Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation
| Autor: | Takahiro Yasumi, Ryuta Nishikomori, Osamu Ohara, Yusuke Kawashima, Tomohiro Morio, Kosaku Murakami, Syuji Takei, Tomohiro Kubota, Toshio Heike, Makio Takahashi, Hirokazu Kanegane, Hidetoshi Takada, Masahiko Isa-Nishitani, Atsushi Hijikata, Moeko Ito, Takeshi Shiba, Shunsuke Kajikawa, Tadateru Yasu, Naoko Nakano, Shouichi Ohga, Tsubasa Okano, Hiroaki Umebayashi, Junko Takita, Yoshinori Hasegawa, Dai Keino, Sachiko Iwaki-Egawa, Etsuro Nanishi, Hiroshi Nihira, Kazushi Izawa, Yoji Sasahara, Yoshitaka Honda |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Proteomics 0301 basic medicine Adenosine Deaminase 2 Deficiency Adolescent Adenosine Deaminase Immunology Pathogenesis Transcriptome Interferon-gamma 03 medical and health sciences 0302 clinical medicine Asian People Japan Agammaglobulinemia Humans Immunology and Allergy Medicine STAT1 Allele Child 030203 arthritis & rheumatology biology business.industry Gene Expression Profiling Interferon-stimulated gene Infant medicine.disease STAT1 Transcription Factor 030104 developmental biology Child Preschool Leukocytes Mononuclear biology.protein Intercellular Signaling Peptides and Proteins Aicardi–Goutières syndrome Female Severe Combined Immunodeficiency Tumor necrosis factor alpha business |
| Zdroj: | Journal of Allergy and Clinical Immunology. 148:550-562 |
| ISSN: | 0091-6749 |
| DOI: | 10.1016/j.jaci.2021.01.018 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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