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

Aurélie Berland, Jérémie Rosain, Sophie Kaltenbach, Vincent Allain, Nizar Mahlaoui, Isabelle Melki, Alice Fievet, Catherine Dubois d'Enghien, Marie Ouachée-Chardin, Laurence Perrin, Nathalie Auger, Funda Erol Cipe, Andrea Finocchi, Figen Dogu, Felipe Suarez, Despina Moshous, Thierry Leblanc, Alexandre Belot, Claire Fieschi, David BoutboulMarion Malphettes, Lionel Galicier, Eric Oksenhendler, Stéphane Blanche, Alain Fischer, Patrick Revy, Dominique Stoppa-Lyonnet, Capucine Picard, Jean-Pierre de Villartay

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
DOIs
Publication statusE-pub ahead of print - Jun 12 2018

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V(D)J Recombination
T-Cell Antigen Receptor
Severe Combined Immunodeficiency
DNA Repair
Early Diagnosis
Flow Cytometry
Transplantation Conditioning
Nijmegen Breakage Syndrome
DNA Repair-Deficiency Disorders
Exome
T-Lymphocytes
Recombinational DNA Repair
Ataxia Telangiectasia
Multiplex Polymerase Chain Reaction
Hematopoietic Stem Cell Transplantation
Stem Cell Transplantation
Autoimmunity
Immune System
Biomarkers

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PROMIDISα : A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects. / Berland, Aurélie; Rosain, Jérémie; Kaltenbach, Sophie; Allain, Vincent; Mahlaoui, Nizar; Melki, Isabelle; Fievet, Alice; Dubois d'Enghien, Catherine; Ouachée-Chardin, Marie; Perrin, Laurence; Auger, Nathalie; Cipe, Funda Erol; Finocchi, Andrea; Dogu, Figen; Suarez, Felipe; Moshous, Despina; Leblanc, Thierry; Belot, Alexandre; Fieschi, Claire; Boutboul, David; Malphettes, Marion; Galicier, Lionel; Oksenhendler, Eric; Blanche, Stéphane; Fischer, Alain; Revy, Patrick; Stoppa-Lyonnet, Dominique; Picard, Capucine; de Villartay, Jean-Pierre.

In: Journal of Allergy and Clinical Immunology, 12.06.2018.

Research output: Contribution to journalArticle

Berland, A, Rosain, J, Kaltenbach, S, Allain, V, Mahlaoui, N, Melki, I, Fievet, A, Dubois d'Enghien, C, Ouachée-Chardin, M, Perrin, L, Auger, N, Cipe, FE, Finocchi, A, Dogu, F, Suarez, F, Moshous, D, Leblanc, T, Belot, A, Fieschi, C, Boutboul, D, Malphettes, M, Galicier, L, Oksenhendler, E, Blanche, S, Fischer, A, Revy, P, Stoppa-Lyonnet, D, Picard, C & de Villartay, J-P 2018, 'PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2018.05.028
Berland, Aurélie ; Rosain, Jérémie ; Kaltenbach, Sophie ; Allain, Vincent ; Mahlaoui, Nizar ; Melki, Isabelle ; Fievet, Alice ; Dubois d'Enghien, Catherine ; Ouachée-Chardin, Marie ; Perrin, Laurence ; Auger, Nathalie ; Cipe, Funda Erol ; Finocchi, Andrea ; Dogu, Figen ; Suarez, Felipe ; Moshous, Despina ; Leblanc, Thierry ; Belot, Alexandre ; Fieschi, Claire ; Boutboul, David ; Malphettes, Marion ; Galicier, Lionel ; Oksenhendler, Eric ; Blanche, Stéphane ; Fischer, Alain ; Revy, Patrick ; Stoppa-Lyonnet, Dominique ; Picard, Capucine ; de Villartay, Jean-Pierre. / PROMIDISα : A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects. In: Journal of Allergy and Clinical Immunology. 2018.
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title = "PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects",
abstract = "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.",
author = "Aur{\'e}lie Berland and J{\'e}r{\'e}mie Rosain and Sophie Kaltenbach and Vincent Allain and Nizar Mahlaoui and Isabelle Melki and Alice Fievet and {Dubois d'Enghien}, Catherine and Marie Ouach{\'e}e-Chardin and Laurence Perrin and Nathalie Auger and Cipe, {Funda Erol} and Andrea Finocchi and Figen Dogu and Felipe Suarez and Despina Moshous and Thierry Leblanc and Alexandre Belot and Claire Fieschi and David Boutboul and Marion Malphettes and Lionel Galicier and Eric Oksenhendler and St{\'e}phane Blanche and Alain Fischer and Patrick Revy and Dominique Stoppa-Lyonnet and Capucine Picard and {de Villartay}, Jean-Pierre",
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T1 - PROMIDISα

T2 - A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects

AU - Berland, Aurélie

AU - Rosain, Jérémie

AU - Kaltenbach, Sophie

AU - Allain, Vincent

AU - Mahlaoui, Nizar

AU - Melki, Isabelle

AU - Fievet, Alice

AU - Dubois d'Enghien, Catherine

AU - Ouachée-Chardin, Marie

AU - Perrin, Laurence

AU - Auger, Nathalie

AU - Cipe, Funda Erol

AU - Finocchi, Andrea

AU - Dogu, Figen

AU - Suarez, Felipe

AU - Moshous, Despina

AU - Leblanc, Thierry

AU - Belot, Alexandre

AU - Fieschi, Claire

AU - Boutboul, David

AU - Malphettes, Marion

AU - Galicier, Lionel

AU - Oksenhendler, Eric

AU - Blanche, Stéphane

AU - Fischer, Alain

AU - Revy, Patrick

AU - Stoppa-Lyonnet, Dominique

AU - Picard, Capucine

AU - de Villartay, Jean-Pierre

N1 - Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

PY - 2018/6/12

Y1 - 2018/6/12

N2 - 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.

AB - 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.

U2 - 10.1016/j.jaci.2018.05.028

DO - 10.1016/j.jaci.2018.05.028

M3 - Article

C2 - 29906526

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

ER -