The Canary

Disclaimer:  I do not have a single medical qualification.  I am not a scientist, nor do I have any research or scientific background.  I’m just a patient who’s had 21 lonnng years of living with my disease and probably know more about it than most physicians on the planet.  I believe about 0.01% of the information I read on the internet, the exceptions being when the claims are backed up by peer-reviewed literature – this piece is backed up by such research.  I apologise to my ill readers for the length of this article – please don’t give yourself a relapse reading it all at once!

I’ve had Myalgic Encephalomyelitis (M.E.) for more than 20 years.  It started with a combination of an allergic reaction to a drug coupled with a stomach bug.  At the time I was working abroad, was homesick and a bit miserable.  I was working exceptionally long hours, and in my time off drinking and partying like it was going out of fashion.  I also had undiagnosed Ehlers-Danlos Syndrome and there is evidence that EDS sufferers have a genetic predisposition to mast cell disease.  At the time I developed M.E. I,  unknowingly, was living in the centre of a perfect storm.

I don’t usually get excited about research into the cause of M.E. as I’ve heard it all over the years and it always comes to nothing.  With this research, however, I’m so excited I can barely contain myself.  The following hypothesis is based on a video presentation in July 2013 by Dr T.C. Theoharides MD PhD, who has been researching mast cells for some years.  The presentation focuses on Autism, although it does mention both fibromyalgia and chronic fatigue syndrome, but it’s easy to take the hypothesis and apply it to M.E..  What follows is my take on the role mast cells could be playing in M.E. – if nothing else, it’s certainly food for thought.

What follows is copyrighted ©jak 2013.  It should not be re-printed, either in part or full, without my written consent.  If you’d like to link to this article, however, feel free.

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“The mast cell is the Canary of the body”
 Dr T.C. Theoharides MD PhD

What are mast cells?

Photo of a mast cell

Mast Cells are the cells involved in allergic reactions, where you have an antigen (eg. pollen, peanuts, animal dander) + an IgE immune reaction, which causes mast cells to de-granulate (kind’ve explode!) and spill their molecular content into the body.  One of these molecules (also known as mediators) is histamine, responsible for the runny nose and itchy eyes of hayfever and the swelling, hives, and anaphylaxis of peanut and other allergies.  In addition to histamine, mast cells contain about 30 other mediators including chemocines (which are involved in both inflammation and maintaining normal tissue development and maintenance) and cytokines (including tumor necrosis factor which causes cell death) [table 1 – see end of article for References].  To complicate matters further, each mediator has it’s own array of direct and indirect, local and remote, effects, which means that mast cells influence more than 200 proteins within the body.

When histamine is released by mast cells it circulates in the body and then binds to receptors.  Depending on which receptor the histamine binds to determines the type of reaction caused.  There are currently 4 known histamine-specific receptors:

  • H1: these are found all over the body and are responsible for typical allergic reactions, eg. hives, itching, tissue swelling, allergic asthma, anaphylaxis.  Medicines such as Benedryl and Clarytin stop histamine from binding to H1 receptors, although they don’t rid the body of histamine per se.
  • H2: these are found in the gut and are responsible for the production of stomach acid.  Histamine is vital for food digestion, but an over-abundance can lead to gastritis, GERD, vomiting, diarrhoea and other GI issues.  Medicines such as Tagamet and Zantac stop histamine from binding to H2 receptors but again don’t rid the body of histamine.
  • H3: these are found in the brain and central nervous system and when activated affect blood pressure, heart rate, smooth muscle contraction and the release of neurotransmitters.
  • H4: not much is known yet about H4 receptors, but they live in white blood cells, the spleen, colon, thymus and bone marrow.  They are thought to regulate the immune system.

