Mast cell activation disorders: mechanisms, comorbidities and look alike

INTRODUCTION: Mast Cells (MCs) are unique tissue immune cells found perivascularly close to nerves at interfaces with the external environment. Upon detection of danger signals, MCs act as master responders aiming to restore homeostasis. If MCs are not optimally regulated, they can contribute to the pathogenesis of MC activation disorders (MCADs) and other chronic neuroinflammatory conditions that affect about 30% of the population. AREAS COVERED: MCs respond to chemical, infectious, physical and stress stimuli, leading to release of hundreds of proinflammatory, neurotoxic, tissue-disrupting and vasoactive mediators, collectively termed 'mast cell activation' (MCA). The release of MC mediators can occur via different secretory mechanisms without always the release of histamine and tryptase. Among MCADs, the criteria for diagnosing mast cell activation syndrome (MCAS) have been confusing, with most specialists requiring elevated serum tryptase, while others advocating elevated urine MC mediator metabolites or multiorgan involvement. Patients with MCADs often present with comorbidities, where MCA is also suspected, and can be mistaken for other conditions with similar symptomatology that worsen with stress, implicating neurohormonal processes. This review aims to clarify inconsistencies and misconceptions while providing practical suggestions whenever possible. EXPERT OPINION: MCA is present in many conditions that do not qualify as MCADs let alone MCAS. Better efforts are needed to more accurately define and regulate MCA, leading to more accurate diagnosis and development of effective inhibitors for the treatment of MCADs and related disorders.