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

被引：42

作者：

Berland, Aurelie ^{[1
,2
]}

Rosain, Jeremie ^{[2
,3
]}

Kaltenbach, Sophie ^{[1
,2
]}

Allain, Vincent ^{[3
]}

Mahlaoui, Nizar ^{[2
,4
]}

Melki, Isabelle ^{[4
,5
]}

Fievet, Alice ^{[6
,7
]}

d'Enghien, Catherine Dubois ^{[7
]}

Ouachee-Chardin, Marie ^{[8
]}

Perrin, Laurence ^{[9
]}

Auger, Nathalie ^{[10
]}

Cipe, Funda Erol ^{[11
]}

Finocchi, Andrea ^{[12
,13
]}

Dogu, Figen ^{[14
]}

Suarez, Felipe ^{[15
]}

Moshous, Despina ^{[1
,2
,4
]}

Leblanc, Thierry ^{[8
]}

Belot, Alexandre ^{[16
]}

Fieschi, Claire ^{[17
]}

Boutboul, David ^{[17
]}

Malphettes, Marion ^{[17
]}

Galicier, Lionel ^{[17
]}

Oksenhendler, Eric ^{[17
]}

Blanche, Stephane ^{[4
]}

Fischer, Alain ^{[2
,3
,18
,19
]}

Revy, Patrick ^{[1
,2
]}

Stoppa-Lyonnet, Dominique ^{[6
,7
,20
]}

Picard, Capucine ^{[2
,3
]}

de Villartay, Jean-Pierre ^{[1
,2
]}

机构：

[1] INSERM, UMR1163, Lab Genome Dynam Immune Syst, Paris, France

[2] Univ Paris 05, Sorbonne Paris Cite, Inst Imagine, Paris, France

[3] Necker Enfants Malad Hosp, APHP, Study Ctr Primary Immunodeficiencies, Paris, France

[4] Necker Enfants Malad Univ Hosp, AP HP, Pediat Immunohaematol & Rheumatol Unit, Paris, France

[5] Hop Robert Debre, APHP, Gen Pediat Infect Dis & Internal Med Dept, Paris, France

[6] Inst Curie, INSERM, U830, Paris, France

[7] Inst Curie, Serv Genet, Paris, France

[8] Robert Debre APHP, Dept Pediat Hematol, Paris, France

[9] Robert Debre Hosp, APHP, Dept Genet, Paris, France

[10] Inst Gustave Roussy, Dept Biopathol, Villejuif, France

[11] Kanuni Sultan Suleyman Res & Training Hosp, Dept Pediat Allergy Immunol, Istanbul, Turkey

[12] Bambino Gesu Pediat Hosp, Univ Dept Pediat, DPUO, Rome, Italy

[13] Univ Tor Vergata, Sch Med, Rome, Italy

[14] Ankara Univ, Sch Med, Dept Pediat Immunol & Allergy, Ankara, Turkey

[15] Necker Enfants Malad Univ Hosp, APHP, Dept Haematol, Paris, France

[16] Hosp Civils Lyon, Hop Femme Mere Enfant, Pediat Rheumatol Nephrol & Dermatol Dept, Lyon, France

[17] Hop St Louis, APHP, Dept Clin Immunol, Paris, France

[18] INSERM, UMR1163, Paris, France

[19] Coll France, Paris, France

[20] Univ Paris 05, Sorbonne Paris Cite, Paris, France

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2019年 / 143卷 / 01期

关键词：

Primary immunodeficiency; V(D)J recombination; T-cell receptor alpha repertoire; ataxia telangiectasia; DNA repair; next-generation sequencing; DNA-LIGASE IV; REPERTOIRE; MECHANISMS;

D O I：

10.1016/j.jaci.2018.05.028

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

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) alpha 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-V alpha 7.2-expressing T lymphocytes in peripheral blood and developed PROMIDIS alpha, a multiplex RT-PCR/next-generation sequencing assay, to evaluate a subset of the TCR alpha repertoire in T lymphocytes. Results: The combined fluorescence-activated cell sorting and PROMIDISa analyses revealed specific signatures in patients with V(D) J recombination-defective primary immunodeficiencies or ataxia telangiectasia/Nijmegen breakage syndromes. Conclusion: Analysis of the TCR alpha 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.

引用

页码：325 / +

页数：12

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