The release of Histamine can wreck havoc on the body, producing a cascade of events:

  • H1 receptors cause symptoms such as period pain during menstruation, stomach cramps, muscle twitches/spasms, bronchial constriction/breathing problems, vomiting, hives, itching, swelling and allergic-type reactions including anaphylaxis.
  • H2 receptors cause symptoms such as IBS, diarrhoea, GERD/reflux, vomiting, breathing problems.
  • H3 receptors cause symptoms such as Orthostatic Intolerance, tachycardia/arrhythmia, low blood pressure, vertigo, headaches, nausea, vomiting, anxiety, panic, depression, wakefulness/drowsiness and affect the circadian rhythm.
  • H4 is thought to regulate mast cell production by its pathway in the bone marrow.  This could be the receptor responsible for the vicious circle of chronic mast cell activation.
Photo of mast cell activation symptoms

Photo downloaded from http://thereluctantrawfoodist.com/resouces/histamine-disorders/ – click image to enlarge

Bear in mind all these issues are caused by just one mast cell mediator: histamine.  Mast cells, however, produce approximately 29 other mediators which in turn affect over 200 proteins within the body.  Amongst other functions, these mediators produce inflammation & pain, stimulate T-lymphocytes (ie. TH1 and TH2 – remember the TH2 research conducted by M.E. physician Dr Cheney?), cause tissue damage, affect platelet activation, thin the blood and affect vasodilation.  Mast cell mediators affect virtually all bodily systems (for a full list of symptoms caused by mast cell mediator release see here).

When is an allergy not an allergy?

Doctors working in the allergy field were finding that many patients were presenting with allergic-type symptoms, eg. hives, itching, food reactions, multiple chemical reactions, nasal problems, GI issues, but didn’t have allergies to anything (ie. normal IgE, IgG and skin prick tests).  They had no signs of mast cell de-granulation (ie. their tryptase levels were normal) and had a normal amount of mast cells which ruled out Mastocytosis.  In addition to allergy-like symptoms most of these patients were also presenting with neurological issues, such as ‘brain fog’, problems with concentration and information processing, problems with memory, problems with sensory input, pain and often severe fatigue.

Dr Theoharides and others discovered that mast cells don’t necessarily have to de-granulate (actually explode) to release all of their molecules[9].  They can also selectively ‘leak’ individual or specific groups of mediators, which may be responsible for the chronic symptoms many of these patients were experiencing.  These leaking mediators can produce allergic-type symptoms but not be allergies in the true sense.  The disease Mast Cell Activation Syndrome was put forward as a way of diagnosing these patients so that they could at least obtain insurance (in the States) and receive treatment.

Brain Mast Cells & Brain Inflammation

Until now, it was thought that mast cells were only found within the immune system and, when triggered, their mediators could not cross the blood-brain barrier.  Instead, the innate immune cells in the brain are called microglia.  Microglia and mast cells communicate extensively with each other [12].

However, mast cells have recently been found to be plentiful in a part of the brain called the Diencephalon, which is made up of smaller parts, including the thalamus and hypothalamus (known to be faulty in ME).  The Diencephalon receives sensory stimuli and sends them out to other parts of the brain (sound/light/touch sensitivity anyone?!).  If the mast cells in the brain orchestrate a reaction to a pathogen, Dr Theoharides purports that the brain can have an ‘allergic reaction’ which does not involve a direct antigen such as pollen, or involve IgE.  But how does this happen?

Mast cells are prolific in the body.  They live in skin, the gut/GI tract, the nose, the mouth, the lungs, in all connective tissue (including the uterus and bladder), bone marrow, the spine and the brain.  They also live on the edge of blood vessels in what is called the blood-brain barrier.  Triggers are needed to cause mast cell activation.  These can include (but are not restricted to) pathogens, viruses, environmental toxins, vaccines, moulds and stress (which we’ll come to later).  Recent research has found that mercury, for example, (found everywhere including canned tuna fish, vaccines, many pesticides) causes activation of brain mast cells [7].  Dr Theoharides is of the opinion that it usually takes more than one trigger to cause brain mast cell activation, eg. when I was working abroad I had a tummy bug, allergic drug reaction, a genetic pre-disposition and was stressed.

When the mast cells living within the blood-brain barrier activate, the resulting mediators widen blood vessels which increases blood-brain permeability.  This has the effect of making the blood-brain barrier leaky, allowing circulating immune chemicals into the brain which otherwise wouldn’t be allowed access.  This in turn causes brain inflammation on top of the problems already present from leaking mast cell mediators – in other words, a brain-related ‘allergic’ reaction.

