The development of in vitro functional assay system for the genetic variants in inherited autoinflammatory diseases.

• Project/Area Number: 21K07770
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Gifu University
• Principal Investigator: Ohnishi Hidenori 岐阜大学, 大学院医学系研究科, 教授 (60381620)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 自己炎症性疾患 / 遺伝子変異 / 原発性免疫不全症 / 遺伝子解析 / 病的意義不明バリアント

Outline of Research at the Start

近年、遺伝性自己炎症疾患を含む原発性免疫不全症(PID)について、次々に新たな責任遺伝子が明らかとなっている。多くの症例で遺伝子解析が行われるようになったが、解析事例の中には病原性不明のバリアント(VUS) が同定され、遺伝子解析だけでは問題解決に至らない症例が多数発生しており問題視されている。 本研究では自験例や、国内で発生し自己炎症疾患が疑われた症例の情報を日本免疫不全・自己炎症学会と連携し集積し、遺伝子解析の結果同定されたVUSについて評価するin vitro実験系を構造生物学的な技術を駆使して構築を試みる。これにより患者の確定診断、適切な治療につなげ医療に貢献することを目的とする。

Outline of Final Research Achievements

The aim of this study was to establish an experimental system for the evaluation of variants of unknown pathological significance in the recently discovered genes responsible for hereditary autoinflammatory diseases, namely the IL36RN, TNFAIP3, PSMB9, SAMD9L and IKBKG genes. This study has established an in vitro experimental system for the evaluation of genetic variants detected in patients using cultured cells of the HEK293 lineage without the use of patient-derived biological samples. On the other hand, with regard to the analysis of the IL-36 ligand-receptor complex structure, it was confirmed that the IL-36Ra protein can functionally inhibit the activity by IL-36α, but the creation of an IL-36 receptor protein that retains the ability to bind to the ligand remains an issue.

Academic Significance and Societal Importance of the Research Achievements

本研究により、IL36RN, TNFAIP3, IKBKG, PSMB9, SAMD9Lそれぞれの遺伝子のバリアントの病的意義の判定を行う、in vitro実験系が構築できた。今後、別途実施中あるいは実施予定の全国症例実態調査や新規に発生した疑い症例で見出された病的意義不明遺伝子バリアントについて、本法を用いることで患者由来生体試料を用いることなく病的意義の判定が可能となった。適切な確定診断を行うことで、効果的な治療を行うことにつながると考えられる。

