Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation

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 rep...

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Bibliographic Details
Published in:Journal of allergy and clinical immunology 2021-08, Vol.148 (2), p.550-562
Main Authors: Nihira, Hiroshi, Izawa, Kazushi, Ito, Moeko, Umebayashi, Hiroaki, Okano, Tsubasa, Kajikawa, Shunsuke, Nanishi, Etsuro, Keino, Dai, Murakami, Kosaku, Isa-Nishitani, Masahiko, Shiba, Takeshi, Honda, Yoshitaka, Hijikata, Atsushi, Yasu, Tadateru, Kubota, Tomohiro, Hasegawa, Yoshinori, Kawashima, Yusuke, Nakano, Naoko, Takada, Hidetoshi, Ohga, Shouichi, Heike, Toshio, Takita, Junko, Ohara, Osamu, Takei, Syuji, Takahashi, Makio, Kanegane, Hirokazu, Morio, Tomohiro, Iwaki-Egawa, Sachiko, Sasahara, Yoji, Nishikomori, Ryuta, Yasumi, Takahiro
Format: Article
Language:English
Subjects:
ADA2 deficiency
Adenosine
Adenosine deaminase
adenosine deaminase 2
anti-TNF-α
Antibodies
Bone marrow
cat eye syndrome critical region protein 1
Cytokines
DADA2
Genes
Genetic analysis
Genetic variability
IFN-γ
Inflammation
Inflammatory diseases
Lymphocytes B
Monocytes
Mutation
Neutrophils
omics
Patients
Proteins
proteome
Proteomes
Skin diseases
STAT1
Stat1 protein
transcriptome
Transcriptomes
Tumor necrosis factor-α
Vascular diseases
vasculitis
γ-Interferon
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Description
Summary: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.
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2021.01.018