So where does stress come in?  Mast cells live close to nerves, in particular the nerves which release corticotropin-releasing hormone (or CRH).  CRH is a hormone which is released in the ‘flight or fight’ reaction when the body is under stress.  Dr Theoharides has published research which shows that CRH and brain mast cells regulate blood-brain permeability during times of acute stress[8]. (Note: Mast cells are also prolific in the GI tract.  When activated they can increase permeability of the intestines, which in turn causes the gut to also become ‘leaky’).

Mitochondria – the energy ‘battery’ of our cells

Mitochondria were, millions of years ago, bacteria which became symbiotic with our own cells.  Mitochondria are responsible for cellular energy and it has always been thought never left the cells which housed them.  If they ever were to leave the cells, the body would still see them as the bacteria they once were and mount a massive immune and inflammatory response.

However Dr Theoharides’ research has shown that mitochondria can, in fact, move[6].  When mast cells activate they cause mitochondria to break down and move away from the centre of cells to the outside of the cell surface.   The immune system then recognise these as bacteria and goes on the attack (fluey symptoms anyone?!), producing inflammation and further mast cell de-granulation.   And I’m assuming that if the mitochondria leave the cell, the cell’s ability to produce energy goes with them – no wonder people with M.E. are all exhausted!

Mast Cells & the Central Nervous System

Extensive crosstalk exists between nerves and mast cells.  The role of this bidirectional communication between mast cells and nerves appears to be multifactorial.  The communication with the nervous system allows the peripheral and central nervous systems to be involved in the regulation of defence mechanisms, inflammation, and response to infection. [11].

When mast cells are activated they also produce neurotransmitters such as histamine and serotonin, which alter mood and appetite as well as regulating the circadian rhythm and orchestrating sleep and wakefulness.

Mast cells are implicated in Multiple Sclerosis, and M.E. shares many symptoms with M.S.[4]

Conclusion

M.E. is a neuro-immune disease.  We now know that mast cells are the ‘orchestra’ of the immune system both within the body and the brain, and in addition regulate the nervous system and affect the energy-producing mitochondria.  The mediators produced through mast cell activation affect virtually every organ and bodily system, from our mood to our heart-rate, pain to cognitive function, our digestion to how well we sleep.  As I’m fond of saying, if something looks like a duck, and quacks like a duck, chances are……..it’s a duck.

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Tying in Mast Cell Activation to M.E. Symptoms

Just to summarize:

  • Mast cells can be activated by viruses, parasites, infections, vaccinations, trauma, environmental toxins such as pesticides, exposure to moulds and by stress.
  • Mast cell activation causes the energy-producing mitochondria to ‘vacate the building’.
  • Mast cells talk extensively to the nervous system.  Mast cells are present within the CNS, produce neurotransmitter mediators, and live next to sensory nerves.
  • Mast cells are abundant in the part of the brain which contains the hypothalamus and the sensatory Diencephalon.
  • Mast cells live within the blood-brain barrier and, when activated, cause leaky blood vessels which allow circulating immune chemicals to enter the brain.

Mast cell activation can cause just about every symptom experienced by people with M.E., including:

  • FatigueEnergy producing mitochondria move to the outside of the cell surface when mast cells activate causing, I assume, profound fatigue.When the mitochondria move to the outside of the cell surface the immune system assumes they are a foreign invader and goes on the attack.  Fatigue is a ‘normal’ symptom when the immune system is activated, as anyone who’s ever had a dose of Flu will know.
  • Insomnia/hypersomnia:

As already outlined, mast cell activation results in the release of various chemical mediators, such as histamine and cytokines.  Histamine is a wake-promoting neurotransmitter (insomnia anyone?!) and peaks at 3am.  If you take anti-histamines they often make you drowsy, the reason being they block the arousal capabilities of histamine.  There are many studies which explain the role histamine plays in wakefulness, just do a Google search or see this recently published study.

  • Migraine:

It has been proposed that mast cells promote neurogenic inflammation and activation of meningeal nociceptors [15, 16].  As they are also vaso-dilators they are increasingly implicated in migraine disorders.