Research Products

• [Journal Article] Pharmacokinetics, safety, and efficacy of 20% subcutaneous immunoglobulin (Ig20Gly) administered weekly or every 2 weeks in Japanese patients with primary immunodeficiency diseases: a phase 3, open-label study (2024)
  • Author(s): Kanegane Hirokazu、Endo Akifumi、Okada Satoshi、Ohnishi Hidenori、Ishimura Masataka、Nishikomori Ryuta、Imai Kohsuke、Nonoyama Shigeaki、Muramatsu Hideki、Wada Taizo、Kuga Atsushi、Sakamoto Ko、Russo-Schwarzbaum Sharon、Chu Liang-Hui、McCoy Barbara、Li Zhaoyang、Yel Leman
  • Journal Title: Immunotherapy Advances Volume: 4 Issue: 1
  • DOI: 10.1093/immadv/ltae001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical Characteristics of Cryopyrin-Associated Periodic Syndrome and Long-Term Real-World Efficacy and Tolerability of Canakinumab in Japan: Results of a Nationwide Survey. (2024)
  • Author(s): Miyamoto T, Izawa K, Masui S, Yamazaki A, Yamasaki Y, Shigemura T, Furuta J, Sato S, Tanaka H, Izumikawa M, Yamamura M, Hasegawa T, Kaneko H, Nakagishi Y, Nakano N, Kashiwado M, Mori M, Kawahata K, Hayama K, etc; Japan CAPS Working Group.
  • Journal Title: Arthritis Rheumatol. Volume: - Issue: 6 Pages: 949-962
  • DOI: 10.1002/art.42808
  • Peer Reviewed / Open Access
• [Journal Article] A case of A20 haploinsufficiency complicated by autoimmune hepatitis (2024)
  • Author(s): Iwasa Taisei、Miwa Takao、Unome Shinji、Hanai Tatsunori、Imai Kenji、Takai Koji、Miwa Yuki、Hori Tomohiro、Ohnishi Hidenori、Matsumoto Munekazu、Niwa Ayumi、Miyazaki Tatsuhiko、Shimizu Masahito
  • Journal Title: Hepatology Research Volume: － Issue: 6 Pages: 606-611
  • DOI: 10.1111/hepr.14003
  • Peer Reviewed
• [Journal Article] Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome (2023)
  • Author(s): Maeda Ayaka、Tsuchida Naomi、Uchiyama Yuri、Horita Nobuyuki、Kobayashi Satoshi、Kishimoto Mitsumasa et al.
  • Journal Title: Rheumatology Volume: - Issue: 8 Pages: 1-10
  • DOI: 10.1093/rheumatology/kead425
  • Peer Reviewed / Open Access
• [Journal Article] A complementary approach for genetic diagnosis of inborn errors of immunity using proteogenomic analysis (2023)
  • Author(s): Sakura F, Noma K, Asano T, Tanita K, Toyofuku E, Kato K, Tsumura M, Nihira H, Izawa K, Mitsui-Sekinaka K, Konno R, Kawashima Y, Mizoguchi Y, Karakawa S, Hayakawa S, Kawaguchi H, Imai K, Nonoyama S, Yasumi T, Ohnishi H, Kanegane H, Ohara O, Okada S
  • Journal Title: PNAS Nexus Volume: 2 Issue: 4 Pages: 1-12
  • DOI: 10.1093/pnasnexus/pgad104
  • Peer Reviewed / Open Access
• [Journal Article] Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates (2023)
  • Author(s): Kawai Hiroki、Takashima Shigeo、Ohba Akiko、Toyoshi Kayoko、Kubota Kazuo、Ohnishi Hidenori、Shimozawa Nobuyuki
  • Journal Title: Brain and Development Volume: 45 Issue: 1 Pages: 58-69
  • DOI: 10.1016/j.braindev.2022.10.001
  • Peer Reviewed
• [Journal Article] A case of VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) with decreased oxidative stress levels after oral prednisone and tocilizumab treatment (2022)
  • Author(s): Tozaki Nagie、Tawada Chisato、Niwa Hirofumi、Mizutani Yoko、Shu En、Kawase Aki、Miwa Yuki、Ohnishi Hidenori、Sasai Hideo、Miyako Keisuke、Hosokawa Junichi、Kato Ayaka、Kobayashi Kazuhiro、Miyazaki Tatsuhiko、Shirakami Yohei、Shimizu Masahito、Iwata Hiroaki
  • Journal Title: Frontiers in Medicine Volume: 9 Pages: 1046820-1046820
  • DOI: 10.3389/fmed.2022.1046820
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and Genetic Characterization of Patients with Artemis Deficiency in Japan (2022)
  • Author(s): Inoue Kento、Miyamoto Satoshi、Tomomasa Dan、Adachi Eriko、Azumi Shohei、Horikoshi Yasuo、Ishihara Takashi、Osone Shinya、Kawahara Yuta、Kudo Ko、Kato Zenichiro、Ohnishi Hidenori、Kashimada Kenichi、Imai Kohsuke、Ohara Osamu、van Zelm Menno C.、Cowan Morton J.、Morio Tomohiro、Kanegane Hirokazu
