PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune
regulator-dependent autoimmunity
#MMPMID25842288
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
J Allergy Clin Immunol
2015[Jun]; 135
(6
): 1578-88.e5
PMID25842288
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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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