Development of the treatment by investigating the mechanism of disseminated BCG in patients with RORgT deficiency

• Project/Area Number: 16K15528
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Hiroshima University
• Principal Investigator: Okada Satoshi 広島大学, 医歯薬保健学研究科(医), 講師 (80457241)
• Co-Investigator(Kenkyū-buntansha): 津村 弥来 広島大学, 医歯薬保健学研究科(医), 研究員 (80646274)
• Research Collaborator: ASANO TAKAKI 広島大学, 大学院医歯薬保健学研究科, 大学院生 ; HAYAKAWA SEIICHI 広島大学, 大学院医歯薬保健学研究科, 大学院生
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: RORγT / RORC / MSMD / CMD / マイコバクテリア易感染症 / BCG / 慢性皮膚粘膜カンジダ症 / 原発性免疫不全症 / マウス / マイコバクテリア / 末梢リンパ節

Outline of Final Research Achievements

We performed whole exome analysis in patients with Mendelian Susceptibility to Mycobacterial Diseases (MSMD) and/or Chronic Mucocutaneous Candidiasis (CMC). Through this study, we succeeded to identify two familial cases with RORγT deficiency. Two novel homozygous mutations in RORC, encoding RORγT, were identified. These two mutations introduced Jurkat cells, an immortalized line of human T lymphocyte cells, failed to upregulate IL17A mRNA, whereas WT RORC introduced cells upregulated them. We thus concluded that identified mutations were loss-of-function or severely hypomorphic. We are planning to pursue molecular mechanism of this disorder by investigating the patients’ cells, together with collecting detail clinical records.
Simultaneously, we have tried to generate inducible conditional-Rorc knockout mouse. We are now investigating generated mouse whether the genetic elimination is obtained by the pIpC injection.

Research Products

• [Int'l Joint Research] The Rockefeller University/University of South Florida/Johns Hopkins(米国)
• [Int'l Joint Research] Inserm/Imagine institute(France)
• [Int'l Joint Research] Garvan Institute of Medical Research(Australia)
• [Int'l Joint Research] Imperial College London(United Kingdom)
• [Int'l Joint Research] The Rockefeller University(米国)
• [Int'l Joint Research] Necker-Enfants Malades Hospital/INSERM(France)
• [Journal Article] Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations (2018)
  • Author(s): Leiding JW, Okada S, Hagin D, Abinun M, Shcherbina A, Balashov DN, Kim VHD, Ovadia A, Guthery SL, Pulsipher M, Lilic D, Devlin LA, Christie S, Depner M, Fuchs S, van Royen-Kerkhof A, et al.
  • Journal Title: J Allergy Clin Immunol. Volume: 141 Issue: 2 Pages: 704-717
  • DOI: 10.1016/j.jaci.2017.03.049
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection (2018)
  • Author(s): Zhang SY, Clark NE, Freije CA, Pauwels E, Taggart AJ, Okada S, Mandel H, Garcia P, Ciancanelli MJ, Biran A, Lafaille FG, Tsumura M, et al.
  • Journal Title: Cell Volume: 172 Issue: 5 Pages: 952-965.e18
  • DOI: 10.1016/j.cell.2018.02.019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Flow cytometry-based diagnosis of primary immunodeficiency diseases (2018)
  • Author(s): Kanegane H, Hoshino A, Okano T, Yasumi T, Wada T, Takada H, Okada S, Yamashita M, Yeh TW, Nishikomori R, Takagi M, Imai K, Ochs HD, Morio T.
  • Journal Title: Allergology International Volume: 67 Issue: 1 Pages: 43-54
  • DOI: 10.1016/j.alit.2017.06.003
  • NAID: 130006322088
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. (2017)
  • Author(s): Hoshino A, Okada S, Yoshida K, Nishida N, Okuno Y, Ueno H, Yamashita M, Okano T, Tsumura M, Nishimura S, Sakata S, Kobayashi M, Nakamura H, Kamizono J, Mitsui-Sekinaka K, Ichimura T, Ohga S, Nakazawa Y, Takagi M, Imai K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Ogawa S, Kojima S, Nonoyama S, Morio T, Kanegane H.
