PROMIDISα: a TCRα signature associated with immunodeficiencies caused by V(D)J recombination defects

Publication date: Available online 12 June 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): 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 Boutboul, Marion Malphettes, Lionel Galicier, Eric Oksenhendler, Stéphane Blanche, Alain Fischer, Patrick Revy, Dominique Stoppa-Lyonnet, Capucine Picard, Jean-Pierre de Villartay
- BackgroundV(D)J recombination ensures the diversity of the adaptive immune system. While its complete defect causes Severe Combined Immunodeficiency (T-B-SCID), 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, in particular when it involves myelo-ablative conditioning regimen for hematopoietic stem cell transplantation (HSCT).- ObjectiveWe aimed at developing biomarkers based on the analysis of TCRα repertoire to assist in the diagnosis of primary immunodeficient patients (PID) with V(D)J recombination and DNA repair deficiencies.- MethodsWe used flow cytometry (FACS) analysis to quantify TCR-Vα7.2 expressing T lymphocytes in peripheral blood and developed PROMIDISα, a multiplex RT-PCR/NGS assay, to evaluate a subset of the TCRα repertoire in T lymphocytes.- ResultsThe combined FACS and PROMIDISα analyses revealed specific signatures in patients with V(D)J recombination defective PIDs or Ataxia telangiectasia/Nijmegen breakage syndromes (AT/NBS).- ConclusionAnalysis 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 and/or DNA repair defect. It also constitutes a valuable tool for the retrospective in vivo functional validation of variants identified through exome or panel sequencing. Its broader implementation may be of interest to assist early diagnosis of patients presenting with hypomorphic DNA repair defects inclined to develop acute toxicity during pre-HSCT conditioning.



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