  • Journal Title: Journal of Clinical Immunology Volume: 43 Issue: 3 Pages: 585-594
  • DOI: 10.1007/s10875-022-01405-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel STAT1 Variants in Japanese Patients with Isolated Mendelian Susceptibility to Mycobacterial Diseases (2022)
  • Author(s): Ono R, Tsumura M, Shima S, Matsuda Y, Gotoh K, Miyata Y, Yoto Y, Tomomasa D, Utsumi T, Ohnishi H, Kato Z, Ishiwada N, Ishikawa A, Wada T, Uhara H, Nishikomori R, Hasegawa D, Okada S, Kanegane H.
  • Journal Title: Journal of Clinical Immunology Volume: 43 Issue: 2 Pages: 466-478
  • DOI: 10.1007/s10875-022-01396-1
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of type I interferon signatures in undifferentiated inflammatory diseases: A Japanese multicenter experience. (2022)
  • Author(s): Miyamoto T, Honda Y, Izawa K, Kanazawa N, Saito MK, Takita J, Nishikomori R, Yasumi T, et al.
  • Journal Title: Front Immunol Volume: 13 Pages: 905960-905960
  • DOI: 10.3389/fimmu.2022.905960
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive targeted next-generation sequencing in patients with slow-flow vascular malformations (2022)
  • Author(s): Nozawa Akifumi、Fujino Akihiro、Yuzuriha Shunsuke、Suenobu Souichi、Kato Aiko、Shimizu Fumiaki、Aramaki-Hattori Noriko、Kuniyeda Kanako、Sakaguchi Kazuya、Ohnishi Hidenori、Aoki Yoko、Ozeki Michio
  • Journal Title: Journal of Human Genetics Volume: 67 Issue: 12 Pages: 721-728
  • DOI: 10.1038/s10038-022-01081-6
  • Peer Reviewed
• [Journal Article] Serum Fibrinogen Level and Cytokine Production as Prognostic Biomarkers for Idiopathic Sudden Sensorineural Hearing Loss (2022)
  • Author(s): Okuda Hiroshi、Aoki Mitsuhiro、Ohashi Toshimitsu、Ogawa Bakushi、Shibata Hirofumi、Ueda Natsuko、Hayashi Hisamitsu、Nishihori Takezumi、Kuze Bunya、Ohnishi Hidenori、Ogawa Takenori
  • Journal Title: Otology & Neurotology Volume: 43 Issue: 7 Pages: 712-719
  • DOI: 10.1097/mao.0000000000003552
  • Peer Reviewed
• [Journal Article] Neutralizing Type I Interferon Autoantibodies in Japanese Patients with Severe COVID-19 (2022)
  • Author(s): Eto S, Nukui Y, Tsumura M, Nakagama Y, Kashimada K, Mizoguchi Y, Utsumi T, Taniguchi M, Sakura F, Noma K, Yoshida Y, Ohshimo S, Nagashima S, Okamoto K, Endo A, Imai K, Kanegane H, Ohnishi H, Hirata S, Sugiyama E, Shime N, Ito M, Ohge H, Kido Y, Bastard P, Casanova JL, Ohara O, Tanaka J, Morio T, Okada S
  • Journal Title: Journal of Clinical Immunology Volume: 42 Issue: 7 Pages: 1360-1370
  • DOI: 10.1007/s10875-022-01308-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An adult case of suspected A20 haploinsufficiency mimicking polyarteritis nodosa (2022)
  • Author(s): Niwano Tomoko、Hosoya Tadashi、Kadowaki Saori、Toyofuku Etsushi、Naruto Takuya、Shimizu Masaki、Ohnishi Hidenori、Koike Ryuji、Morio Tomohiro、Imai Kohsuke、Yoshida Masayuki、Yasuda Shinsuke
  • Journal Title: Rheumatology Volume: 61 Issue: 11 Pages: e337-e340
  • DOI: 10.1093/rheumatology/keac308
  • Peer Reviewed
• [Journal Article] Monogenic causes of pigmentary mosaicism (2022)
  • Author(s): Saida Ken、Chong Pin Fee、Yamaguchi Asuka、...Mitsuhiro Kato, et al.
  • Journal Title: Human Genetics Volume: 141 Issue: 11 Pages: 1771-1784
  • DOI: 10.1007/s00439-022-02437-w
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dysregulation of the Intestinal Microbiome in Patients With Haploinsufficiency of A20 (2022)
  • Author(s): Toyofuku Etsushi、Takeshita Kozue、Ohnishi Hidenori、Kiridoshi Yuko、Masuoka Hiroaki、Kadowaki Tomonori、Nishikomori Ryuta、Nishimura Kenichi、Kobayashi Chie、Ebato Takasuke、Shigemura Tomonari、Inoue Yuzaburo、Suda Wataru、Hattori Masahira、Morio Tomohiro、Honda Kenya、Kanegane Hirokazu