  • Journal Title: J Allergy Clin Immunol. Volume: - Issue: 1 Pages: 390-400
  • DOI: 10.1016/j.jaci.2016.09.029
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Molecular Mechanism and Structural Basis of Gain of Function of STAT1 Caused by Pathogenic R274Q Mutation (2017)
  • Author(s): Fujiki R, Hijikata A, Shirai T, Okada S, Kobayashi M, Ohara O
  • Journal Title: J Biol Chem. Volume: 292 Issue: 15 Pages: 6240-6254
  • DOI: 10.1074/jbc.m116.753848
  • Peer Reviewed / Open Access
• [Journal Article] A gain-of-function mutation of STAT1: A novel genetic factor contributing to chronic mucocutaneous candidiasis (2017)
  • Author(s): Eslami Narges、Tavakol Marzieh、Mesdaghi Mehrnaz、Gharegozlou Mohammad、Casanova Jean-Laurent、Puel Anne、Okada Satoshi、Arshi Saba、Bemanian Mohammad Hassan、Fallahpour Morteza、Molatefi Rasool、Seif Farhad、Zoghi Samaneh、Rezaei Nima、Nabavi Mohammad
  • Journal Title: Acta Microbiol Immunol Hung. Volume: 64 Issue: 2 Pages: 191-201
  • DOI: 10.1556/030.64.2017.014
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anti-human neutrophil antigen-1a, -1b, and -2 antibodies in neonates and children with immune neutropenias analyzed by extracted granulocyte antigen immunofluorescence assay (2017)
  • Author(s): Onodera Rie、Kurita Emi、Taniguchi Kikuyo、Karakawa Shuhei、Okada Satoshi、Kihara Hirotaka、Fujii Teruhisa、Kobayashi Masao
  • Journal Title: Transfusion Volume: 57 Issue: 11 Pages: 2586-2594
  • DOI: 10.1111/trf.14291
  • Peer Reviewed
• [Journal Article] Significant augmentation of regulatory T cell numbers occurs during the early neonatal period (2017)
  • Author(s): Hayakawa S.、Ohno N.、Okada S.、Kobayashi M.
  • Journal Title: Clin Exp Immunol. Volume: 190 Issue: 2 Pages: 268-279
  • DOI: 10.1111/cei.13008
  • Peer Reviewed
• [Journal Article] Individual Clinically Diagnosed with CHARGE Syndrome but with a Mutation in KMT2D, a Gene Associated with Kabuki Syndrome: A Case Report (2017)
  • Author(s): Sakata Sonoko、Okada Satoshi、Aoyama Kohei、Hara Keiichi、Tani Chihiro、Kagawa Reiko、Utsunomiya-Nakamura Akari、Miyagawa Shinichiro、Ogata Tsutomu、Mizuno Haruo、Kobayashi Masao
  • Journal Title: Frontiers in Genetics Volume: 8 Pages: 1-6
  • DOI: 10.3389/fgene.2017.00210
  • Peer Reviewed / Open Access
• [Journal Article] A Case with Spondyloenchondrodysplasia Treated with Growth Hormone (2017)
  • Author(s): Utsumi Takanori、Okada Satoshi、Izawa Kazushi、Honda Yoshitaka、Nishimura Gen、Nishikomori Ryuta、Okano Rika、Kobayashi Masao
  • Journal Title: Front Endocrinol. Volume: 8 Pages: 157-157
  • DOI: 10.3389/fendo.2017.00157
  • NAID: 120006331972
  • Peer Reviewed / Open Access
• [Journal Article] Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial (2017)
  • Author(s): Kitaoka Taichi、Tajima Toshihiro、Nagasaki Keisuke、Kikuchi Toru、Yamamoto Katsusuke、Michigami Toshimi、Okada Satoshi、Fujiwara Ikuma、Kokaji Masayuki、Mochizuki Hiroshi、Ogata Tsutomu、Tatebayashi Koji、Watanabe Atsushi、Yatsuga Shuichi、Kubota Takuo、Ozono Keiichi
  • Journal Title: Clin Endocrinol. Volume: 87 Issue: 1 Pages: 10-19
  • DOI: 10.1111/cen.13343
  • Peer Reviewed
• [Journal Article] Newborn screening for carnitine palmitoyltransferase II deficiency using (C16 + C18:1)/C2: Evaluation of additional indices for adequate sensitivity and lower false-positivity (2017)
  • Author(s): Tajima G, Hara K, Tsumura M, Kagawa R, Okada S, Sakura N, Maruyama S, Noguchi A, Awaya T, Ishige N, Musha I, Ajihara S, Ohtake A, Naito E, Hamada Y, Kono T, Asada T, Sasaio H, Fukaoo T, Fujikip R, Ohara O, Bo R, Yamada K, Kobayashi H, Hasegawa Y, Yamaguchi S, Takayanagis M, Hata I, Shigematsu Y, Kobayashi M
  • Journal Title: Molecular Genetics and Metabolism Volume: 122 Issue: 3 Pages: 67-75
  • DOI: 10.1016/j.ymgme.2017.07.011
  • Peer Reviewed / Open Access
• [Journal Article] Characteristic clinical features of adipsic hypernatremia patients with subfornical organ-targeting antibody (2017)
  • Author(s): Nakamura-Utsunomiya A, Hiyama TY, Okada S, Noda M, Kobayashi M.
