TY - JOUR
T1 - PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity
AU - Mathieu, Anne Laure
AU - Verronese, Estelle
AU - Rice, Gillian I.
AU - Fouyssac, Fanny
AU - Bertrand, Yves
AU - Picard, Capucine
AU - Chansel, Marie
AU - Walter, Jolan E.
AU - Notarangelo, Luigi D.
AU - Butte, Manish J.
AU - Nadeau, Kari Christine
AU - Csomos, Krisztian
AU - Chen, David J.
AU - Chen, Karin
AU - Delgado, Ana
AU - Rigal, Chantal
AU - Bardin, Christine
AU - Schuetz, Catharina
AU - Moshous, Despina
AU - Reumaux, Héloïse
AU - Plenat, François
AU - Phan, Alice
AU - Zabot, Marie Thérèse
AU - Balme, Brigitte
AU - Viel, Sébastien
AU - Bienvenu, Jacques
AU - Cochat, Pierre
AU - Van Der Burg, Mirjam
AU - Caux, Christophe
AU - Kemp, E. Helen
AU - Rouvet, Isabelle
AU - Malcus, Christophe
AU - Méritet, Jean Francois
AU - Lim, Annick
AU - Crow, Yanick J.
AU - Fabien, Nicole
AU - Ménétrier-Caux, Christine
AU - De Villartay, Jean Pierre
AU - Walzer, Thierry
AU - Belot, Alexandre
N1 - Publisher Copyright:
© 2015 American Academy of Allergy, Asthma & Immunology.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
KW - Autoimmune regulator
KW - DNA-dependent protein kinase catalytic subunit
KW - PRKDC
KW - VDJ recombination
KW - autoimmunity
KW - recombination-activating gene
KW - severe combined immunodeficiency
KW - tolerance
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U2 - 10.1016/j.jaci.2015.01.040
DO - 10.1016/j.jaci.2015.01.040
M3 - Article
C2 - 25842288
AN - SCOPUS:84942619984
SN - 0091-6749
VL - 135
SP - 1578-1588.e5
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 6
ER -