E-resources
-
Mathieu, Anne-Laure, PhD; Verronese, Estelle, BS; Rice, Gillian I., PhD; Fouyssac, Fanny, MD; Bertrand, Yves, MD, PhD; Picard, Capucine, MD, PhD; Chansel, Marie, MSc; Walter, Jolan E., MD, PhD; Notarangelo, Luigi D., MD; Butte, Manish J., MD, PhD; Nadeau, Kari Christine, MD, PhD; Csomos, Krisztian, PhD; Chen, David J., PhD; Chen, Karin, MD; Delgado, Ana, BS; Rigal, Chantal, BS; Bardin, Christine, BS; Schuetz, Catharina, MD, PhD; Moshous, Despina, MD, PhD; Reumaux, Héloïse, MD; Plenat, François, MD, PhD; Phan, Alice, MD, PhD; Zabot, Marie-Thérèse, PharmD, PhD; Balme, Brigitte, MD; Viel, Sébastien, PharmD; Bienvenu, Jacques, PharmD, PhD; Cochat, Pierre, MD, PhD; van der Burg, Mirjam, PhD; Caux, Christophe, PhD; Kemp, E. Helen, BSc, PhD; Rouvet, Isabelle, PharmD, PhD; Malcus, Christophe, PharmD, PhD; Méritet, Jean-Francois, PharmD, PhD; Lim, Annick, MSc; Crow, Yanick J., MD, PhD; Fabien, Nicole, PharmD, PhD; Ménétrier-Caux, Christine, PhD; De Villartay, Jean-Pierre, PhD; Walzer, Thierry, PhD; Belot, Alexandre, MD, PhD
Journal of allergy and clinical immunology, 06/2015, Volume: 135, Issue: 6Journal Article
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 TH 2 and TH 1 but not TH 17. 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.
Author
Shelf entry
Permalink
- URL:
Impact factor
Access to the JCR database is permitted only to users from Slovenia. Your current IP address is not on the list of IP addresses with access permission, and authentication with the relevant AAI accout is required.
Year | Impact factor | Edition | Category | Classification | ||||
---|---|---|---|---|---|---|---|---|
JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
Select the library membership card:
If the library membership card is not in the list,
add a new one.
DRS, in which the journal is indexed
Database name | Field | Year |
---|
Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
---|
Source: Personal bibliographies
and: SICRIS
The material is available in full text. If you wish to order the material anyway, click the Continue button.