  • Journal Title: Clinical Pediatric Endocrinology Volume: 26 Issue: 4 Pages: 197-205
  • DOI: 10.1297/cpe.26.197
  • NAID: 130006105714
  • ISSN: 0918-5739, 1347-7358
  • Peer Reviewed
• [Journal Article] Clinical characteristics of septo-optic dysplasia accompanied by congenital central hypothyroidism in Japan (2017)
  • Author(s): Nagasaki Keisuke、Kubota Takuo、Kobayashi Hironori、Sawada Hirotake、Numakura Chikahiko、Harada Shohei、Takasawa Kei、Minamitani Kanshi、Ishii Tomohiro、Okada Satoshi、Kamasaki Hotaka、Sugihara Shigetaka、Adachi Masanori、Tajima Toshihiro
  • Journal Title: Clinical Pediatric Endocrinology Volume: 26 Issue: 4 Pages: 207-213
  • DOI: 10.1297/cpe.26.207
  • NAID: 130006105766
  • ISSN: 0918-5739, 1347-7358
  • Peer Reviewed
• [Journal Article] 慢性皮膚粘膜カンジダ症 (2017)
  • Author(s): 岡田 賢
  • Journal Title: 日本臨床免疫学会会誌 Volume: 40 Pages: 109-117
  • NAID: 130005696887
• [Journal Article] Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants (2016)
  • Author(s): Kagawa R, Fujiki R, Tsumura M, Sakata S, Nishimura S,Itan Y, Kong XF, Kato Z, Ohnishi H, Hirata O, Saito S, Ikeda M,Baghdadi JE, Bousfiha A, Fujiwara K, Oleastro M, Yancoski J,Perez L, Danielian S, Ailal F, Takada H, Hara T, Anne Puel A, Boisson-Dupuis S, Bustamante J, Casanova JL, Ohara O, Okada S, Masao Kobayashi M.
  • Journal Title: J Allergy Clin Immunol. Volume: － Issue: 1 Pages: 232-241
  • DOI: 10.1016/j.jaci.2016.09.035
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17 immunity. (2016)
  • Author(s): Okada S, Puel A, Casanova JL, Kobayashi M
  • Journal Title: Clin Transl Immunology. Volume: 5
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency. (2016)
  • Author(s): Levy R, Okada S, Beziat V, Moriya K, Liu C, Chai LY, Migaud M, Hauck F, Al Ali A, Cyrus C, Vatte C, Patiroglu T, Unal E, Ferneiny M, Hyakuna N, Nepesov S, Oleastro M, Ikinciogullari A, Dogu F, Asano T, et al.
  • Journal Title: Proc Natl Acad Sci USA Volume: 113 Issue: 51
  • DOI: 10.1073/pnas.1618300114
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets (2016)
  • Author(s): Ma CS, Wong N, Rao G, Nguyen A, Avery DT, Payne K, Torpy J, O'Young P, Deenick E, Bustamante J, Puel A, Okada S, Kobayashi M, Martinez-Barricarte R, Elliott M, Sebnem Kilic S, El Baghdadi J, Minegishi Y, Bousfiha A, Robertson N, et al.
  • Journal Title: J Exp Med. Volume: 213 Issue: 8 Pages: 1589-608
  • DOI: 10.1084/jem.20151467
  • NAID: 120006959745
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. (2016)
  • Author(s): Tsujita Y, et al.
  • Journal Title: J Allergy Clin Immunol. Volume: 138 Issue: 6 Pages: 1672-1680
  • DOI: 10.1016/j.jaci.2016.03.055
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype: an international survey of 276 patients from 169 kindreds (2016)
  • Author(s): Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, Ouachee-Chardin M, Fouyssac F, Girisha KM, Etzioni A, Van Montfrans J, Camcioglu Y, Kerns LA, Belohradsky B, Blanche S, Bousfiha A, Rodriguez-Gallego C, Meyts I, Kisand K, Reichenbach J, et al.
