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PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects

Authors :
Felipe Suarez
Vincent Allain
Figen Dogu
Catherine Dubois d'Enghien
Patrick Revy
Funda Erol Cipe
Andrea Finocchi
Jean-Pierre de Villartay
Alain Fischer
Claire Fieschi
Marion Malphettes
David Boutboul
Alexandre Belot
Nizar Mahlaoui
Nathalie Auger
Despina Moshous
Jérémie Rosain
Marie Ouachée-Chardin
Sophie Kaltenbach
Dominique Stoppa-Lyonnet
Aurélie Berland
Lionel Galicier
Laurence Perrin
Stéphane Blanche
Capucine Picard
Isabelle Melki
Alice Fiévet
Thierry Leblanc
Eric Oksenhendler
Genome dynamics in the immune system (Equipe Inserm U1163)
Imagine - Institut des maladies génétiques (IMAGINE - U1163)
Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Center for the Study of Primary Immunodeficiencies [Paris]
Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Pediatric Immuno-Haematology and Rheumatology Unit
CHU Necker - Enfants Malades [AP-HP]
AP-HP Hôpital universitaire Robert-Debré [Paris]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Unité de génétique et biologie des cancers (U830)
Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)
Chaire Médecine expérimentale (A. Fischer)
Collège de France (CdF (institution))
Service de Génétique Oncologique
Institut Curie [Paris]
Service d'hématologie et immunologie pédiatrique
Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Service de génétique clinique [Debré]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré
Institut Gustave Roussy (IGR)
Département de biologie et pathologie médicales [Gustave Roussy]
Kanuni Sultan Suleyman Research and Training Hospital [Istanbul]
Children's Hospital Bambino Gesù IRCCS [Rome]
University of Rome TorVergata
Ankara University School of Medicine [Turkey]
Hôpital Femme Mère Enfant [CHU - HCL] (HFME)
Hospices Civils de Lyon (HCL)
Hopital Saint-Louis [AP-HP] (AP-HP)
CCSD, Accord Elsevier
Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Collège de France - Chaire Médecine expérimentale (A. Fischer)
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)
Source :
Journal of Allergy and Clinical Immunology, Journal of Allergy and Clinical Immunology, Elsevier, 2019, 143 (1), pp.325-334.e2. ⟨10.1016/j.jaci.2018.05.028⟩, Journal of Allergy and Clinical Immunology, 2019, 143 (1), pp.325-334.e2. ⟨10.1016/j.jaci.2018.05.028⟩
Publication Year :
2017

Abstract

International audience; BACKGROUND:V(D)J recombination ensures the diversity of the adaptive immune system. Although its complete defect causes severe combined immunodeficiency (ie, T-B- severe combined immunodeficiency), its suboptimal activity is associated with a broad spectrum of immune manifestations, such as late-onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, particularly when it involves a myeloablative conditioning regimen for hematopoietic stem cell transplantation.OBJECTIVE:We aimed at developing biomarkers based on analysis of the T-cell receptor (TCR) α repertoire to assist in the diagnosis of patients with primary immunodeficiencies with V(D)J recombination and DNA repair deficiencies.METHODS:We used flow cytometric (fluorescence-activated cell sorting) analysis to quantify TCR-Vα7.2-expressing T lymphocytes in peripheral blood and developed PROMIDISα, a multiplex RT-PCR/next-generation sequencing assay, to evaluate a subset of the TCRα repertoire in T lymphocytes.RESULTS:The combined fluorescence-activated cell sorting and PROMIDISα analyses revealed specific signatures in patients with V(D)J recombination-defective primary immunodeficiencies or ataxia telangiectasia/Nijmegen breakage syndromes.CONCLUSION:Analysis of the TCRα repertoire is particularly appropriate in a prospective way to identify patients with partial immune defects caused by suboptimal V(D)J recombination activity, a DNA repair defect, or both. It also constitutes a valuable tool for the retrospective in vivo functional validation of variants identified through exome or panel sequencing. Its broader implementation might be of interest to assist early diagnosis of patients presenting with hypomorphic DNA repair defects inclined to experience acute toxicity during prehematopoietic stem cell transplantation conditioning.

Details

ISSN :
10976825 and 00916749
Volume :
143
Issue :
1
Database :
OpenAIRE
Journal :
The Journal of allergy and clinical immunology
Accession number :
edsair.doi.dedup.....73a68f29311c5c040b29428e5181f666