Pathogenesis and pathophysiology of CARD15 related inflammatory disorders

• Project/Area Number: 24591551
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyushu University
• Principal Investigator: HIDETOSHI Takada 九州大学, 医学(系)研究科(研究院), 教授 (70294931)
• Co-Investigator(Kenkyū-buntansha): TAKIMOTO Tomohito 九州大学, 大学病院, 医師不足分野等教育指導者 (50599511) ; TANAKA Tamami 九州大学, 大学院医学研究院, 学術研究員 (60423547)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: iPS細胞 / CARD15 / 自己炎症性疾患 / 炎症性疾患 / 自己炎症 / Card15

Outline of Final Research Achievements

We analyzed the genetic causes of uveitis, familial Mediterranean fever, and CINCA syndrome patients, and established disease specific iPS cells from peripheral blood cells of the patients using SeV vector for the induction of OCT4, SOX2, KLF4, and MYC expression. Embryoid bodies were established form the iPS cells, and differentiated into hematopoietic cells. CD34-positive cells were purified from embryoid cells by using magnetic beads, and differentiated into vascular endothelial cells and vascular wall cells. In addition, myeloid cells were differentiated by incubating the cells with AGM-S3 stromal cells. When we analyzed the responsiveness to produce cytokines, individual cells derived from disease-specific iPS cells showed characteristically enhanced responsiveness compared with normal control cells.

Research Products

• [Journal Article] Idiopathic disseminated bacillus Calmette–Guerin infection in three infants (2015)
  • Author(s): Kido J, Mizukami T, Ohara O, Takada H, Yanai M
  • Journal Title: Pediatrics International Volume: in press
  • Peer Reviewed
• [Journal Article] Wiskott-Aldrich syndrome in a girl caused by heterozygous WASP mutation and extremely skewed X-chromosome inactivation: a novel association with maternal uniparental isodisomy 6 (2015)
  • Author(s): Takimoto T, Takada H, Ishimura M, Kirino M, Hata K, Ohara O, Morio T, Hara T
  • Journal Title: Neonatology Volume: 107 Issue: 3 Pages: 185-190
  • DOI: 10.1159/000370059
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Kawasaki disease-specific molecules in the sera are linked to microbe-associated molecular patterns in the biofilms (2014)
  • Author(s): Kusuda T, Nakashima Y, Murata K, Kanno S, Nishio H, Saito M, Tanaka T, Yamamura K, Sakai Y, Takada H, Miyamoto T, Mizuno Y, Ouchi K, Waki K, Hara T
  • Journal Title: PLoS One Volume: 20 Issue: 11 Pages: e113054-e113054
  • DOI: 10.1371/journal.pone.0113054
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Two Novel Gain-of-Function Mutations of STAT1 Responsible for Chroni Mucocutaneous Candidiasis Disease: Impaired Production of IL-17A and IL-22, and the Presence of anti-IL-17F Autoantibody (2014)
  • Author(s): Yamazaki Y, Yamada M, Kawai T, Morio T, Onodera M, Ueki M, Watanabe N, Takada H, Takezaki S, Chida N, Kobayashi I, Ariga T
  • Journal Title: J Immunol Volume: 193 Issue: 10 Pages: 4880-4887
  • DOI: 10.4049/jimmunol.1401467
  • Peer Reviewed
• [Journal Article] Successful treatment of non-Hodgkin's lymphoma using R-CHOP in a patient with Wiskott-Aldrich syndrome followed by a reduced-intensity stem cell transplant. (2014)
