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
(encoding β-tryptase) and
(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
-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,
genotyping should be included in the diagnostic algorithm in patients with symptomatic SM, severe anaphylaxis or MCAS.
In normal humans, tryptase, a serine protease with multiple biological activities, is synthesized nearly exclusively by mast cells (MCs). While immature forms of tryptase (α- and β- monomers) are ...constantly released by MCs and can be measured in the serum of normal individuals as the basal serum tryptase (BST) level, mature tryptases (mostly tetramers of β-tryptase) are retained in the secretory granules of MCs and are released only upon cell activation. Such MC activation occurs during IgE-mediated allergic reactions and increased levels of tryptase, which can be measured immediately after degranulation, are involved in the pathophysiology of immediate hypersensitivity. Interestingly, recent studies have reported that around 5% of the general population present with a genetic trait called hereditary alpha-tryptasemia (HαT). In HαT+ patients, the BST level is increased. Mastocytosis are a group of hematologic neoplasms characterized by an accumulation of atypical MCs in one or several organs/tissues, often accompanied by MC activation. Increased BST level is a hallmark of systemic mastocytosis (SM) and a diagnostic, prognostic and follow-up marker. Interestingly, the incidence of the HαT trait has been found increased in SM patients (up to 18% of the cases) and HαT+ SM patients are more prone to develop anaphylaxis, making HαT a disease penetrance and phenotype modifier.
Chez le sujet normal, la tryptase, une sérine protéase aux multiples activités biologiques, est synthétisée presque exclusivement par les mastocytes (MCs). Alors que les formes immatures de tryptase (monomères α- et β-) sont constamment libérées par les MCs et peuvent être mesurées dans le sérum des sujets normaux en tant que taux basal de tryptase, les tryptases matures (principalement des tétramères de β-tryptase) sont retenues dans les granules de sécrétion des MC et ne sont libérées que lors de l’activation cellulaire. Une telle activation des MCs se produit au cours des réactions allergiques IgE-dépendantes et des niveaux accrus de tryptase, qui peuvent être mesurés immédiatement après la dégranulation, sont impliqués dans la physiopathologie de l’hypersensibilité immédiate. Fait intéressant, des études récentes ont rapporté qu’environ 5 % de la population générale présente un trait génétique appelé alpha-tryptasémie héréditaire (HαT). Chez les patients HαT+, le taux basal de tryptase sérique est augmenté. Les mastocytoses sont un groupe d’hémopathies malignes caractérisées par une accumulation de MCs atypiques dans un ou plusieurs organes/tissus, souvent accompagnée d’une activation de ces cellules. L’augmentation du taux basal de tryptase sérique est une caractéristique des mastocytoses systémiques (MS) et un marqueur du diagnostic, du pronostic et du suivi de ces maladies. Fait intéressant, l’incidence du trait HαT est augmentée chez les patients avec MS (jusqu’à 18 % des cas) et les patients MS HαT+ sont plus enclins à développer des réactions anaphylactiques, faisant de l’HαT un modulateur de la pénétrance et du phénotype de la maladie.
Purpose of Review
To describe inherited and acquired genetic variants and clinical entities associated with increased basal serum tryptase (BST), distinguish these levels from those which acutely ...rise due to mast cell activation, and finally to characterize the association between chronically elevated basal serum tryptase and episodic mast cell activation.
Recent Findings
Hereditary alpha-tryptasemia is a commonly inherited genetic cause for basally elevated serum tryptase and explains elevated BST in many individuals who do not have evidence of clonal myeloid or mast cell disease. When clonal myeloid disease is present, BST may be elevated and can be a biomarker of a number of disparate disorders of the myeloid compartment.
Summary
Elevated BST is most commonly caused by hereditary alpha tryptasemia but may also be indicative of clonal myeloid disease. Clinical reports suggest that elevated BST is associated with increased risk for more severe systemic allergic reactions to a number of eliciting agents and exposures. Additional studies are needed to determine the role that inherited or acquired genetic variants associated with elevated BST and clonal or non-clonal myeloid diseases may play in these reactions.
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.
Summary
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.
Purpose of Review
The current article aims to provide a comprehensive update on diagnostic criteria for mast cell activation syndrome (MCAS), addressing challenges in diagnosing and classifying MCAS ...and its variants.
Recent Findings
In recent years, there has been a significant increase in our knowledge regarding the underlying mechanisms responsible for the activation of mast cells (MCs) in various pathological conditions. Furthermore, a set of criteria and a classification for MCASs have been established. MCAS is characterized by the presence of typical clinical symptoms, a substantial elevation in serum tryptase levels during an attack compared to the patient’s baseline tryptase levels, and a response to MC mediator–targeting therapy.
Summary
In this report, a thorough examination was conducted on the contemporary literature relating to MCAS, with a focus on comparing the specificity, sensitivity, and robustness of MCAS-related parameters within proposals for diagnosing and classifying MCAS and its variants. Moreover, the significance of employing specific consensus criteria in the assessment and categorization of MCAS in individual patients was underscored, due to the escalating occurrence of patients receiving a misdiagnosis of MCAS based on nonspecific criteria.
Hereditary alpha-tryptasemia (HαT) is an autosomal dominant disorder estimated to affect 5% of the population. High baseline tryptase level is a consistent finding, but there is a great variability ...of clinic manifestations, including no symptoms at all. We describe a case of HαT in a 5 years 8 months old girl manifesting with idiopathic anaphylaxis and elevated baseline tryptase level. As more cases of HαT are described, a better understanding of the clinical phenotype will be acquired.
