Mast cell activation disorders: mechanisms, comorbidities and look-alike

Introduction: Mast Cells (MCs) are unique tissue perivascular immune cells found 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 neuroinflammatory conditions. Areas covered: MCs respond to chemical, infectious, physical and stress stimuli leading to release of hundreds of proinflammatory, neurotoxic, tissue-disrupting and vasoactive mediators, known as MCA. The release of MC mediators can occur via different mechanisms without always release of tryptase. Among MCADs, the criteria for diagnosing mast cell activation syndrome (MCAS) require elevated serum tryptase or elevated urine MC mediator metabolites and/or multi-organ involvement. Patients with MCADs often present with comorbidities with suspected MCA or are 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 for the clinician. Expert opinion: MCA is present in many conditions that do not qualify as MCADs. Research is needed to better define and regulate MCA, leading to more accurate diagnosis and effective inhibitors for the treatment of MCADs and related disorders.