Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation.
Adenosine Deaminase
/ deficiency
Adolescent
Adult
Agammaglobulinemia
/ genetics
Asian People
Child
Child, Preschool
Female
Gene Expression Profiling
Humans
Infant
Intercellular Signaling Peptides and Proteins
/ deficiency
Interferon-gamma
/ genetics
Japan
Leukocytes, Mononuclear
/ immunology
Male
Proteomics
STAT1 Transcription Factor
/ genetics
Severe Combined Immunodeficiency
/ genetics
ADA2 deficiency
DADA2
IFN-γ
STAT1
adenosine deaminase 2
anti-TNF-α
cat eye syndrome critical region protein 1
omics
proteome
transcriptome
vasculitis
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
05
07
2020
revised:
15
01
2021
accepted:
21
01
2021
pubmed:
3
2
2021
medline:
21
10
2021
entrez:
2
2
2021
Statut:
ppublish
Résumé
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear. This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis. Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases. Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients' monocytes and B cells after IFN-γ stimulation. Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2.
Sections du résumé
BACKGROUND
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear.
OBJECTIVES
This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis.
METHODS
Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases.
RESULTS
Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients' monocytes and B cells after IFN-γ stimulation.
CONCLUSIONS
Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2.
Identifiants
pubmed: 33529688
pii: S0091-6749(21)00157-3
doi: 10.1016/j.jaci.2021.01.018
pii:
doi:
Substances chimiques
IFNG protein, human
0
Intercellular Signaling Peptides and Proteins
0
STAT1 Transcription Factor
0
STAT1 protein, human
0
Interferon-gamma
82115-62-6
ADA2 protein, human
EC 3.5.4.4
Adenosine Deaminase
EC 3.5.4.4
Types de publication
Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
550-562Informations de copyright
Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.