Mastocytosis is a rare and complex disease characterized by expansion of clonal mast cells (MC) in skin and/or various internal organ systems. Involvement of internal organs leads to the diagnosis of ...systemic mastocytosis (SM). The WHO classification divides SM into indolent SM, smoldering SM and advanced SM variants, including SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Historically, genetic analysis of individuals with pure cutaneous mastocytosis (CM) and SM have focused primarily on cohort studies of inherited single nucleotide variants and acquired pathogenic variants. The most prevalent pathogenic variant (mutation) in patients with SM is
p.D816V, which is detectable in most adult patients. Other somatic mutations have also been identified-especially in advanced SM-in
,
,
,
,
and
, and shown to impact clinical and cellular phenotypes. Although only small patient cohorts have been analyzed, disease associations have also been identified in several germline variants within genes encoding certain cytokines or their receptors (
,
,
,
,
) and toll-like receptors. More recently, an increased prevalence of hereditary alpha-tryptasemia (HαT) caused by increased
copy number encoding alpha-tryptase has been described in patients with SM. Whereas HαT is found in 3-6% of general Western populations, it is identified in up to 17% of patients with SM. In the current manuscript we review the prevalence, functional role and clinical impact of various germline and somatic genetic variants in patients with mastocytosis.
Idiopathic anaphylaxis (IA) is a diagnosis of exclusion and is based on the inability to identify a causal relationship between a trigger and an anaphylactic event, despite a detailed patient history ...and careful diagnostic assessment. The prevalence of IA among the subset of people who experienced anaphylaxis is challenging to estimate and varies widely, from 10 to 60%; most commonly noted is ∼20% in the adult anaphylactic population. Comorbid atopic conditions, such as food allergy, allergic rhinitis, and asthma, are present in up to 48% of patients with IA. Improved diagnostic technologies and an increased understanding of conditions that manifest with symptoms associated with anaphylaxis have improved the ability to determine a more accurate diagnosis for patients who may have been initially diagnosed with IA.
Literature search was conducted on PubMed, Google Scholar and Embase.
Galactose-α-1,3-galactose (α-gal) allergy, mast cell disorders, and hereditary a-tryptasemia are a few differential diagnoses that should be considered in patients with IA. Unlike food allergy, when anaphylaxis occurs within minutes to 2 hours after allergen consumption, α-gal allergy is a 3-6-hour delayed immunoglobulin E-mediated anaphylactic reaction to a carbohydrate epitope found in red meat (e.g., beef, lamb, pork). The more recently described hereditary α-tryptasemia is an inherited autosomal dominant genetic trait caused by increased germline copies of tryptase human gene alpha-beta 1 (TPSAB1), which encodes α tryptase and is associated with elevated baseline serum tryptase. Acute management of IA consists of carrying an epinephrine autoinjector to be administered immediately at the first signs of anaphylaxis. Long-term management for IA with antihistamines and other agents aims to potentially reduce the frequency and severity of the anaphylactic reactions, although the evidence is limited. Biologics are potentially steroid-sparing for patients with IA; however, more research on IA therapies is needed.
The lack of diagnostic criteria, finite treatment options, and intricacies of making a differential diagnosis make IA challenging for patients and clinicians to manage.
Il existe une association spécifique entre désordre mastocytose clonal (DMC), alpha-tryptasémie héréditaire (ATH), et anaphylaxie au venin d’hyménoptère (AVH) sévère. Près de 8 % des patients ...allergiques au venin d’hyménoptère présentent un DMC. Une ATH est retrouvée chez au moins 8,5 % des patients présentant une AVH de grade 4. Pour ces patients le risque d’anaphylaxie fatale est majeur. La coexistence des deux maladies accroît le risque d’AVH sévère voire fatale.
La présentation souvent atypique des réactions allergiques en cas de DMC ou d’ATH peut conduire à des erreurs de prise en charge si elle est méconnue, soulignant l’importance et le besoin de stratégies diagnostiques pour pouvoir identifier correctement ces patients. Une réaction à prédominance cardiovasculaire en l’absence d’urticaire ou d’angioedème après piqûre d’hyménoptère est suspecte de DMC sous-jacent, même en cas de tryptasémie basale normale, et ne devrait pas être confondue avec une attaque de panique ou une syncope vaso-vagale. De même, un antécédent de syncope inexpliquée ou d’anaphylaxie “idiopathique” peut révéler une mastocytose ou une ATH.
Une immunothérapie allergénique (ITA) est indispensable pour tout patient allergique au venin d’hyménoptère avec DMC sous-jacent ou tryptasémie basale élevée, et devrait être proposée à vie du fait d’un risque élevé de rechute d’allergie sévère et parfois fatale à l’arrêt de l’immunothérapie.
Severe hymenoptera venom anaphylaxis (HVA) is specifically associated with clonal mast cell disorder (CMD) and hereditary alpha-tryptasémia (HαT). About 8% of hymenoptera venom allergic patients present a CMD. HαT is found in at least 8.5% of patients with Müller grade 4 HVA. For these patients the risk for fatal anaphylaxis is highest. The coexistence of HαT with CMD increases the risk of severe or fatal HVA.
The atypical presentation of allergic reactions in case of CMD or HαT might lead to inappropriate care and management if proper diagnosis is missed, underscoring the importance and need for diagnostic strategies in order to correctly identify these patients. Predominant cardiovascular symptoms in the absence of urticaria or angioedema after an insect sting are suggestive of underlying CMD, and should be distinguished from panic attack or vasovagal syncope. Similarly, an unexplained syncope or an “idiopathic” anaphylaxis might reveal mastocytosis or HαT.
Venom immunotherapy (VIT) is essential for all patients with CMD or with elevated basal tryptase levels and should be maintained life-long because of the high risk of severe or sometimes fatal relapse when VIT is discontinued.
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