PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator–dependent autoimmunity - 05/06/15

Doi : 10.1016/j.jaci.2015.01.040

Anne-Laure Mathieu, PhD ^a,^b,^c,^d, Estelle Verronese, BS ^e, Gillian I. Rice, PhD ^f, Fanny Fouyssac, MD ^g, Yves Bertrand, MD, PhD ^h, Capucine Picard, MD, PhD ⁱ, Marie Chansel, MSc ^j, Jolan E. Walter, MD, PhD ^k, Luigi D. Notarangelo, MD ^l, Manish J. Butte, MD, PhD ^m, Kari Christine Nadeau, MD, PhD ^m, Krisztian Csomos, PhD ^k, David J. Chen, PhD ⁿ, Karin Chen, MD ^o, Ana Delgado, BS ^e, Chantal Rigal, BS ^e, Christine Bardin, BS ^e, Catharina Schuetz, MD, PhD ^p, Despina Moshous, MD, PhD ^j, Héloïse Reumaux, MD ^q, François Plenat, MD, PhD ^r, Alice Phan, MD, PhD ^v, Marie-Thérèse Zabot, PharmD, PhD ^t, Brigitte Balme, MD ^s, Sébastien Viel, PharmD ^a,^b,^c,^d,^u, Jacques Bienvenu, PharmD, PhD ^a,^b,^c,^d,^u, Pierre Cochat, MD, PhD ^v, Mirjam van der Burg, PhD ^w, Christophe Caux, PhD ^e, E. Helen Kemp, BSc, PhD ^x, Isabelle Rouvet, PharmD, PhD ^t, Christophe Malcus, PharmD, PhD ^y, Jean-Francois Méritet, PharmD, PhD ^z, Annick Lim, MSc ^aa, Yanick J. Crow, MD, PhD ^f, Nicole Fabien, PharmD, PhD ^u, Christine Ménétrier-Caux, PhD ^e, Jean-Pierre De Villartay, PhD ^j, Thierry Walzer, PhD ^a,^b,^c,^d, Alexandre Belot, MD, PhD ^a,^b,^c,^d,^v,^⁎
^a CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France
^b Inserm U1111, Lyon, France
^c Ecole Normale Supérieure de Lyon, Lyon, France
^d CNRS, UMR5308, Lyon, France
^e Université de Lyon, INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Plateforme d'Innovation en Immuno-monitoring et Immunothérapie, Centre Léon Bérard, and in the framework of the LABEX DevWeCan (ANR-10-LABX-0061) of University de Lyon, within the program “Investissements d'Avenir” (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR), Lyon, France
^f Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, Manchester Academic Health Centre, Manchester, United Kingdom
^g Pediatric Haematology and Oncology Department, Children Hospital–CHU NANCY Vandoeuvre les Nancy, Nancy, France
^h Institut d'Hématologie et d'Oncologie Pédiatrique (Hospices Civils de Lyon), Université Claude Bernard Lyon I, Lyon, France
ⁱ Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Sorbonne Paris Cité, Paris Descartes University, Imagine Institute, Paris Descartes University, Paris, France
^j INSERM UMR 1163, Laboratoire Dynamique du Génome et Système Immunitaire Université Paris Descartes–Sorbonne Paris Cité, Imagine Institute, Paris, France
^k Pediatric Allergy & Immunology and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Mass
^l Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, Mass
^m Department of Pediatrics, Division of Immunology, Allergy and Rheumatology, Stanford University, Stanford, Calif
ⁿ Division of Molecular Radiation Biology Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Tex
^o Department of Pediatrics, Division of Allergy, Immunology & Rheumatology, University of Utah School of Medicine, Salt Lake City, Utah
^p Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
^q Pediatric Rheumatology and Emergency Unit, Jeanne de Flandre Hospital, Lille, France
^r Pathology Department, Hémato-Oncologie Pédiatrique, CHU Nancy, Nancy, France
^s Pathology Department, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Lyon, France
^t Biotechnology Department, Hospices Civils de Lyon, Lyon, France
^u Immunobiology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France
^v Pediatric Rheumatology, Nephrology and Dermatology Department and EPICIME Hospices Civils de Lyon and Université Claude-Bernard Lyon 1, Lyon, France
^w Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
^x Department of Human Metabolism, University of Sheffield, Sheffield, United Kingdom
^y Cell Immunology Department, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
^z Virology Unit, Hopital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France
^aa Immunoscope Group, Immunology Department, Institut Pasteur, Paris, France

^∗Corresponding author: Alexandre Belot, MD, PhD, Service de Néphrologie, Rhumatologie, Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, 57 Bd Pinel, 69677 Bron Cedex, France.

