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

Anne Laure Mathieu, Estelle Verronese, Gillian I. Rice, Fanny Fouyssac, Yves Bertrand, Capucine Picard, Marie Chansel, Jolan E. Walter, Luigi D. Notarangelo, Manish J. Butte, Kari Christine Nadeau, Krisztian Csomos, David J. Chen, Karin Chen, Ana Delgado, Chantal Rigal, Christine Bardin, Catharina Schuetz, Despina Moshous, Héloïse ReumauxFrançois Plenat, Alice Phan, Marie Thérèse Zabot, Brigitte Balme, Sébastien Viel, Jacques Bienvenu, Pierre Cochat, Mirjam Van Der Burg, Christophe Caux, E. Helen Kemp, Isabelle Rouvet, Christophe Malcus, Jean Francois Méritet, Annick Lim, Yanick J. Crow, Nicole Fabien, Christine Ménétrier-Caux, Jean Pierre De Villartay, Thierry Walzer, Alexandre Belot

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1578-1588e5
JournalJournal of Allergy and Clinical Immunology
Volume135
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

DNA-Activated Protein Kinase
Granuloma
Autoimmunity
Mutation
Catalytic Domain
V(D)J Recombination
Double-Stranded DNA Breaks
T-Lymphocytes
Calcium-Sensing Receptors
Hashimoto Disease
Bone Marrow Transplantation
Autoantibodies
Interferons
Molecular Biology
B-Lymphocytes
Transcription Factors
Phosphotransferases
Cell Count
Epithelial Cells
Cytokines

Keywords

  • Autoimmune regulator
  • autoimmunity
  • DNA-dependent protein kinase catalytic subunit
  • PRKDC
  • recombination-activating gene
  • severe combined immunodeficiency
  • tolerance
  • VDJ recombination

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Mathieu, A. L., Verronese, E., Rice, G. I., Fouyssac, F., Bertrand, Y., Picard, C., ... Belot, A. (2015). PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. Journal of Allergy and Clinical Immunology, 135(6), 1578-1588e5. https://doi.org/10.1016/j.jaci.2015.01.040

PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. / Mathieu, Anne Laure; Verronese, Estelle; Rice, Gillian I.; Fouyssac, Fanny; Bertrand, Yves; Picard, Capucine; Chansel, Marie; Walter, Jolan E.; Notarangelo, Luigi D.; Butte, Manish J.; Nadeau, Kari Christine; Csomos, Krisztian; Chen, David J.; Chen, Karin; Delgado, Ana; Rigal, Chantal; Bardin, Christine; Schuetz, Catharina; Moshous, Despina; Reumaux, Héloïse; Plenat, François; Phan, Alice; Zabot, Marie Thérèse; Balme, Brigitte; Viel, Sébastien; Bienvenu, Jacques; Cochat, Pierre; Van Der Burg, Mirjam; Caux, Christophe; Kemp, E. Helen; Rouvet, Isabelle; Malcus, Christophe; Méritet, Jean Francois; Lim, Annick; Crow, Yanick J.; Fabien, Nicole; Ménétrier-Caux, Christine; De Villartay, Jean Pierre; Walzer, Thierry; Belot, Alexandre.

In: Journal of Allergy and Clinical Immunology, Vol. 135, No. 6, 01.06.2015, p. 1578-1588e5.

Research output: Contribution to journalArticle

Mathieu, AL, Verronese, E, Rice, GI, Fouyssac, F, Bertrand, Y, Picard, C, Chansel, M, Walter, JE, Notarangelo, LD, Butte, MJ, Nadeau, KC, Csomos, K, Chen, DJ, Chen, K, Delgado, A, Rigal, C, Bardin, C, Schuetz, C, Moshous, D, Reumaux, H, Plenat, F, Phan, A, Zabot, MT, Balme, B, Viel, S, Bienvenu, J, Cochat, P, Van Der Burg, M, Caux, C, Kemp, EH, Rouvet, I, Malcus, C, Méritet, JF, Lim, A, Crow, YJ, Fabien, N, Ménétrier-Caux, C, De Villartay, JP, Walzer, T & Belot, A 2015, 'PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity', Journal of Allergy and Clinical Immunology, vol. 135, no. 6, pp. 1578-1588e5. https://doi.org/10.1016/j.jaci.2015.01.040
Mathieu, Anne Laure ; Verronese, Estelle ; Rice, Gillian I. ; Fouyssac, Fanny ; Bertrand, Yves ; Picard, Capucine ; Chansel, Marie ; Walter, Jolan E. ; Notarangelo, Luigi D. ; Butte, Manish J. ; Nadeau, Kari Christine ; Csomos, Krisztian ; Chen, David J. ; Chen, Karin ; Delgado, Ana ; Rigal, Chantal ; Bardin, Christine ; Schuetz, Catharina ; Moshous, Despina ; Reumaux, Héloïse ; Plenat, François ; Phan, Alice ; Zabot, Marie Thérèse ; Balme, Brigitte ; Viel, Sébastien ; Bienvenu, Jacques ; Cochat, Pierre ; Van Der Burg, Mirjam ; Caux, Christophe ; Kemp, E. Helen ; Rouvet, Isabelle ; Malcus, Christophe ; Méritet, Jean Francois ; Lim, Annick ; Crow, Yanick J. ; Fabien, Nicole ; Ménétrier-Caux, Christine ; De Villartay, Jean Pierre ; Walzer, Thierry ; Belot, Alexandre. / PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. In: Journal of Allergy and Clinical Immunology. 2015 ; Vol. 135, No. 6. pp. 1578-1588e5.
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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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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

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 - autoimmunity

KW - DNA-dependent protein kinase catalytic subunit

KW - PRKDC

KW - recombination-activating gene

KW - severe combined immunodeficiency

KW - tolerance

KW - VDJ recombination

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U2 - 10.1016/j.jaci.2015.01.040

DO - 10.1016/j.jaci.2015.01.040

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