  • Journal Title: Blood Volume: 127 Issue: 25 Pages: 3154-64
  • DOI: 10.1182/blood-2015-11-679902
  • Peer Reviewed / Int'l Joint Research
• [Presentation] STAT1機能獲得型変異による原発性免疫不全症患者に対する造血幹細胞移植の有効性と問題点の検討 (2018)
  • Author(s): 岡田 賢, Jennifer W. Leiding, Troy R. Torgerson, 今井耕輔, 井口晶裕, 有賀 正, 小林正夫
  • Organizer: 第40回 日本造血細胞移植学会総会
• [Presentation] STAT1機能獲得型変異による原発性免疫不全症 (2018)
  • Author(s): 岡田 賢
  • Organizer: 第1 回日本免疫不全・自己炎症学会総会・学術集会
  • Invited
• [Presentation] Asfotase Alfa投与によりミオパチー症状の軽快を得た成人型低ホスファターゼ症 (2017)
  • Author(s): 岡田 賢, 坂田園子, 香川礼子, 宇都宮朱里, 立川 加奈子, 北岡太一, 道上敏美, 大薗恵一, 小林正夫
  • Organizer: 第90回 日本内分泌学会学術集会
• [Presentation] Primary immunodeficiency associate with functional defect of RORγT (2016)
  • Author(s): Satoshi Okada, Janet Markle, Anne Puel, Masao Kobayashi, Jean-Laurent Casanova
  • Organizer: The 39th Annual Meeting of the Molecular Biology
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] International survey of clinical manifestations of patients with STAT1 gain-offunction mutations (2016)
  • Author(s): 岡田賢, 津村弥来, 西村志帆, 坂田園子, 香川礼子, Julie Toubiana, Anne Puel, Jean-Laurent Casanova, 小林正夫
  • Organizer: 第78回 日本血液学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Alanine-scanning mutagenesis of human STAT1 to estimate the loss- or gain-offunction nature of variants (2016)
  • Author(s): Satoshi Okada, Ryoji Fujiki, Reiko Kagawa, Miyuki Tsumura, Xiaofei Kong, Sonoko Sakata, Shiho Nishimura, Zenichiro Kato, Hidenori Ohnishi, Yuval Itan, Stephanie Boisson-Dupuis, Jacinta Bustamante, Jean-Laurent Casanova, Osamu Ohara, and Masao Kobayashi
  • Organizer: 17th Biennial Meeting of the European Society for immunodeficiencies
  • Place of Presentation: Barcelona (Spain)
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] STAT1機能獲得型変異を有する原発性免疫不全症患者の臨床症状の国際調査 (2016)
  • Author(s): 岡田賢, 津村弥来, 西村志帆, 坂田園子, Julie Toubiana, Anne Puel, Jean-Laurent Casanova, 小林正夫
  • Organizer: 第44回 日本臨床免疫学会
  • Place of Presentation: 東京
  • Year and Date: 2016-09-08
• [Presentation] Loss-of-function and dominant negative STAT1 coiled-coil domain mutations in MSMD (2016)
  • Author(s): Satoshi Okada, Reiko Kagawa, Ryoji Fujiki, Zenichiro Kato, Hidenori Ohnishi, Stephanie Boisson-Dupuis, Jacinta Bustamante, Jean-Laurent Casanova, Osamu Ohara, and Masao Kobayashi
  • Organizer: Congress of Asia Pacific Society for Immunodeficiencies
  • Place of Presentation: Hong Kong (China)
  • Year and Date: 2016-04-30
  • Int'l Joint Research
• [Book] 原発性免疫不全症症候群 診療の手引き (2017)
  • Author(s): 岡田 賢
  • Total Pages: 10
  • Publisher: 診断と治療社
• [Book] 臨床免疫・アレルギー科 (2017)
  • Author(s): 岡田 賢, 津村弥来, 小林正夫
  • Total Pages: 7
  • Publisher: 科学評論社
• [Book] 日本臨床 免疫症候群III (2016)
  • Author(s): 岡田 賢
  • Total Pages: 17
  • Publisher: 日本臨牀社
• [Remarks] 【研究成果】まれな原発性免疫不全症に対する造血幹細胞移植の有効性と問題点を解明
  • URL: https://www.hiroshima-u.ac.jp/news/40053
• [Remarks] STAT1遺伝子変異の病的意義を高精度に予測するツール
  • URL: https://www.hiroshima-u.ac.jp/news/36849