PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects.
DNA repair
Primary immunodeficiency
T-cell receptor α repertoire
V(D)J recombination
ataxia telangiectasia
next-generation sequencing
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
20
11
2017
revised:
17
04
2018
accepted:
25
05
2018
pubmed:
16
6
2018
medline:
13
11
2019
entrez:
16
6
2018
Statut:
ppublish
Résumé
V(D)J recombination ensures the diversity of the adaptive immune system. Although its complete defect causes severe combined immunodeficiency (ie, T 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. 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. 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. 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.
Sections du résumé
BACKGROUND
V(D)J recombination ensures the diversity of the adaptive immune system. Although its complete defect causes severe combined immunodeficiency (ie, T
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.
Identifiants
pubmed: 29906526
pii: S0091-6749(18)30849-2
doi: 10.1016/j.jaci.2018.05.028
pii:
doi:
Substances chimiques
Receptors, Antigen, T-Cell, alpha-beta
0
Types de publication
Clinical Trial
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
325-334.e2Informations de copyright
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.