  • Author(s): Yuhki Koga, Hidetoshi Takada, Aiko Suminoe, Shouichi Ohga, Toshiro Hara
  • Journal Title: Pediatric Transplantation Volume: VOL.18 Issue: 6
  • DOI: 10.1111/petr.12297
  • Peer Reviewed / Open Access
• [Journal Article] Early progression of atherosclerosis in children with chronic infantile neurological cutaneous and articular syndrome (2014)
  • Author(s): Yamamura K, Takada H, Uike K, Nakashima Y, Hirata Y, Nagata H, Takimoto T, Ishimura M, Morihana E, Ohga S, Hara T
  • Journal Title: Rheumatology Volume: 53 Issue: 10 Pages: 1783-1787
  • DOI: 10.1093/rheumatology/keu180
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Efficacy and safety of IgPro20, a subcutaneous immunoglobulin, in Japanese patients with primary immunodeficiency diseases (2014)
  • Author(s): Kanegane H, Imai K, Yamada M, Takada H, Ariga T, Bexon M, Rojavin M, Hu W, Kobayashi M, Lawo JP, Nonoyama S, Hara T, Miyawaki T
  • Journal Title: J Clin Immunol Volume: 34 Issue: 2 Pages: 204-211
  • DOI: 10.1007/s10875-013-9985-z
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Successful non-myeloablative allogeneic bone marrow transplantation after R-CHOP therapy in a 17-year-old Wiskott-Aldrich syndrome patient with malignant lymphoma (2014)
  • Author(s): Koga Y, Takada H, Suminoe A, Ohga S, Hara T
  • Journal Title: Pediatric Transplantation Volume: in press
  • Peer Reviewed
• [Journal Article] Early Progression of Atherosclerosis in Children with CINCA Syndrome (2014)
  • Author(s): Yamamura K, Takada H, Uike K, Nakashima Y, Hirata Y, Nagata H, Takimoto T, Ishimura M, Morihana E, Ohga S, Hara T
  • Journal Title: Rheumatology Volume: in press
  • Peer Reviewed
• [Journal Article] Development of Kawasaki disease in a patient with PFAPA (2013)
  • Author(s): Ninomiya T, Takada H, Nagatomo Y, Nanishi E, Nagata H, Yamamura K, Doi T, Ikeda K, Hara T
  • Journal Title: Pediatr Int Volume: 55 Issue: 6 Pages: 801-802
  • DOI: 10.1111/ped.12225
  • Peer Reviewed
• [Journal Article] B cell function after unrelated umbilical cord blood transplantation using minimal-intensity conditioning regimen in patients with X-SCID. (2013)
  • Author(s): Kumaki S, Sasahara Y, Kamachi Y, Muramatsu H, Morio T, Goi K, Sugita K, Urabe T, Takada H, Kojima S, Tsuchiya S, Hara T
  • Journal Title: Int J Hematol Volume: 98 Issue: 3 Pages: 355-60
  • DOI: 10.1007/s12185-013-1408-7
  • Peer Reviewed
• [Journal Article] Polymyxin B-immobilized fiber column hemoperfusion therapy for septic shock (2013)
  • Author(s): Koga Y, Oba U, Takimoto T, Suminoe A, Takada H, Hara T
  • Journal Title: Shock Volume: 40 Issue: 3 Pages: 233-233
  • DOI: 10.1097/shk.0b013e31829f218f
  • Peer Reviewed
• [Journal Article] Long-term liposteroid therapy for idiopathic pulmonary hemosiderosis (2013)
  • Author(s): Doi T, Ohga S, Ishimura M, Takada H, Ishii K, Ihara K, Nagai H, Hara T
  • Journal Title: Eur J Pediatr Volume: 172 Issue: 11 Pages: 1475-1478
  • DOI: 10.1007/s00431-013-2065-9
  • Peer Reviewed
• [Journal Article] Limited renal prophylaxis in regular plasmatherapy for heritable ADAMTS13 deficiency. (2013)
  • Author(s): Doi T, Ohga S, Ito N, Ishimura M, Suga N, Nomura A, Takada H, Matsumoto M, Fujimura Y, Hara T.
