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

AL Mathieu, E Verronese, GI Rice, F Fouyssac, Y Bertrand, C Picard, M Chansel, JE Walter, LD Notarangelo, MJ Butte, KC Nadeau, K Csomos, DJ Chen, Kuo-Ting Chen, A Delgado, C Riga, C Bardin, C Schuetz, D Moshous, H ReumauxF Plenat, A Phan, MT Zabot, B Balme, S Viel, J Bienvenu, P Cochat, Mirjam van der Burg, C Caux, EH Kemp, I Rouvet, C Malcus, JF Meritet, A Lim, YJ Crow, N Fabien, C Menetrier-Caux, JP de Villartay, T Walzer, A Belot

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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 T(H)2 and T(H)1 but not T(H)17. 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.
Original languageUndefined/Unknown
Pages (from-to)1578-U294
JournalJournal of Allergy and Clinical Immunology
Issue number6
Publication statusPublished - 2015

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  • EMC MM-02-72-01

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