Hypothesis: Myalgic Encephalomyelitis (ME) as a Mast Cell Activation Disorder (MCAD)

Background: Myalgic encephalomyelitis (ME) is a severely debilitating neuroimmune disease with the characteristic feature of post-exertional malaise (PEM). Whilst multiple studies have found various abnormalities, there is significant heterogeneity in findings; as such there is no consensus regarding the underlying aetiology. Mast cells are immune cells most commonly recognised for their role in allergy. The scope of biological effects mast cells have is growing in recognition, with inappropriate mast cell degranulation increasingly recognised to cause a range of symptoms and downstream effects. Hypothesis: ME may be a mast cell activation disorder variant, with exertion being the primary trigger to inappropriate mast cell degranulation, possibly due to mast cell hypersensitivity to metabolically produced reactive oxygen species. Mast cell activation releases mitochondrial components which further act as an “autopathogen”, whilst each degranulation cycle reduces mast cell metabolic flexibility. This cycle is perpetuated in those with genetic susceptibility towards Th2-dominance, which acts to both impede pathogen clearance and drive autoinflammation. The resultant chronic immune activation triggers immune and host metabolic changes resembling sickness metabolism. This causes a range of multisystemic symptoms, worsened by exertion, akin to a chronic sickness behaviour. Due to the close and bidirectional interactions between mast cells, the nervous system, and mitochondria, such a hypothesis can potentially explain various aspects of ME, such as: Why ME can be caused by a range of exposures; the core symptoms of ME; individual variances in clinical presentations; why pacing can prevent worsening; and time trends and symptoms of PEM. Several potential counterarguments are also discussed, along with methods to try and test the hypothesis. Conclusion: Several lines of evidence suggest it is at least plausible that (a subgroup of) ME could be a unique and distinct variant of a mast cell activation disorder. As the immune system and metabolism are intrinsically linked, it could be argued this is an immunometabolic mast cell disorder phenotype. However, this is one of many plausible hypotheses, requires testing and validation, and does not change the current recommendations for managing ME, nor should it be used as evidence that the aetiology of ME is established.