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PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. journal of allergy and clinical immunology Mathieu, A., Verronese, E., Rice, G. I., Fouyssac, F., Bertrand, Y., Picard, C., Chansel, M., Walter, J. E., Notarangelo, L. D., Butte, M. J., Nadeau, K. C., Csomos, K., Chen, D. J., Chen, K., Delgado, A., Rigal, C., Bardin, C., Schuetz, C., Moshous, D., Reumaux, H., Plenat, F., Phan, A., Zabot, M., Balme, B., Viel, S., Bienvenu, J., Cochat, P., van der Burg, M., Caux, C., Kemp, E. H., Rouvet, I., Malcus, C., Méritet, J., Lim, A., Crow, Y. J., Fabien, N., Ménétrier-Caux, C., de Villartay, J., Walzer, T., Belot, A. 2015; 135 (6): 1578-88 e5

Abstract

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.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.Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency.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.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.

View details for DOI 10.1016/j.jaci.2015.01.040

View details for PubMedID 25842288