mast-cell and natural killer cell links have been gaining more and more traction in the CFS literature (and along with some newer theories about latent viruses hiding out in the vagus) and may eventually prove out part of the mechanisms (along with Substance P specifically in Fibromyalgia) underlying these diseases. I think your summary is on the right track. BUT …..I read all the articles you cited and did the genetic analysis (in livewello and promethease). First, if you had your sequencing done by 23andme (in the last few years, the # of SNPs has changed) only the SNPs from the article by Marshall-Gradisnik et al. on “transient receptor potential ion channels” can be analyzed (the SNP’s from the same groups acetycholine paper are not part of the SNP’s 23andme analyzes”. Which sucks. When I entered all the SNPs for TRPM3, TRPA1, and TRPC4 into livewello only 6/13 are sequenced by 23andme (I got a few ++ mutations which was not a surprise), but there is still a lot of data missing from the 23andme data that is part of the 13 main SNP markers from the paper. Second, its important to look at Table 1 showing the rank order frequency of the 13 SNP markers that differed significantly between CFS/ME and controls. While the authors are obviously correct in their conclusion regarding the significant difference in %frequency most of these are rather minor in genetic terms (combined the picture is more robust of course, but that is a different type of analysis). For example, the marker with the biggest difference was rs12682832 (unfortunately not one of the ones analyzed by 23andme) and it shows a 44.4% frequency in CFS and a 29.3% frequency in controls. So significant, yes (at p=0.003) but not a marker that could be used to diagnose. The rest of the markers that differ show a similar pattern with differences between CFS and controls around 14% on average. If you are familiar with how genetics differ in different populations this is really key (promethease is a great way to look at this) as different ethnic groups show widely different frequencies. Finally, the study is not yet “proof”. It is more a pilot study and while uber-interesting needs to be replicated in other populations and with much higher number of patients/controls. This is not to poo poo this at all. Its fascinating and I think they (and you) are on the right track, but I would not over-hype this one gene study. That being said, I myself am being treated with mast-cell stabilisers and based on this and other papers: “Mast Cell-Mediated Mechanisms of Nociception” (link: http://www.mdpi.com/1422-0067/16/12/26151/htm) have also added palmitoylethanolamide (PEA) to my treatment (which includes tramadol, sodium cromoglicate – a mast cell stabilizer, among other supplements). Also check out: ” Mast cell–glia axis in neuroinflammation
    and therapeutic potential of the anandamide congener
    palmitoylethanolamide” link: https://pdfs.semanticscholar.org/d0c6/eb96f2c18e22533541345dd525e31baf6dea.pdf. I am only a few weeks into this combined cocktail and was advised to wait at least 2 months to determine whether I saw a reduction in symptoms). In summary, i think you are on right track with your overall research and mechanisms but just want to warn against over-hyping this one gene study. While super important, it is young days yet for genetics and CFS. Great work and glad to have found your blog.

    • Atabeyra Velázquez

      Interesting. I looked on 23 and Me and found two genes TRPA1 and TRMP3. I am a little lost since the information found is too technical for my level of knowledge.

  • nancyblake

    Very interesting, seems on the right lines. Except for the suggestion to exercise. The US IOM Report, ‘Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness’
    concludes that this is a serious, disablimg chronic disease. The defining feature is that ‘exertion of any kind – physical, cognitive or emotional – may adversely affect many organ systems’. Exercise does harm.

    Researchers at Workwell have established that the aerobic metabolism is disfunctional in this disease, so that all exercise becomes anaerobic..walking across the room is like weight-lifting for people with ME/CFS.

    Les Simpson established that in ME, some unidentified factor causes the red blood cell population to become dominated by irregular shapes which cannot travel through the capillaries, causing the failure of the aerobic metavolism, as oxygen is not getting to the cells, This can explain the muscle failure, cognitive problems and the symptoms of endocrine dysregulation – disrupted sleep rhythms, body temperature regulation.

    It is possible that a retrovirus is involved, as suggested by the symptoms of immune activation.

    This leads us to the importance of conserving our body’s energy for the use of our immune system…the function of ‘sickness behaciour’…nature forcing us to stop other activity while healing processes are taking place.

    Ramsay was unequivocal that complete rest from the inception gave the best prognosis, and Jason’s research confirms that keeping activity below perceived energy levels over a period results in gradual improvement.

    People with ME/CFS need to know that complete rest, maximum conservation of exertion is the path to improvement.

    • Tamara Romanuk

      Agreed. The only caveat is that something needs to be done to halt deconditioning, which can become one of those vicious cycles. The concept of what “exercise” is to someone with ME/CFS may be more along the lines of a few minutes of hanna somatics, qi gong, gentle stretching, or slow short walks. It appears that there is a “set” point which will differ for everyone in term of heart rate – once you go above it – it leads to flares and crashes so keeping exertion below this point is key.

      • I totally agree. Exercise should be more properly termed as movement to capacity. I think that the pejorative, manipulated, PACE trials have made people jumpy about the word exercise. The reality is that movement (or exercise) is good for the body in all sorts of ways provided it is done to capacity. I find if I stop movement that my body deconditions. If I move then my cfs is better. Its all a question of listening to your body and not pushing through.

  • CREED

    Great article and gives hope for those who have long suffered from CFS. The supplements and regimes that have worked best for me are the following but not in order of importance or effect:

    – Cranial sacral adjustments.

    – Acupuncture

    – Exercise, mostly walking or hiking – this has worked wonders for me and can elevate my symptoms for hours or even days. But, over do it, get back into the gym with weights – I blow out for days or even weeks. I have to be gentle on myself. Exercise for me is an absolute must.

    – supplements – high quality minerals with no iodine as have thyroid issue. COQ10 – Pregnenalone – C – 7Keto – digestive enzymes and probiotics – Full spectrum B

    – low, low carb diet with tons of veggies and no sugar, even fruit, but do ear berries. Good clean protein from vegetable sources as well as fish and chicken. Always organic, none GMO and I stay away from Gluten as it just blows me out. I stay clear of all inflammatory foods, coffee, sugar, dairy… and drink plenty of clean water. Interesting, when I have symptoms, a good 16 to 32 oz of water can calm the symptoms down?

    I tried Bravo but ended up bloated with indigestion, but I am lactose intolerant and that may be why. Will look further into GcMAF. I think I see light at the end of the tunnel for me and CFS sufferers, and its not a train coming!

    Good luck everyone

    • Thankyou! sounds like you are making good progress! Yes do try the GcMaf it is a good option when dairy is not tolerated. Enjoy!

  • Tamara Romanuk

    If you are on livewello there are a number of templates people have already put together to look at them. Alison listed the main SNPs typically available in her table in the article.

  • Tamara Romanuk