  • Dysautonomia/POTS:

As already discussed, mast cells live on the edge of blood vessels and next to nerves.  When mast cells activate, their mediators widen blood vessels.  Widened blood vessels means lower blood pressure, which means vertigo, an increase in heart-rate and the typical symptoms of POTS or Orthostatic Intolerance.  Some people with POTS also flush.  Flushing is a well recognised symptom of mast cell activation [17].

  • Pain:

There are several ways mast cells could be involved in pain production, including:

      • Through their proximity to sensory nerve endings.
      • By infiltrating the Central Nervous System and/or by their communication with the CNS.
      • Through their role as producers of pain and inflammatory mediators (eg. serotonin, chymase, substance P, LTC4, prostaglandins, cytokines).
      • By changing sensory input in the Diencephalon (hyper-sensitivity to light, smells, touch, sound).

Mast cells have now been implicated in a range of chronic pain disorders, including CRPS (complex regional pain syndrome), Interstitial Cystitis and Fibromyalgia [10].

I started a low histamine diet 9 months ago, and now take both H1 and H2 anti-histamines daily.  After having back pain of unknown cause for over 30 years I can honestly say my back pain has resolved by about 60%!

  • Increasing M.E. symptoms at menstruation and menopause:

Mast cells are known to express estrogen receptors [13] and can be activated by estrogens, which enhance degranulation and mediator release.  In other words, menstruation causes mast cell activation.  Changes in estrogen levels are also linked to migraine attacks in women, perhaps due to cerebral mast cell interaction [14].

  • Muscle spasms, twitching, fascilations, myoclonus:

When mast cells are activated their mediators affect smooth muscle contraction, which is why people with allergic asthma get bronchial-constriction.  Many people having an allergic reaction also have stomach cramps as the muscles of the GI tract are also contracted.  Chronic mast cell activation could, I propose, cause contraction of any muscle or muscle group.

  • Feeling fluey:

There could be several reasons for the fluey symptoms experienced by M.E. sufferers:

  • As a general result of chronic immune activation (it’s mast cell mediators like cytokines which cause us to feel ill when we have a virus).
  • And/or activation of H4 histamine receptors, as these regulate the immune system.
  • And/or as a result of the immune system recognising mitochondria as bacteria, thinking the body is under attack, and mounting an immune response.
  • And/or several other reasons related to mast cell involvement that I’m not clever enough to work out!

Food, drug & environmental ‘allergies’:

Apart from drug allergies, I didn’t have any other ‘typical’ allergic symptoms (hayfever, hives, food allergies) until I’d had M.E. for 18 years!  Just because you don’t have ‘typical’ allergic-type symptoms doesn’t mean you don’t have leaking mast cells.  It may be in the case of M.E. that H3 or H4 histamine receptors are being activated which would cause brain and nervous system symptoms, and not the more typical H1 or H2 which would cause skin, bronchial and gut symptoms.

Saying all that, I don’t know anyone with M.E. who doesn’t have some kind of allergic symptom: asthma, pollen allergy/hayfever, gut issues/food intolerances etc.  We’re classed as being “sensitive” souls!  Many people with M.E. have also already been diagnosed with Multiple Chemical Sensitivity (MCS), including myself, although my diagnosis has now been over-ridden by one of Mast Cell Activation Syndrome.

Many drugs act as triggers for mast cell activation, including (but not limited to) opiates including codeine, NSAIDs such as ibuprofen, anaesthetics, some local anaesthetics, contrast dyes used in CT and MRI scans, aspirin and alcohol (for a more extensive drug list see here).  I personally react to just about all medications now, including all pain-killers including paracetomol, all sedatives, all sleeping tablets, all anti-depressants, muscle relaxants, anti-nausea drugs, even laxatives!

In fact, many people with M.E. react to just about everything, including a wide variety of foods, changes in weather/barometric pressure, being too hot, being too cold, and moulds.  Stress, menstruation and catching any kind of bug also worsens symptoms in M.E. for reasons previously stated.  This is extremely common in mast cell disease as can be seen on the trigger list on the Canadian Mastocytosis website.

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Can We Test For Mast Cell Activation?

