Mast cells and post-exertional malaise

By Paolo Maccallini

There is a rare disease in which mast cells degranulation is induced by an exercise of low intensity, particularly by exercises that require whole body involvement, such as jogging, aerobics and walking (Barg W et al. 2011). The name of this disease is exercise-induced anaphylaxis (EIA). There is another recently defined disorder due to abnormal activity of mast cells, the name of which is mast cell activation syndrome (MCAS), that has been linked to fatigue, brain fog, and orthostatic intolerance (Akin L, 2010).

The hypothesis
MCAS has already been somehow associated to ME/CFS by various Authors (Afrin L et al. 2016) however, to my knowledge, nobody has suggested that the possible link between CFS and MCAS may be an exercise-induced increased release of mediators by mast cells. In other words, post-exertional malaise (PEM) could be – according to this hypothesis – a form of exercise-induced mast cell activation similar to EIA, but without anaphylaxis. A possible reason for exercise-induced mediators release could be found in the abnormally high level of C4a, six hours after exercise in CFS (Sorensen, 2003). C4a – along with C4b – is the split product of C4, a protein of the complement system. As C4a is also an anaphylatoxin (i.e. a protein which stimulates mast cells) it could be a trigger for exercise-induced activation. One of the feasible mechanisms for mast cells induced fatigue is the following one: release of fragmented mitochondria by activated mast cells (Zhang et al. 2012) may be a trigger for the cell danger response (CDR) through activation of the purinergic system, with consequent shut down of mitochondria (Naviaux R, 2013).

Experimental proof
This hypothesis can be verified by measuring mast cells specific mediators after a physical effort. These mediators are:

Less specific mast cells mediators are IL-1, IL-6, IL-8, TNF-alpha, and VEGF, among others.

Mast cells and Lyme disease
It has been demonstrated in vitro the potential for mast cells activation by B. burgdorferi spirochetes, with a consequent TNF-α release (Talkington et al. 1999). Thus, a possible link between mast cells mediators and currently unexplained symptoms of Lyme disease and – more importantly – of post-treatment Lyme disease syndrome (PTLDS), should be investigated.

Please, visit also this post on mast cells and anti-cardiolipin antibodies in CFS and Lyme disease.


11 thoughts on “Mast cells and post-exertional malaise

  1. This is a terrific essay. Thank you for writing it.

    Today I “discovered” mast cells. I’ve been vaguely aware of their existence for a while, but I never gave them much thought, since the mast cell disease folks seem to be severely allergic to nearly anything and everything. I certainly don’t have symptoms like that, for which I am grateful.

    Anyway I saw a reference some place to a possible connection between POTS and mast cells, so I searched Pubmed and found “Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders” [1] and “The role of mast cells in functional GI disorders” [2]. It was like getting hit between the eyes. Mast cell activation explains many of my symptoms better than auto-antibodies to adrenergic receptors [3], although I don’t know any reason a person couldn’t have both.

    You wrote: “release of fragmented mitochondria by activated mast cells (Zhang et al. 2012) may be a trigger for the cell danger response”.

    Wow. I’m sure you know by now that Ron Davis and team have isolated a “Substance X” from patient serum that causes healthy cells to shut down and is now working overtime to identify it. We will soon know if the mysterious Substance X is fragmented mitochondria, an auto-antibody, or something else. We are finally about to see some real answers from real researchers.


    Liked by 1 person

    1. Thank you for this thoughtful comment to my article! You might be interested in the following paper, where the Authors were able to identify a group of patients with POTS, fatigue and joint hypermobility who are carrier of a specific genetic defect: a duplication or triplication of the gene for triptase, one of the main proteolitic enzymes of mast cells:

      These patients can be identified by mesuring triptase level in blood.


  2. I wonder why there is so little interest in mast cells among the ME patient and researcher communities. The more I learn about mast cells and how their actions might relate to my symptoms, the more I want to study them.

    I keep thinking that *someone* must’ve looked for mast cell problems in a “CFS” cohort, so I checked both the IOM report (2015)and the AHRQ evidence report.(2014). Nada.The phrase “mast cell” only appears once in a list of studies that were excluded from review. Those two reports cost about two million dollars, as I recall, but they were unable to uncover any of the three studies I listed above, or the studies referenced in Paolo’s article. I guess that’s what happens when rigid protocols exclude intuition and actual thinking.

    Liked by 1 person

    1. Dear jimells, recently the Australian group from Griffith University has found an increase in a specific subpopulation of mast cells in blood samples from CFS patients, compared to healthy controls. Moreover, mast cells from CFS patients seem to be more active in antigen presentation than mast cells from healthy volunters are. You can find this study here:

      Thank you for reading. Take care!


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