  • Journal Title: Pediatr Blood Cancer. Volume: 60 Issue: 9 Pages: 1557-1558
  • DOI: 10.1002/pbc.24553
  • Peer Reviewed
• [Journal Article] A non-invasive diagnosis of histiocytic necrotizing lymphadenitis by means of gene expression profile analysis of peripheral blood mononuclear cells (2013)
  • Author(s): Ishimura M, Yamamoto H, Mizuno Y, Takada H, Goto M, Doi T, Hoshina T, Ohga S, Ohshima K, Hara T
  • Journal Title: J Clin Immunol Volume: 33(5) Issue: 5 Pages: 1018-26
  • DOI: 10.1007/s10875-013-9897-y
  • Peer Reviewed
• [Journal Article] Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin-associated periodic syndrome as established in the first open-label, phase-3 pivotal study (24-week results) (2013)
  • Author(s): Imagawa T, Nishikomori R, Takada H, Takeshita S, Patel N, Kim D, Lheritier K, Heike T, Hara T, Yokota S
  • Journal Title: Clin Exp Rheumatol Volume: 31 Pages: 302-309
  • Peer Reviewed
• [Journal Article] Guidance on the use of canakinumab in patients with cryopyrin-associated periodic syndrome in Japan (2013)
  • Author(s): Yokota S, Nishikomori R, Takada H, Kikuchi M, Nozawa T, Kanetaka T, Kizawa T, Miyamae T, Mori M, Heike T, Hara T, Imagawa T
  • Journal Title: Mod Rheumatol Volume: 23 Issue: 3 Pages: 425-429
  • DOI: 10.1007/s10165-012-0769-8
  • NAID: 10031175900
  • Peer Reviewed
• [Journal Article] The identification of a novel splicing mutation in C1qB in a Japanese family with C1q deficiency: a case report (2013)
  • Author(s): Higuchi Y, Shimizu J, Hatanaka M, Kitano E, Kitamura H, Takada H, Ishimura M, Hara T, Ohara O, Asagoe K, Kubo T
  • Journal Title: Pediatr Rheumatol Online J Volume: 28 Issue: 1 Pages: 41-41
  • DOI: 10.1186/1546-0096-11-41
  • Peer Reviewed
• [Journal Article] Primary immunodeficiency in Japan; epidemiology, diagnosis, and pathogenesis (2013)
  • Author(s): Takada H
  • Journal Title: Pediatr Int Volume: 55 Issue: 6 Pages: 671-674
  • DOI: 10.1111/ped.12224
  • Peer Reviewed
• [Journal Article] Human CD3γ, but not CD3δ, haploinsufficiency differentially impairs γδ versus αβ surface TCR expression (2013)
  • Author(s): Muñoz-Ruiz M, Pérez-Flores V, Garcillán B, Guardo AC, Mazariegos MS, Takada H, Allende LM, Kilic SS, Sanal O, Roifman CM, López-Granados E, Recio MJ, Martínez-Naves E, Fernández-Malavé E, Regueiro JR
  • Journal Title: BMC Immunol Volume: 21 Issue: 1 Pages: 3-3
  • DOI: 10.1186/1471-2172-14-3
  • Peer Reviewed
• [Journal Article] NKRP1A+ γδ and αβ T cells are preferentially induced in patients with Salmonella infection. (2012)
  • Author(s): Hoshina T
  • Journal Title: Hum Immunol Volume: 73 Issue: 4 Pages: 623-628
  • DOI: 10.1111/j.1365-2265.2012.04390.x
  • Peer Reviewed
• [Journal Article] Complete immunotolerance induction after FEIBA prophylaxis in a haemophilia A patient with high-titre inhibitor (2012)
  • Author(s): Nanishi E, Ohga S, Doi T, Ishimura M, Ihara K, Takada H, Shima M, Hara T
  • Journal Title: Haemophilia Volume: 18 Issue: 3
  • DOI: 10.1111/j.1365-2516.2012.02776.x
  • Peer Reviewed
• [Journal Article] Recurrent bacterial meningitis by three different pathogens in an isolated asplenic child (2012)
  • Author(s): Uchida Y, Matsubara K, Wada T, Oishi K, Morio T, Takada H, Iwata A, Yura K, Kamimura K, Nigami H, Fukaya T
  • Journal Title: J Infect Chemother Volume: 18 Issue: 4 Pages: 576-80
  • DOI: 10.1007/s10156-011-0341-z
