Mast cell activation: beyond histamine and tryptase.

Mast cells are found in all tissues and express numerous surface receptors allowing them to sense and respond to allergic, autoimmune, environmental, neurohormonal, pathogenic and stress triggers. Stimulated mast cells are typically called 'activated' but the mechanisms involved and the mediators released can vary considerably. Mast cell activation diseases (MCADs) include primary, secondary and idiopathic conditions, especially mast cell activation syndrome (MCAS), but mast cells are activated in many other disorders making the diagnosis and treatment challenging. Mast cells can release numerous biologically active mediators, some of which are prestored in secretory granules while others are newly synthesized and released without degranulation. Most of the emphasis has so far been on secretion of histamine and tryptase, which do not explain all the multisystemic symptoms experienced by patients with MCADs. As a result, drug development has focused on antiproliferative therapy or blocking the action of individual mediators and not on inhibitors of mast cell activation. Activated mast cells are involved in the pathogenesis of MCADs, but also in other disorders making appropriate diagnosis and treatment challenging. The definition of mast cell activation should be expanded beyond histamine and tryptase, with an emphasis on better detection and treatments.