Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes - 04/01/24

Doi : 10.1016/j.jaci.2023.08.015

Laura Polivka, MD, PhD ^a,^b, Marine Madrange, MSc ^b, Cristina Bulai-Livideanu, MD ^c, Stéphane Barete, MD, PhD ^d, Thomas Ballul, MD ^b,^e, Antoine Neuraz, MD, PhD ^f, Celine Greco, MD, PhD ^b,^g, Julie Agopian, MSc ^h,ⁱ, Fabienne Brenet, PhD ^h,ⁱ, Patrice Dubreuil, PhD ^h,ⁱ, Charles Burdet, MD, PhD ^j, Richard Lemal, MD, PhD ^k, Olivier Tournilhac, MD, PhD ^l, Louis Terriou, MD ^m, David Launay, MD, PhD ^m,ⁿ, Laurence Bouillet, MD, PhD ^o, Clément Gourguechon, MD ^p, Ghandi Damaj, MD, PhD ^q, Laurent Frenzel, MD, PhD ^b,^e, Cécile Meni, MD ^b, Hassiba Bouktit, MSc ^b, Anne Florence Collange, BTech ^b, Caroline Gaudy-Marqueste, MD, PhD ^r, Marie Gousseff, MD ^s, Edwige Le Mouel, MD ^t, Mohamed Hamidou, MD, PhD ^u, Antoine Neel, MD, PhD ^u, Dana Ranta, MD ^v, Roland Jaussaud, MD, PhD ^w, Philippe Guilpain, MD, PhD ^x, Danielle Canioni, MD ^y, Thierry Jo Molina, MD, PhD ^b,^y, Julie Bruneau, MD, PhD ^y, Ludovic Lhermitte, MD, PhD ^z, Nicolas Garcelon, PhD ^aa, Rose-Marie Javier, MD ^bb, Fabien Pelletier, MD, PhD ^cc, Florence Castelain, MD ^cc, Frederique Retornaz, MD, PhD ^dd, Quentin Cabrera, MD ^ee, Patricia Zunic, MD, PhD ^ee, Marie Pierre Gourin, MD ^ff, Ewa Wierzbicka-Hainaut, MD, MSc ^gg, Jean François Viallard, MD, PhD ^hh, Christian Lavigne, MD, PhD ⁱⁱ, Cyrille Hoarau, MD, PhD ^jj, Isabelle Durieu, MD, PhD ^kk, Maël Heiblig, MD, PhD ^ll, Sophie Dimicoli-Salazar, MD, PhD ^mm, Jose Miguel Torregrosa-Diaz, MD ⁿⁿ, Angèle Soria, MD, PhD ^oo, Michel Arock, MD, PhD ^pp, Olivier Lortholary, MD, PhD ^b, Christine Bodemer, MD, PhD ^a,^b, Olivier Hermine, MD, PhD ^b,^e,^⁎ , Julien Rossignol, MD, PhD ^b,^e
on behalf the
CEREMAST network
^a Department of Dermatology, Reference Center for Genodermatoses (MAGEC), AP-HP, Necker-Children’s Hospital, Paris Centre University, Paris, France
^b CEREMAST, the Imagine Institute, INSERM U1163, AP-HP, Necker-Children’s Hospital, Paris Centre University, Paris, France
^c CEREMAST, the Department of Dermatology, Hôpital Larrey, CHU Toulouse, Toulouse, France
^d CEREMAST, the Department of Dermatology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
^e CEREMAST, the Department of Hematology, Necker-Children’s Hospital, AP-HP, Paris Centre University, Paris, France
^f Department of Bioinformatics, Necker-Children’s Hospital, AP-HP, Paris Centre University, Imagine Institute, INSERM U1163, Paris, France
^g CEREMAST, the Department of Pain and Palliative Care Unit, Necker-Children’s Hospital, AP-HP, Paris Centre University, Paris, France
^h Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Marseille, France
ⁱ Association Française pour les Initiatives de Recherche sur le Mastocyte et les Mastocytoses (AFIRMM), Marseille, France
^j Centre d’Investigation Clinique, INSERM CIC 1425, AP-HP, Bichat Hospital, Paris Centre University, Paris, France
^k Histocompatibility Laboratory, EA 7453, Université Clermont Auvergne, CHU de Clermont-Ferrand, Clermont-Ferrand, France
^l CEREMAST, the Adult Clinical Hematology, CHU Clermont-Ferrand, INSERM CIC501, EA 7453, Clermont Auvergne University, Clermont-Ferrand, France
^m CEREMAST, the Department of Internal Medicine and Clinical Immunology, Claude Huriez Hospital, CHRU Lille, Lille, France
ⁿ Lille University, INSERM U995 LIRIC, CHU Lille, and Referral Center for Rare Systemic Autoimmune Diseases North and North-west of France, Lille, France
^o CEREMAST, the Clinical Immunology/Internal Medicine Department, National Reference Center for Angioedema, Grenoble University Hospital, Grenoble, France
^p Department of Haematology, Amiens University Hospital, Amiens, France
^q CEREMAST, the Haematology Institute, Normandy University School of Medicine, Caen, France
^r CEREMAST, the Department of Dermatology, Aix-Marseille University, CHU Timone, Marseille, France
