TY - JOUR
T1 - Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation
AU - Nihira, Hiroshi
AU - Izawa, Kazushi
AU - Ito, Moeko
AU - Umebayashi, Hiroaki
AU - Okano, Tsubasa
AU - Kajikawa, Shunsuke
AU - Nanishi, Etsuro
AU - Keino, Dai
AU - Murakami, Kosaku
AU - Isa-Nishitani, Masahiko
AU - Shiba, Takeshi
AU - Honda, Yoshitaka
AU - Hijikata, Atsushi
AU - Yasu, Tadateru
AU - Kubota, Tomohiro
AU - Hasegawa, Yoshinori
AU - Kawashima, Yusuke
AU - Nakano, Naoko
AU - Takada, Hidetoshi
AU - Ohga, Shouichi
AU - Heike, Toshio
AU - Takita, Junko
AU - Ohara, Osamu
AU - Takei, Syuji
AU - Takahashi, Makio
AU - Kanegane, Hirokazu
AU - Morio, Tomohiro
AU - Iwaki-Egawa, Sachiko
AU - Sasahara, Yoji
AU - Nishikomori, Ryuta
AU - Yasumi, Takahiro
N1 - Funding Information:
This research was partially supported by the following grants: Health Labor Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health , Labour and Welfare of Japan (H29-Nanchi-Ippan-020 and JPMH20317089 ); the Practical Research Project for Rare /Intractable Diseases from the Japan Agency for Medical Research and Development ( JP19ek0109200 , JP20ek0109477 ); the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research ) from Japan Agency for Medical Research and Development ( JP20am0101111 ); and a research grant from the Morinaga Hoshikai.
Publisher Copyright:
© 2021 American Academy of Allergy, Asthma & Immunology
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jaci.2021.01.018
DO - 10.1016/j.jaci.2021.01.018
M3 - Article
C2 - 33529688
AN - SCOPUS:85101868517
VL - 148
SP - 550
EP - 562
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 2
ER -