I’ve had M.E. for a very, very long time.  I have had every test known to man, including MRIs, CTs, EEGg, ECGs, heart scan, POTS test, nerve conduction tests and enough blood taken to sink a ship.  Nothing has ever come back abnormal (with the exception of my sleep study which confirmed I sleep badly – tell me something I don’t know!).  I have had meningitis, have awful burning pain just about everywhere particularly during menstruation and have chronic gastritis (stomach inflammation) yet none of my immune markers show any kind of inflammation.  It’s beyond frustrating (in fact I’ve cried many, many tears) that I am so incredibly ill yet appear, to a lab technician at least, as fit as a fiddle.  As it turns out, we just weren’t looking in the right places for the right things.

Mast cell de-granulation, which is what happens in a true allergic response such as a peanut allergy, produces a rise in a proteinase in the blood called tryptase, which can easily be measured.  If tryptase is elevated, a bone marrow biopsy usually shows further evidence of mast cell activity (this is how the rare mast cell disease Mastocytosis is diagnosed).  However, selective mast cell activation (ie. leakage rather than de-granulation) does not affect tryptase and. as we have normal amounts of mast cells, it’s unlikely that a bone marrow biopsy would be abnormal.  What we do have is over-active mast cells.

It’s possible to test for mast cell specific mediators, eg. n-methylhistamine, heparin, chromogranin A and prostaglandins (specifically PD2) in both blood and urine.  However, both histamine and PD2 degrade rapidly, therefore very careful handling of samples is paramount.  They must be kept chilled at all times (histamine begins to degrade after only 15 seconds at room temperature), or in the case of some histamine tests must be immediately frozen.  In the UK there is only one lab in the whole country who can adequately test for histamine (the private Doctor’s Lab in London).  Dr Seneviratne at the Lindo Wing of St Mary’s Hospital is also able to arrange for plasma and urine PD2 and leukotrienes to be tested, though the samples have to be sent to America which is expensive and not covered on the NHS.   We currently don’t test for heparin or Chromogranin A.  All the mast cell mediator tests are available in the States but are still offered by only a handful of laboratories.

In addition, it would be impossible to test for brain mast cells, as in order to do this you’d need to do a brain biopsy – better performed on mice in the lab, preferably after death!

It is, however, possible to detect circulating mitochondrial DNA and/or ATP, which would be an indicator that mast cells have moved mitochondria from cellular to extra-cellular, and therefore show both mast cell activation and mitochondrial dysfunction [6].

So, how are we to prove mast cell activation is responsible for the symptoms of M.E.?  I wish I knew.  I’m just a regular person, not a scientist, but I’m hoping someone much cleverer than I will come up with a solution………and soon.

Therapy

Can anything stabilize mast cells and stop them from being quite so trigger happy (we can’t disable them altogether otherwise we’d have no immunity and the first pathogen we came across would kill us)?  The answer is currently a rather weak “yes”, but much better drugs are needed.

As mentioned, currently available anti-histamines can help with symptoms attributed to histamine mediator release such as insomnia, reflux, asthmatic issues, IBS.  However, although they stop histamine binding to H1 and H2 receptors, they still leave the histamine floating around the body where it’s free to bind to H3 and H4 receptors causing other symptoms.  The first generation anti-histamine Hydroxyzine, however, crosses the blood-brain barrier and acts as both an anti-histamine and mast cell stabilizer.  It has been shown to inhibit allergic encephalomyelitis and associated brain mast cell activation in animals[5].  It is also useful for anxiety (possibly as a result of CNS activation through mast cells), but can be very sedating.

To reduce the amount of histamine the body has to cope with you could, like me, try following a low histamine diet.  But again, this only deals with histamine not the other 29 mast cell mediators.  For that, you need to stop mast cells from unnecessarily spilling their mediator contents in the first place.

Sodium chromoglycate stabilizes mast cells in the skin and GI tract but cannot penetrate the blood-brain barrier.  SC may be useful if you have persistent GI symptoms such as cramp, nausea, diarrhoea, or persistent allergy-type symptoms such as food intolerance, chemical sensitivity, asthma/breathing problems etc.  A table of other drugs currently used to treat MCAD can be found within this research paper.

