Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond

Abstract

Tryptase is a serine protease that is predominantly produced by tissue mast cells (MCs) and stored in secretory granules together with other pre-formed mediators. MC activation, degranulation and mediator release contribute to various immunological processes, but also to several specific diseases, such as IgE-dependent allergies and clonal MC disorders. Biologically active tryptase tetramers primarily derive from the two genes TPSB2 (encoding β-tryptase) and TPSAB1 (encoding either α- or β-tryptase). Based on the most common gene copy numbers, three genotypes, 0α:4β, 1α:3β and 2α:2β, were defined as “canonical”. About 4–6% of the general population carry germline TPSAB1-α copy number gains (2α:3β, 3α:2β or more α-extra-copies), resulting in elevated basal serum tryptase levels. This condition has recently been termed hereditary alpha tryptasemia (HαT). Although many carriers of HαT appear to be asymptomatic, a number of more or less specific symptoms have been associated with HαT. Recent studies have revealed a significantly higher HαT prevalence in patients with systemic mastocytosis (SM) and an association with concomitant severe Hymenoptera venom-induced anaphylaxis. Moreover, HαT seems to be more common in idiopathic anaphylaxis and MC activation syndromes (MCAS). Therefore, TPSAB1 genotyping should be included in the diagnostic algorithm in patients with symptomatic SM, severe anaphylaxis or MCAS.

Mastocytosis and Mast Cell Activation Disorders: Clearing the Air

“…Atiakshin and others have evaluated the secretome involving chymase, tryptase, and carboxypeptidase, but detailed descriptions of these are beyond the scope of this review and the reader is referred to other publications [ 4 , 18 , 48 , 49 , 50 ]. Tryptase, a neural serine protease that exists as two isoforms, alpha and beta, encoded by separate genes (TPSB2 and TPSAB1), is stored in secretory granules, often in association with other mediators [ 51 ]. Tryptase is released from secretory granules as inactive proenzymes (alpha- and beta-protryptase) following mast cell activation by IgE-dependent and independent processes.…”

“…Tryptase release is coordinated with the development of allergic and inflammatory responses, the latter being associated with tissue remodeling [ 48 ]. Tryptase has many biological effects, including the inactivation of substrates (fibrinogen, fibronectin, collagens, and lipoproteins), regulation of mesenchymal cell proliferation and survival, upregulation of adhesion molecules, and induction of growth factors and cytokines [ 51 ].…”

“…Human tryptase is encoded by genes located on chromosome 16, and three regulatory genes have been described which effect alpha (α), beta (β), and gamma (γ) tryptase expression. Of these, TPSB2 encodes β-tryptase and TPSAB1 encodes either α- or β-tryptase [ 51 ]. The genes TPSABI and TPSB2 can be assessed by the digital drop PCR technique, which usually involves studying a buccal cell sample, and duplications, triplications, and quintuplications are associated with corresponding elevations in basal tryptase levels in the serum.…”

Global Classification of Mast Cell Activation Disorders: An ICD-10-CM–Adjusted Proposal of the ECNM-AIM Consortium

“…[11][12][13][14][15] The severity of an anaphylactic reaction is further determined by the numbers of MCs involved, cytokine exposure, the nature and number of triggers and cofactors (eg, IgE-reactive allergens, nonsteroidals, and toxins such as those within venoms), the type and amount of IgE, the presence of comorbidities (eg, allergy, infectious diseases, or mastocytosis), epigenetic factors, and other patient-related variables (cardiovascular status, physical exercise, nutrition, alcohol, drugs). 3,[11][12][13][14][15][16][17][18][19][20] MC activation (MCA) occurs in a number of physiologic and pathologic states. Acute MCA accompanies IgE-dependent allergic reactions and may result in the clinical picture of anaphylaxis.…”

Mast Cell Diseases in Practice and Research: Issues and Perspectives Raised by Patients and Their Recommendations to the Scientific Community and Beyond

“…They may be influenced by disease-modifying genetic traits, including hereditary a-tryptasemia (HaT), 9 and by comorbidities (eg, IgEdependent allergies, hypersensitivity disorders, certain inflammatory diseases or immune and hematologic disorders). 1,[10][11][12] A potential relationship of MCAS and HaT to other conditions, such as dysautonomia, connective tissue diseases, or immunodeficiency, is under investigation. [11][12][13][14][15] These conditions should be considered in the differential diagnosis.…”