PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity

Anne-Laure Mathieu (1) , Estelle Verronese (2) , Gillian I. Rice (3) , Fanny Fouyssac (4) , Yves Bertrand (5) , Capucine Picard (6) , Marie Chansel (6) , Jolan E. Walter (7) , Luigi D. Notarangelo (8) , Manish J. Butte (9) , Kari Christine Nadeau (9) , Krisztian Csomos (7) , David J. Chen (10) , Karin Chen (11) , Ana Delgado (2) , Chantal Rigal (2) , Christine Bardin (2) , Catharina Schuetz (12) , Despina Moshous (6) , Héloïse Reumaux (13) , François Plenat (14) , Alice Phan (15) , Marie-Thérèse Zabot (16) , Brigitte Balme (17) , Sébastien Viel (1) , Jacques Bienvenu (1) , Pierre Cochat (15) , Mirjam van Der Burg (18) , Christophe Caux (2) , E. Helen Kemp (19) , Isabelle Rouvet (16) , Christophe Malcus (20) , Jean-Francois Méritet (21) , Annick Lim (22) , Yanick J. Crow (3) , Nicole Fabien (23) , Christine Ménétrier-Caux (2) , Jean-Pierre de Villartay (6) , Thierry Walzer (1) , Alexandre Belot (1)

1 Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases
2 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
3 MCGM - Manchester Centre for Genomic Medicine [Manchester, UK]
4 Service d'Oncologie Pédiatrique [CHRU Nancy]
5 IHOPe - Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL]
6 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
7 Center for Immunology and Inflammatory Diseases [Boston, MA, USA]
8 HMS - Harvard Medical School [Boston]
9 Department of Microbiology and Immunology [Stanford]
10 University of Texas Southwestern Medical Center
11 University of Utah School of Medicine [Salt Lake City]
12 Department of Pediatrics and Adolescent Medicine
13 Unité Pédiatrique [Jeanne de Flandre]
14 Service de Pathologie [CHRU Nancy]
15 EPICIME - Epidémiologie, Pharmacologie, Investigation Clinique, Information médicale, Mère-Enfant
16 HCL - Hospices Civils de Lyon
17 Département de Pathologie [CHU Lyon-Sud - HCL]
18 Erasmus MC - Erasmus University Medical Center [Rotterdam]
19 University of Sheffield [Sheffield]
20 Hospices Civils de Lyon, Laboratoire d'Immunologie, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437, Lyon Cedex 03, France
21 Service de Virologie [CHU Cochin]
22 IP - Institut Pasteur [Paris]
23 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]

BACKGROUND: PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. OBJECTIVE: We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. METHODS: Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. RESULTS: We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T~cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in~vitro. The latter defect correlated in~vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1~had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. CONCLUSION: Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

Mots clés: Adolescent; Animals; Autoantibodies; Autoimmune regulator; Autoimmunity; B-Lymphocytes; DNA End-Joining Repair; DNA-Activated Protein Kinase; DNA-dependent protein kinase catalytic subunit; Female; Gene Expression Regulation; Granuloma; Humans; Immune Tolerance; Immunologic Deficiency Syndromes; Male; Mice; Mutation; Nuclear Proteins; PRKDC; recombination-activating gene; severe combined immunodeficiency; Skin Neoplasms; Th1 Cells; Th2 Cells; tolerance; Transcription Factors; V(D)J Recombination; VDJ recombination; Young Adult

Domaines: Immunologie; Bactériologie; Virologie

Anne-Laure Mathieu, Estelle Verronese, Gillian I. Rice, Fanny Fouyssac, Yves Bertrand, et al.. PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. Journal of Allergy and Clinical Immunology, 2015, 135 (6), pp.1578-1588.e5. ⟨10.1016/j.jaci.2015.01.040⟩. ⟨hal-01917848⟩