  • NAID: 10030948289
  • Peer Reviewed
• [Journal Article] Treatment choice of immunotherapy or further chemotherapy for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (2011)
  • Author(s): Shiraishi A, Ohga S, Doi T, Ishimura M, Takimoto T, Takada H, Miyamoto T, Abe Y, Hara T
  • Journal Title: Pediatr Blood Cancer Volume: (in press) Issue: 2 Pages: 265-270
  • DOI: 10.1002/pbc.24039
  • Peer Reviewed
• [Presentation] Wiskott-Aldrich syndrome in a girl caused by heterozygous WASP mutation and extremely skewed X-chromosome inactivation: an association of non-random X-chromosome inactivation and uniparental isodisomy 6 (2014)
  • Author(s): Takada H, Takimoto T, Ishimura M, Urata M, Morio T, Hara T
  • Organizer: 16th Biennial Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Prague, Czech Repubic
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] Mutations in Bruton’s tyrosine kinase impair IgA responses (2014)
  • Author(s): Mitsuiki N, Yang X, Bartol S, Kosaka Y, Takada H, Imai K, Kanegane H, Mizutani S, Burg VD, Zeim MV, Ohara O, Morio T
  • Organizer: 16th Biennial Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Prague, Czech Repubic
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] Association between primary immunodeficiency diseases and vasculitis syndrome (2014)
  • Author(s): Hara T, Ishimura M, Takada H, Kusuda Y, Nakashima Y, Murata K, Kanno S, Nishio H
  • Organizer: 16th Biennial Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Prague, Czech Repubic
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] Safety and tolerability of Hizentra in patients with primary immunodeficiency in Japan, Europe, and the US (2014)
  • Author(s): Kanegane H, Imai K, Yamada M, Takada H, Ariga T, Hara T, Rojavin M, Hu W, Hubsch A, Nonoyama S
  • Organizer: 16th Biennial Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Prague, Czech Repubic
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] Autoimmune diseases in patients with primary immunodeficiency diseases (2013)
  • Author(s): Hara T, Ishimura M, Takada H
  • Organizer: The 2nd International Congress on Controversies in Rheumatology and Autoimmunity
  • Place of Presentation: Budapest, Hungary
• [Presentation] Innate immunity異常の新たな疾患、トピックス (2013)
  • Author(s): 高田英俊
  • Organizer: 第116回日本小児科学会
  • Place of Presentation: 広島
  • Invited
• [Presentation] WASPのヘテロ接合変異とX染色体不活化異常により発症したWiskott-Aldrich症候群の女児 (2013)
  • Author(s): 高田英俊、瀧本智仁、浦田万起子、石村匡崇、金城唯宗、落合正行、土居岳彦、森尾友宏、原 寿郎
  • Organizer: 第116回日本小児科学会
  • Place of Presentation: 広島
• [Presentation] Early progression of atherosclerosis in children with cryopyrin-associated periodic syndrome (2013)
  • Author(s): Yamamura K, Uike K, Nakashima Y, Hirata Y, Nagata H, Takimoto T, Ishimura M, Takada H, Ohga S, Hara T
  • Organizer: 9th Congress of Asian Society for Pediatric Research
  • Place of Presentation: Sarawak, Malaysia
• [Presentation] Clinical and genetic characteristics of interleukin-1 receptor-associated kinase-4 deficiency in Japan (2013)
  • Author(s): Takada H
  • Organizer: The 4th Japanese Society of Hematollgy International Symposium
  • Place of Presentation: Matsuyama
  • Invited
• [Presentation] A Japanese female case of Wiskott-Aldrich syndrome with skewed X-chromosome inactivation (2013)
  • Author(s): Takimoto T, Ishimura M, Takada H, Morio T, Ohga S, Hara T
  • Organizer: The 4th Japanese Society of Hematollgy International Symposium