Luteolin is a flavanoid which is an anti-oxidant, anti-inflammatory, mild metal chelator, mast cell inhibitor and is neuro-protective – it crosses the blood-brain barrier where sodium chromoglycate does not.  You can buy luteolin in capsule/powder form, however only 5% goes into the bloodstream.  Ideally a much better way of getting luteolin into the brain is needed.  Dr Theoharides has developed a non-prescription capsule called Neuroprotek which contains Lutoelin, and 2 other flavaoids known for their mast cell stabilizing properties Quercetin and Rutin, mixed with olive kernel oil which helps the body deliver and absorb the flavonoids.  This is not a cure for mast cell disease but may help the severity of symptoms.  (Note: Dr Theoharides makes no money from the sale of Neuroprotek). 

Luteolin, Quercetin and Rutin are also found in various foods, so it can’t do anything but good to include these in the diet:

    • Luteolin is present in celery, green pepper, parsley, thyme, dandelion, chamomile tea, carrots, olive oil, peppermint, rosemary and oregano.
    • Quercetin is found in many foods, particularly buckwheat, blueberries, red grapes, red onion, capers, dill, watercress, kale and sweet potato.
    • Rutin is found in buckwheat, asparagus, citrus fruits, apple and berries such as cranberry.

Other treatments

There have been some exciting recent developments in M.E. treatment in a trial using the anti-cancer drug Rituximab.  Rituximab works on b-lymphocytes and, strangely enough, b-lymphocytes are controlled by mast cells.  The anti-cancer drug Imatinib has been used by Dr Afrin to treat MCAD (as discussed in his 2011 MCAS lecture) with great success.  Strange that these two very similar drugs have been used to treat the same symptoms in two supposedly separate diseases!

Low dose Naltrexone (an immune modulator) has also been used with some success by people suffering from M.E.  And, again, Naltrexone is also used to treat MCAD.

Some of the drugs generally used to treat the symptoms in M.E. have mast cell mediator properties.  For example, some people find the anti-depressants Zispin, Doxepin and Amitriptylene helpful for both pain and insomnia – the reason being they all have anti-histamine properties (I didn’t have any problems at all with hives or itching until I became allergic to Zispin and had to stop taking it – then my hives appeared apparently ‘out of no-where’).  Some people have found a reduction in M.E. symptoms by taking high doses of Vitamin C – the reason being Vitamin C is a mast cell stabilizer (and used quite widely by people with MCAD and Mastocytosis).  The reason these drugs help but don’t cure M.E. is that they’re a sticking plaster over symptoms caused by mast cell mediators, but don’t get to the root of the problem which in my very humble, and totally non-medical opinion, is mast cell activation.

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REFERENCES & FURTHER READING

Table 1:

Photo of table of mast cell mediators

4. Gerwyn Morris, Michael Maes:
Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics
BMC Medicine 2013, 11:205

5.Dimitriadou V, Pang X, Theoharides TC.:
 Hydroxyzine inhibits experimental allergic encephalomyelitis (EAE) and associated brain mast cell activation.
Int J Immunopharmacol 2000;22:673–84.

6. Theoharis C. Theoharides, MS, PhD, MD
Extracellular Mitochondrial Components Secreted from Activated Live Mast Cells Act as “Innate Pathogens” and Contribute to Autism Pathogenesis
International Trends in Immunity Vol.1 No.2, April 2013

7. Duraisamy Kempuraj, Shahrzad Asadi, Bodi Zhang, Akrivi Manola, Jennifer Hogan, Erika Peterson, Theoharis C Theoharides:
 Mercury induces inflammatory mediator release from human mast cells
Journal of Neuroinflammation 2010, 7:20

8. Theoharis C. Theoharides and Aphrodite D.Konstantinidou:
Corticotropin-releasing hormone and the blood-brain-barrier
Frontiers in Bioscience 12, 1615-1628, January 1, 2007

9.Theoharis C. Theoharides, Duraisamy Kempuraj, Michael Tagen, Pio Conti, Dimitris Kalogeromitros
Differential release of mast cell mediators and the pathogenesis of inflammation
Immunological Reviews 2007 Vol. 217: 65–78

10. H.J. LUCAS, C.M. BRAUCH and T.C. THEOHARIDES:
Fibromyalgia – New Concepts of pathogenesis and Treatment
International Journal of Immunopathology and Pharmacology Vol. 19, no. 1, 5-9 (2006)

11. Hanneke PM van der Kleij and John Bienenstock:
Significance of conversation between mast cells and nerves
Allergy, Asthma & Clinical Immunology 2005, 1:65-80

12. Stephen D. Skaper, Pietro Giusti, and Laura Facci:
Microglia and mast cells: two tracks on the road to neuro-inflammation
The FASEB Journal article fj.11-197194. Published online April 19, 2012.