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 T_H2 and T_H1 but not T_H17. 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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Key words : Autoimmune regulator, tolerance, DNA-dependent protein kinase catalytic subunit, PRKDC, autoimmunity, VDJ recombination, severe combined immunodeficiency, recombination-activating gene

Abbreviations used : AIRE, ANA, APECED, BAFF, BCR, BMT, CaSR, CID, DCLRE1C, DNA-PK, DNA-PKcs, DSB, LIG4, mTEC, NK, OS, PMA, RAG, SCID

Plan

Methods

Results

Clinical features of 2 patients with combined immunodeficiency

PRKDC mutations are present in both patients with CID

Patients' fibroblasts are defective in DNA double-strand break repair

The T-cell receptor Vβ repertoire is limited in patients with PRKDC mutations

Patients with PRKDC mutations have increased BAFF levels and numbers of inflammatory monocytes and memory T cells expressing T_H1 and T_H2, but not T_H17, cytokines on activation

AIRE-dependent peripheral tissue antigen expression is impaired by PRKDC mutations

Patients have positive autoantibody responses against the CaSR

Discussion

Supported by Hospices Civils de Lyon, Société Francaise de Rhumatologie, INSERM and ANR (ANR-14-CE14-0026-03) (to A.B.), as well as National Institutes of Health grant CA162804 (to D.J.C.), CPRITRP110465 (to D.J.C.), and LYRIC grant INCa_4664 (to C.C.). T.W.'s laboratory is supported by European Research Council (ERC-Stg 281025), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1, ENS de Lyon. Y.J.C. acknowledges the European Research Council (GA 309449).

Disclosure of potential conflict of interest: This study was supported by Hospices Civils de Lyon and INSERM, as well as National Institutes of Health (NIH) grant CA162804; CPRITRP110465. G. I. Rice's institution has received funding from the European Research Council (GA309449: Fellowship to Y.J.C.). J. E. Walter and his institution have received funding from the NIH and National Institute of Allergy and Infectious Diseases (NIAID) (5K08AI103035). L. D. Notarangelo is employed at Boston Children's Hospital and is on the Board of Scientific Counselors of the NIAID and NIH, has received or has grants pending from the NIH and the March of Dimes, and receives royalties from UpToDate. M. Butte's institution has received funding from the NIH (R01 GM110482). H. Reumaux has received compensation for travel and other meeting-related expenses from the European League Against Rheumatism (EULAR). P. Cochat has received compensation for supplying expert testimony from Novartis, as well as for travel and other meeting-related expenses from Raptor Pharmaceuticals. M. van der Burg's institution received funding from ZonMW Vidi grant 91712323. Y. J. Crow has received funding from the European Research Council (GA 309449: Fellowship to Y.J.C.) and from the European Union's Seventh Framework Programme (FP7/2007-2013). J.-P. De Villartay's institution has received grants from INCa (PLBIO11-151) and Ligue National contre le Cancer. T. Walzer's institution has received funding from the European Research Council (ERC), and has received support for travel for this study or other purposes from ERC and his laboratory is supported by Agence Nationale de la Recherche, the European Research Council (ERC-Stg 281025), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1, and ENS de Lyon. A. Belot's institution has received funding from the Institut national de la santé et de la recherche médicale, the French Society of Rheumatology, and Hospices Civils de Lyon; he has received compensation for delivering expert testimony from Pfizer, as well as compensation for travel and other meeting-related expenses from Novartis; and he has received or has grants pending from Advances in Neuroblastoma Research 2014. The rest of the authors declare that they have no other relevant conflicts of interest.

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Vol 135 - N° 6

P. 1578 - juin 2015 Retour au numéro

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PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator–dependent autoimmunity - 05/06/15

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Plan

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