^s Department of Internal Medicine, Centre Hospitalier Bretagne Atlantique, Vannes, France
^t CEREMAST, the Department of Internal Medicine and Clinical Immunology, Rennes University Hospital, Rennes, France
^u CEREMAST, the Department of Internal Medicine, Hôtel-Dieu University Hospital, Nantes, France
^v Department of Haematology, Nancy University Hospital, Nancy, France
^w Department of Internal Medicine and Clinical Immunology, Vandoeuvre-lès-Nancy, France
^x CEREMAST, the Department of Internal Medicine-Multi-organ Diseases, Saint-Eloi University Hospital, Montpellier University, Montpellier, France
^y CEREMAST, the Department of Pathology, Necker-Children’s Hospital, AP-HP, Paris Centre University, Paris, France
^z CEREMAST, the Laboratory of Onco-hematology, Necker Children’s Hospital, AP-HP, Paris, France
^aa Paris Centre University, Imagine Institute, Data Science Platform, INSERM UMR 1163, F-75015, Paris, France
^bb CEREMAST, the Department of Rheumatology, Strasbourg University Hospital, Strasbourg, France
^cc CEREMAST, the Department of Dermatology, Allergology Unit, University Hospital of Besançon, Besançon, France
^dd Unité de soins et de recherche en médecine interne et maladies infectieuses, European Hospital, Marseille, France
^ee Department of Haematology, Sud Reunion University Hospital, Saint Pierre, La Réunion, France
^ff CEREMAST, the Department of Hematology, CHU Dupuytren, Limoges, France
^gg CEREMAST, the Department of Dermatology, CHU de Poitiers, Poitiers, France
^hh Department of Internal Medicine and Infectious Diseases, Haut-Lévêque Hospital, CHRU Bordeaux, Bordeaux University, Bordeaux, France
ⁱⁱ CEREMAST, the Department of Internal Medicine and Clinical Immunology, University Hospital, Angers, France
^jj CEREMAST, the Service d’Immunologie Clinique et d’Allergologie, Centre Hospitalier Régional Universitaire, Tours, France
^kk CEREMAST, the Department of Internal Medicine, Adult Cystic Fibrosis Care Center, Hospices Civils de Lyon, Lyon, France
^ll CEREMAST, the Department of Hematology, Lyon-Sud Hospital, Hospices Civils de Lyon, Pierre-Bénite, France
^mm Department of Hematology, CHU de Bordeaux, Bordeaux, France
ⁿⁿ Department of Hematology, CHU de Poitiers, Poitiers, France
^oo CEREMAST, the Department of Dermatology and Allergy, Tenon Hospital, Sorbonne University, Paris, France
^pp CEREMAST, the Laboratory of Hematology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France

^∗Corresponding author: Olivier Hermine, MD, PhD, 149 rue de Sevres, 75015, Paris, France.149 rue de SevresParis75015France

Abstract

Background

Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal.

Objective

We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT.

Methods

Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases.

Results

We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT⁺ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT⁻ patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01).

Conclusion

Here we confirm the increase incidence of anaphylaxis in HαT⁺ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

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Key words : Mastocytosis, MMAS, hereditary α-tryptasemia, TPSAB1, osteoporosis, anaphylaxis, KIT D816V mutation

Abbreviations used : advSM, AFIRMM, AHN, ASM, BMM, CEREMAST, HαT, ISM, MC, MCA, MMAS, SM, SSM

Plan

Introduction

Results and discussion

Disclosure statement

The first 2 authors contributed equally to this article, and both should be considered first author. The last 2 authors contributed equally to this article, and both should be considered senior author.

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Vol 153 - N° 1

P. 349 - janvier 2024 Retour au numéro

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Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes - 04/01/24

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