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 11 Pages: 787667-787667
  • DOI: 10.3389/fcimb.2021.787667
  • Peer Reviewed / Open Access
• [Journal Article] Case Report: Analysis of Preserved Umbilical Cord Clarified X-Linked Anhidrotic Ectodermal Dysplasia With Immunodeficiency in Deceased, Undiagnosed Uncles (2021)
  • Author(s): Inaba Satoshi、Aizawa Yuta、Miwa Yuki、Imai Chihaya、Ohnishi Hidenori、Kanegane Hirokazu、Saitoh Akihiko
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 786164-786164
  • DOI: 10.3389/fimmu.2021.786164
  • Peer Reviewed / Open Access
• [Journal Article] A20 Haploinsufficiency in East Asia (2021)
  • Author(s): Kadowaki Tomonori、Kadowaki Saori、Ohnishi Hidenori
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 780689-780689
  • DOI: 10.3389/fimmu.2021.780689
  • Peer Reviewed / Open Access
• [Journal Article] Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency (2021)
  • Author(s): Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, M.H, K.A, M.T, H.S, K.N, K.S, H.Y, I.K, N.R, T.M, Y.Y, T.S, O.T, O.T, K.T, S.I, F.Y, W.N, I.Y, K.K, O.S, T.T, N.K, M.S, Y.K, Kaisho T
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 0-0
  • DOI: 10.1038/s41467-021-27085-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An infant with X-linked anhidrotic ectodermal dysplasia with immunodeficiency presenting with Pneumocystis pneumonia: A case report. (2021)
  • Author(s): Toyohara M, Kajiho Y, Toyofuku E, Takahashi C, Owada K, Kanda S, Harita Y, Ohnishi H, Wada T, Imai K, Kanegane H, Morio T, Oka A
  • Journal Title: Clin Case Rep Volume: 9 Issue: 11
  • DOI: 10.1002/ccr3.5093
  • Peer Reviewed / Open Access
• [Journal Article] Hematopoietic Cell Transplantation Ameliorates Autoinflammation in A20 Haploinsufficiency (2021)
  • Author(s): Shiraki, M. Williams, E. Yokoyama, N. Shinoda, K. Nademi, Z. Matsumoto, K. Nihira, H. Honda, Y. Izawa, K. Nishikomori, R. Slatter, M. A. Cant, A. J. Gennery, A. R. Ohnishi, H. Kanegane, H.
  • Journal Title: J Clin Immunol Volume: 41 Issue: 8 Pages: 1954-1956
  • DOI: 10.1007/s10875-021-01124-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor (2021)
  • Author(s): Kataoka S, Kawashima N, Okuno Y, Muramatsu H, Miwata S, Narita K, Hamada M, Murakami N, Taniguchi R, Ichikawa D, Kitazawa H, Suzuki K, Nishikawa E, Narita A, Nishio N, Yamamoto H, Fukasawa Y, Kato T, Yamamoto H, Natsume J, Kojima S, Nishio I, Taketani T, Ohnishi H, Tahakashi Y.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: - Issue: 2 Pages: 639-644
  • DOI: 10.1016/j.jaci.2021.03.010
  • NAID: 120007192018
  • Peer Reviewed
• [Presentation] 自己炎症性疾患up to date 2023 (2023)
  • Author(s): 大西秀典
  • Organizer: 日本リウマチ学会総会・学術集会 (第67回)
• [Presentation] 免疫異常疾患における小児科と歯科・口腔外科のクロストーク (2023)
  • Author(s): 大西秀典
  • Organizer: 日本小児歯科学会 中部地方会大会(第42回)
• [Presentation] 希少遺伝子変異と免疫疾患 自己炎症性疾患 炎症性腸疾患(IBD)を呈する疾患を中心として (2023)
  • Author(s): 大西秀典
  • Organizer: 日本臨床免疫学会総会(第51回)
• [Presentation] A20ハプロ不全症の全国疫学調査 (2023)
  • Author(s): 大西秀典, 白木真由香, 三輪友紀, 門脇紗織, 門脇朋範
  • Organizer: 日本小児リウマチ学会学術集会(第32回)
• [Presentation] 原発性免疫不全症の新生児マススクリーニングの現状について (2023)
  • Author(s): 大西秀典
  • Organizer: 日本小児感染症学会総会・学術集会(第55回)
• [Presentation] 自己炎症性症候群の現状の把握、未来に向けてのメッセージ 自己炎症性症候群の新規疾患. (2022)
  • Author(s): 大西 秀典
  • Organizer: 日本小児リウマチ学会総会・学術集会(第31回)
• [Presentation] 自己炎症性疾患 PFAPAその鑑別疾患（HA20、高IgD症候群など）. (2022)
  • Author(s): 大西 秀典
  • Organizer: 日本小児感染症学会学術集会(第54回)
• [Presentation] 免疫不全症を伴う遺伝性自己炎症性疾患 (2022)
  • Author(s): 大西秀典
  • Organizer: 日本免疫不全・自己炎症学会総会(第5回)
• [Presentation] 先天性免疫異常症におけるJAK阻害剤の適応と最近の話題 (2021)
  • Author(s): 大西秀典
  • Organizer: 日本小児リウマチ学会総会・学術集会(第30回)
• [Presentation] Monogenic VasculitisとしてのA20ハプロ不全症 (2021)
  • Author(s): 大西秀典
  • Organizer: 日本小児リウマチ学会総会・学術集会(第30回)