Human RELA dominant-negative mutations underlie type I interferonopathy with autoinflammation and autoimmunity.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
04 09 2023
04 09 2023
Historique:
received:
09
11
2021
revised:
28
08
2022
accepted:
07
04
2023
medline:
7
6
2023
pubmed:
5
6
2023
entrez:
5
6
2023
Statut:
ppublish
Résumé
Inborn errors of the NF-κB pathways underlie various clinical phenotypes in humans. Heterozygous germline loss-of-expression and loss-of-function mutations in RELA underlie RELA haploinsufficiency, which results in TNF-dependent chronic mucocutaneous ulceration and autoimmune hematological disorders. We here report six patients from five families with additional autoinflammatory and autoimmune manifestations. These patients are heterozygous for RELA mutations, all of which are in the 3' segment of the gene and create a premature stop codon. Truncated and loss-of-function RelA proteins are expressed in the patients' cells and exert a dominant-negative effect. Enhanced expression of TLR7 and MYD88 mRNA in plasmacytoid dendritic cells (pDCs) and non-pDC myeloid cells results in enhanced TLR7-driven secretion of type I/III interferons (IFNs) and interferon-stimulated gene expression in patient-derived leukocytes. Dominant-negative mutations in RELA thus underlie a novel form of type I interferonopathy with systemic autoinflammatory and autoimmune manifestations due to excessive IFN production, probably triggered by otherwise non-pathogenic TLR ligands.
Identifiants
pubmed: 37273177
pii: 214144
doi: 10.1084/jem.20212276
pmc: PMC10242411
pii:
doi:
Substances chimiques
Interferon Type I
0
NF-kappa B
0
RELA protein, human
0
Toll-Like Receptor 7
0
Transcription Factor RelA
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001866
Pays : United States
Organisme : NCI NIH HHS
ID : F99 CA274708
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI061093
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI127564
Pays : United States
Informations de copyright
© 2023 Moriya et al.
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