Hiroshi Nihira1, Kazushi Izawa2, Moeko Ito3, Hiroaki Umebayashi4, Tsubasa Okano5, Shunsuke Kajikawa6, Etsuro Nanishi7, Dai Keino8, Kosaku Murakami9, Masahiko Isa-Nishitani1, Takeshi Shiba10, Yoshitaka Honda1, Atsushi Hijikata11, Tadateru Yasu12, Tomohiro Kubota13, Yoshinori Hasegawa14, Yusuke Kawashima14, Naoko Nakano15, Hidetoshi Takada16, Shouichi Ohga7, Toshio Heike17, Junko Takita1, Osamu Ohara14, Syuji Takei13, Makio Takahashi18, Hirokazu Kanegane19, Tomohiro Morio5, Sachiko Iwaki-Egawa3, Yoji Sasahara20, Ryuta Nishikomori21, Takahiro Yasumi1. 1. Department of Pediatrics, Kyoto University, Kyoto, Japan. 2. Department of Pediatrics, Kyoto University, Kyoto, Japan. Electronic address: kizawa@kuhp.kyoto-u.ac.jp. 3. Department of Pharmacy, Hokkaido University of Science, Sapporo, Japan. 4. Department of Rheumatology, Miyagi Children's Hospital, Sendai, Japan. 5. Department of Pediatrics and Development Biology, Tokyo Medical and Dental University, Tokyo, Japan. 6. Department of Neurology, Kyoto University, Kyoto, Japan. 7. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 8. Division of Hematology/Oncology, Kanagawa Children's Medical Center, Yokohama, Japan. 9. Department of Rheumatology and Clinical Immunology, Kyoto University, Kyoto, Japan. 10. Department of Pediatrics, Tenri Hospital, Tenri, Japan. 11. Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan. 12. Department of Pediatrics, Nagasaki Medical Center, Omura, Japan. 13. Department of Pediatrics, Kagoshima University, Kagoshima, Japan. 14. Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan. 15. Department of Pediatrics, Ehime University, Toon, Japan. 16. Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 17. Department of Pediatrics, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan. 18. Department of Neurology, Osaka Red Cross Hospital, Osaka, Japan. 19. Department of Child Health and Development, Tokyo Medical and Dental University, Tokyo, Japan. 20. Department of Pediatrics, Tohoku University, Sendai, Japan. 21. Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.
Abstract
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.
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.
Authors: Karyl S Barron; Ivona Aksentijevich; Natalie T Deuitch; Deborah L Stone; Patrycja Hoffmann; Ryan Videgar-Laird; Ariane Soldatos; Jenna Bergerson; Camilo Toro; Cornelia Cudrici; Michele Nehrebecky; Tina Romeo; Anne Jones; Manfred Boehm; Jennifer A Kanakry; Dimana Dimitrova; Katherine R Calvo; Hawwa Alao; Devika Kapuria; Gil Ben-Yakov; Dominique C Pichard; Londa Hathaway; Alessandra Brofferio; Elisa McRae; Natalia Sampaio Moura; Oskar Schnappauf; Sofia Rosenzweig; Theo Heller; Edward W Cowen; Daniel L Kastner; Amanda K Ombrello Journal: Front Immunol Date: 2022-01-10 Impact factor: 7.561