Alpha-Tryptase as a Risk-Modifying Factor for Mast Cell-Mediated Reactions

Abstract

Purpose of review: To provide an overview on the current understanding of genetic variability in human tryptases and summarize the literature demonstrating the differential impact of mature tryptases on mast cell-mediated reactions and associated clinical phenotypes.

Recent findings: It is becoming increasingly recognized that tryptase gene composition, and in particular the common genetic trait hereditary alpha-tryptasemia (HαT), impacts clinical allergy. HαT has consistently been associated with clonal mast cell disorders (MCD) and has also been associated with more frequent anaphylaxis among these patients, and patients in whom no allergic trigger can be found, specifically idiopathic anaphylaxis. Additionally, more severe anaphylaxis among Hymenoptera venom allergy patients has been linked to HαT in both retrospective and prospective studies. An increased relative number of α-tryptase-encoding gene copies, even in the absence of HαT, has also been associated with systemic mastocytosis and has been shown to positively correlate with the severity of mast cell-mediated reactions to vibration and food. These findings may be due to increased generation of α/β-tryptase heterotetramers and differences in their enzymatic activity relative to β-tryptase homotetramers. HαT is a naturally occurring overexpression model of α-tryptase in humans. Increased relative α-tryptase expression modifies immediate hypersensitivity symptoms and is associated with more frequent and severe mast cell-mediated reactions, ostensibly due to increased α/β-tryptase heterotetramer production.

Keywords: Anaphylaxis; Basal serum tryptase; Hereditary alpha-tryptasemia; Mastocytosis.

Fig. 1

Frequency of reported tryptase haplotypes and genotypes arising from TPSB2 and TPSAB1. *Unknown prevalence

Fig. 2

Schematic demonstrating unique α/β-tryptase heterotetrameric activity after mast cell degranulation on EMR2 and PAR2

Fig. 3

Gene-dosage effect of α-tryptase on severity of mast cell–mediated reactions. A Symptom scores indicative of reaction severity induced by vibration challenge [5]. B Severity of mediator symptoms in mastocytosis patients using a validated scoring system [16]. C Severity of allergic reaction during an oral peanut challenge in peanut-allergic children [32•]

Fig. 4

Prevalence of HαT in MCD and impact on anaphylaxis. A Prevalence of HαT among healthy volunteers (HV, gray bars) and among individuals with clonal mast cell disorders (MCD, black bars) from six independent studies [–52]. B Prevalence of anaphylaxis among individuals with MCD based upon presence HαT (black bars) or absence of HαT (gray bars). Combined shown on the far right. P-values were calculated from the primary data of these studies using Fisher’s exact test