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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 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
Abstract : 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.
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Submitted on : Friday, November 9, 2018 - 5:07:51 PM
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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, Elsevier, 2015, 135 (6), pp.1578-1588.e5. ⟨10.1016/j.jaci.2015.01.040⟩. ⟨hal-01917848⟩



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