13. Narita S,  Goldblum RM,  Watson CS,  Brooks EG,  Estes DM,  Curran EM,  Midoro-Horiuti T:  Environmental estrogens induce mast cell degranulation and enhance IgE-mediated release of allergic mediators.
Environ Health Perspect 2007,  115:48-52.

14. Levy D,  Strassman AM,  Burstein R:
A critical view on the role of migraine triggers in the genesis of migraine pain.
Headache 2009, 49:953-957.

15. Levy D,  Burstein R,  Kainz V,  Jakubowski M,  Strassman AM:
 Mast cell degranulation activates a pain pathway underlying migraine headache.
pain 2007, 130:166-176.

16. Theoharides TC,  Donelan J,  Kandere-Grzybowska K,  Konstantinidou A:
The role of mast cells in migraine pathophysiology.
Brain Res Brain Res Rev 2005, 49:65-76. 

17. Cyndya Shibao, Carmen Arzubiaga, L. Jackson Roberts II, Satish Raj, Bonnie Black, Paul Harris, Italo Biaggioni:
Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders
Hypertension. 2005; 45: 385-390

Further Reading

  • A list of all research papers on mast cells conducted by Dr Theohardies can be found here.

©jak 2013.  All rights reserved.

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26 thoughts on “The Canary

  1. Sam

    This is one interesting read. I can see why you are excited. It’s helped made it clearer in my head about the areas each affect and some meds to suggest to consultant. Thanks for finding and sharing.

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    1. bertieandme Post author

      I *am* excited Sam! I don’t think H1 and H2 receptors are implicated in M.E., but I really do think H3 and H4 are.

      Soz not been in touch with you (or anyone else!) this past week or so. It’s taken hours every single day to write this article – I was so buzzed though I couldn’t put it down 😉 Will catch up privately later this week now I’ve got it off my chest lol! xx

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  2. Pingback: IV saline experiment… causes histamine release and angioedema. | Rag and Bone Shop of the Heart

  3. Tricia

    This is a very informative article and fairly easy to understand too. Thank you so much for the time and effort you put in to writing it. Well done!

    Liked by 1 person

    Reply
  4. luciduniverse

    Jak, yes the doctor does mention Fibromyalgia and Chronic Fatigue Syndrome and related disorders. I did not catch the minutes it starts at but it is a Bubble Diagram where he briefly makes a connection between other disorders which are related to eachother.

    Liked by 1 person

    Reply
  5. Mohamad

    I really found the most important thing in this work that it has been written with emotions and passion which give it very magic feeling more important than science….

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  6. Valancy

    I just found your site and this post in Pinterest. Thank you from the bottom of my heart. Thank you for taking the time and energy to make such a comprehensive post/summary with all the links. I have been doing a lot of internet searching for Mast Cell and your post is very well done and will be very useful.

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  7. ChiefHomeExec

    This is a Very Helpful Article indeed. Years and years ago, when diagnosed as a teen with autoimmune issues, the dr tried to give the explanation as to what was happening. I replied with words to the effect that I understood that basically I was allergic to myself and still remember to this day the doctor laughing at me and shaking his head at the silliest thing he had ever heard. I have had varying reactions to the same theory ever since but it has only become more cemented in my mind, and your mast cell research fully explains my symptoms and observations! Even down to the inexplicably off-the-charts-high IgE readings. I am so very glad of your blog. Thank you!

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    1. bertieandme Post author

      I think we’ve all had the laughing doctor scenario sadly. I was told by many doctors it was impossible to react to all classes of drugs as they all work differently and I was just having a panic attack for no good reason – that advice could have killed me, because i was actually having anaphylaxis and, as it turns out, severe multiple drug reactions are very common in MCAD.

