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

doi:10.1016/j.jaci.2015.01.040

Journal of Allergy and Clinical Immunology

Volume 135, Issue 6, June 2015, Pages 1578-1588.e5

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https://doi.org/10.1016/j.jaci.2015.01.040 Get rights and content

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.

Section snippets

Methods

Details of the materials and methods used in this study are provided in the Methods section in this article's Online Repository at www.jacionline.org.

Clinical features of 2 patients with combined immunodeficiency

This male patient 1 (Pt1) was born to a consanguineous couple of Turkish background (Fig 1, A). A younger nonidentical twin brother died in the first year of life with a diagnosis of aspiration pneumonia, chronic diarrhea, and failure to thrive. At birth, Pt1 was unremarkable with normal weight and occipitofrontal head circumference. He was given a diagnosis of persistent asthma in the first 2 years of life and experienced occasional ear infections. At the age of 6 years, he presented with

Discussion

Extending the phenotype of patients with PRKDC mutations, we report here the cases of 2 unrelated patients with manifestations of CID with immunodeficiency, granuloma, and autoimmunity caused by a homozygous p.Leu3062Arg mutation in PRKDC. Recurrent infections were documented in both cases, but their clinical history did not reveal opportunistic infections. Inflammatory manifestations were prominent in Pt1, who was initially given a diagnosis of ANA-positive oligoarticular juvenile idiopathic

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: 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.), CPRIT RP110465 (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; CPRIT RP110465. 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.

View full text

Immune deficiencies, infection, and systemic immune disordersPRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator–dependent autoimmunity

Background

Objective

Methods

Results

Conclusion

Section snippets

Methods

Clinical features of 2 patients with combined immunodeficiency

Discussion

Immunity

Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Blood

Curr Opin Immunol

Immunity

Blood

Immunity

Cell

Cytokine Growth Factor Rev

Am J Med

V(D)J recombination deficiencies

Adv Exp Med Biol

An immunodeficiency disease with RAG mutations and granulomas

N Engl J Med

Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency

J Exp Med

Aire

Annu Rev Immunol

Immune deficiencies, infection, and systemic immune disorders
PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator–dependent autoimmunity