Tryptase genetics and anaphylaxis

Abstract

Tryptases secreted by tissue mast cells and basophils can enter the bloodstream. In human subjects tryptases are encoded by several genes and alleles, including alpha, beta, gamma, and delta. Common variations include complete absence of alpha genes. Until recently, alpha tryptase was considered to be the major tryptase secreted at baseline and in mastocytosis. However, lack of alpha tryptase genes has little effect on circulating tryptase levels, which are now thought mainly to consist of inactive pro-beta tryptase secreted constitutively rather than stored in granules with mature tryptases. Pro-beta tryptase levels thus might reflect total body mast cell content. In contrast, mature beta tryptase can increase transiently in severe systemic anaphylaxis and confirm the diagnosis. However, it might fail to increase in food anaphylaxis or might increase nonspecifically in samples acquired after death. Thus pro- and mature beta tryptase measurements are useful but associated with false-negative and false-positive results, which need to be considered in drawing clinical conclusions in cases of suspected anaphylaxis.

FIG 1

Activation and secretion of α, β, and γ tryptases. Catalytically inactive protryptases in the endoplasmic reticulum (ER) follow regulated or constitutive secretory pathways. β Tryptases processed by removal of the propeptide are assembled into catalytically active, heparin-stabilized tetramers and stored within the mast cell secretory granule, along with other preformed mediators. γ Tryptases activated by propeptide removal remain membrane associated. α Tryptases, which have a mutation preventing removal of the propeptide, are directly secreted, along with residual pro-β tryptase. On secretion, some mature β tryptases make their way to the bloodstream, where they are detected by tryptase immunoassays, along with secreted pro-α and pro-β tryptase. On release from the secretory granule, γ tryptase remains attached to the external surface of the mast cell plasma membrane.