      Sorry to hear you’ve suffered so long with symptoms, but glad you’re finding the blog helpful and I hope you can find a good mast cell doctor to get tested and hopefully treated.

      Jak x

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  8. Teresa Wilkinson

    Hi, thanks for all your research and ponderings! I’m a bit confused re citrus fruits. Under “Therapy” you say Rutin is found in various foods, and it can’t do anything but good to include these in the diet. But amongst the foods mentioned are citrus fruits, usually listed – and elsewhere by you too – as a major no-no. My own feeling is that citrus fruits are helpful to my health, but I’ve cut them out, over the past month, as part of a low-histamine diet. Some of my symptoms have got a lot worse since then, and though I can’t be sure why, I would be very interested in your thoughts on citrus, yes or no! (I was diagnosed last year with EDS and PoTS, after 30 years of apparent M.E. One of the EDS doctors suspects mast cell activation disorder too.) Many thanks! Teresa

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  9. Adi Setyawan

    I’m glad to these written, became add my knowing about general disease that start from intolerance histamine. Thank you Dr Theoharides.Also, I ‘m follow all you journal about systemic mast cell activation syndrome. It’s have suggest in established to my diagnosis for my infertility patient woman. As we know that female have higher risk to autoimmune disease than male, if them have sedentary lifestyles, in which more high fat diet, of course become high histamine diet.

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  10. zippy890

    Jak, Good article. I’ve had M.E./CFS for over 30 years, and some form of mast cell disorder for 25 years. I’m very sorry to hear about your sufferings. There is an usual therapy you might want to take a look at. It is infecting yourself with parasitic worms. Sounds crazy, I know. Believe me, I nearly went blind studying this issue for months before I decided to take the plunge ! Here is my blog on this therapy: https://zippy890.wordpress.com/
    Contained in the blog, I have a long, four part, post on CFS and the theory of Biome Depletion under the tab “Miscellaneous Musings”. I encourage you to pursue that article, esp. the various link outs. I live in the U.S., and am friends with other Masties. One is going to the Center For Excellence in Mastocytosis in Boston, MA.. They are also a prominent figure in the worm community, and their physician is aware of their use of worms. Here is a 2010 article partly about worms, notice the physician involved, Dr. Marianna Castells, a prominent doctor in mastocytosis. http://www.alternet.org/story/148949/are_we_killing_ourselves_with_cleanliness_as_number_of_allergy_sufferers_soar%2C_potential_cures_are_more_radical
    Also, the parasite that I am currently using, rat tapeworms, is being produced at a lab in Lancaster, U.K. , for a U.S. based company, Biome Restoration
    http://biomerestoration.com/ I’ve gotten to know some of the people there, and they are great folks. Anyway, it’s interesting that the lab is sort of in your neck of the woods. Also, here is a 2012 article from a chap on your side of the pond, Graham A. W. Rook is Emeritus Professor of Medical Microbiology at the Centre for Clinical Microbiology, University College London, United Kingdom.
    https://www.microbemagazine.org/index.php?option=com_content&view=article&id=4700:a-darwinian-view-of-the-hygiene-or-old-friends-hypothesis&catid=950&Itemid=1301

    So Jak, if you haven’t heard of this before, you are likely quite amazed by now. Understandably so. Now, I am not well. And this therapy might not help you at all. Who knows ? Further, I have NOTHING to sell. I’m just a fellow traveler, who knows the torments of CFS and MCADS. You have a great blog site, and I wanted to make you aware of this, in case you didn’t know. You can contact me at my blog site, if you like. I will assist you in anyway I can.

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  11. Kerry

    Thank you so much for this article. I have fallen down a rabbit hole of epic proportions while trying to work out how to feel well again but this site has been by far the most informative, easy to digest and trustworthy. And this article, in particular, explains an awful lot that I needed to understand. I am so tired of my doctor’s receptionist knowing my voice on the phone without me having to tell her who I am. I am so tired of all my tests coming back negative even though I feel like an old dishrag. I finally feel as though there is an end in sight. I can’t thank you enough for that!

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