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PRKDC mutations associated with immunodeficiency, granuloma and aire-dependent autoimmunity

Introduction

PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-PK) crucial for DNA double-strand break (DSB) repair and V(D)J recombination. In mice, DNA-PK also interacts with the transcription factor AIRE (autoimmune regulator) to promote central T cell tolerance.

Objectives

We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity, associated to decreasing T and B cell counts over time diagnosed in two 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 DSB repair and V(D)J recombination. Circulating T cells had a skewed cytokine response typical of Th1 and Th2 profiles. Moreover, mutated DNA-PKcs failed to promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo, with the production of anti-Calcium Sensing Receptor (anti-CaSR) autoantibodies, which are usually found in AIRE-deficient patients.

Conclusion

Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoantibodies and these findings highlight the essential role of DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human.

Disclosure of interest

None declared.

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Correspondence to Alexandre Belot.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Belot, A., Mathieu, A., Veronese, E. et al. PRKDC mutations associated with immunodeficiency, granuloma and aire-dependent autoimmunity. Pediatr Rheumatol 12, P42 (2014). https://doi.org/10.1186/1546-0096-12-S1-P42

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Keywords

  • Inflammatory Disease
  • Catalytic Subunit
  • Autoimmune Response
  • Cell Tolerance
  • Unrelated Patient