  • Place of Presentation: Matsuyama
• [Presentation] A Non-invasive Diagnosis of Histiocytic Necrotizing Lymphadenitis (2013)
  • Author(s): Hara T, Ishimura M, Yamamoto H, Mizuno Y, Takada H, Ohshima K
  • Organizer: Frontiers in Immunology Research 2013 International Conference
  • Place of Presentation: Monte Carlo, Monaco
• [Presentation] Treatment Choice of Immunotherapy or Further Chemotherapy for Epstein–Barr Virus-Associated Hemophagocytic Lymphohistiocytosis (2013)
  • Author(s): Shiraishi A, Ohga S, Doi T, Ishimura M, Takimoto T, Takada H, Miyamoto T, Abe Y, Hara T
  • Organizer: The 24th Fukuoka International Symposium on Pediatric/Maternal-Child Health Research
  • Place of Presentation: Fukuoka
• [Presentation] 原発性免疫不全症候群の新たな知見 ～特定の病原体に易感染性を示す疾患～ (2013)
  • Author(s): 高田英俊
  • Organizer: 第23回日本外来小児科学会
  • Place of Presentation: 福岡
• [Presentation] IRAK4欠損症 (2013)
  • Author(s): 高田英俊
  • Organizer: 第18回日本神経感染症学会
  • Place of Presentation: 宮崎
  • Invited
• [Presentation] 原発性免疫不全症の年齢による特徴～XLAとCVIDを中心に～ (2013)
  • Author(s): 石村匡崇、高田英俊、瀧本智仁、土居岳彦、今井耕輔、金兼弘和、森尾友宏、野々山恵章、宮脇利男、原 寿郎
  • Organizer: 第41回日本臨床免疫学会
  • Place of Presentation: 下関
• [Presentation] 二世代および三世代にわたって見られた家族性地中海熱 (2013)
  • Author(s): 高田英俊、石村匡崇、瀧本智仁、井田弘明、原 寿郎
  • Organizer: 第41回日本臨床免疫学会
  • Place of Presentation: 下関
• [Presentation] 原発性免疫不全症 Overview (2013)
  • Author(s): 高田英俊
  • Organizer: 第55回日本小児血液・がん学会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] Nation-wide survey of patients with primary immunodeficiency diseases in Japan: 2008 (2012)
  • Author(s): Takada H, Ishimura M, Doi T, Imai K, Sasahara Y, Kanegane H, Nishikomori R, Morio T, Heike T, Kobayashi M, Ariga S, Tsuchiya S, Nonoyama S, Miyawaki T, Hara T
  • Organizer: 15th Biennial Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Firenze
• [Presentation] Endocrine complications in primary immunodeficiency diseases in Japan (2012)
  • Author(s): Takada H, Nozaki M, Ishimura M, Ihara K, Imai K, Morio T, Kobayashi M, Nonoyama S, Hara T
  • Organizer: 15th Biennial Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Firenze
• [Presentation] Endocrine complications in primary immunodeficiency diseases in Japan (2012)
  • Author(s): Takada H, Ishimura M, Imai K, Morio T, Kobayashi M, Nonoyama S, Hara T
  • Organizer: 第41回日本免疫学会
  • Place of Presentation: 神戸
• [Presentation] A Japanese female case of Wiskott-Aldrich syndrome with skewed X-chromosome inactivation (2012)
  • Author(s): Takimoto T、Ishimura M、Takada H、Morio T、Hara T
  • Organizer: 第41回日本免疫学会
  • Place of Presentation: 神戸
• [Presentation] 臍帯血NK細胞は成人末梢血NK細胞よりもTLR-8刺激によるIFN-gamma産生能が高い (2012)
  • Author(s): 高田英俊、土居岳彦、大賀正一、原 寿郎
  • Organizer: 第115回日本小児科学会学術集会
  • Place of Presentation: 福岡
• [Presentation] 原発性免疫不全症全国疫学調査結果報告 (2012)
  • Author(s): 石村匡崇、高田英俊、土居岳彦、平家俊男、小林正夫、有賀 正、土屋 滋、野々山恵章、宮脇利男、原 寿郎
  • Organizer: 第115回日本小児科学会学術集会
  • Place of Presentation: 福岡
• [Presentation] 原発性免疫不全症（PID）の合併症としての内分泌疾患：PIDの全国疫学調査結果より (2012)
  • Author(s): 野崎高史、高田英俊、石村匡崇、井原健二、今井耕輔、森尾友宏、小林正夫、野々山恵章、原 寿郎
  • Organizer: 第115回日本小児科学会学術集会
  • Place of Presentation: 福岡
• [Presentation] 原発性免疫不全症全国疫学調査結果より XLAとCVIDに関して (2012)
  • Author(s): 石村匡崇、高田英俊、土居岳彦、金兼弘和、森尾友宏、宮脇利男、原 寿郎
  • Organizer: 第115回日本小児科学会学術集会
  • Place of Presentation: 福岡
• [Presentation] インターフェロン誘導遺伝子発現上昇は壊死性リンパ節炎（菊池病）の診断に有用である (2012)
  • Author(s): 石村匡崇、水野由美、高田英俊、後藤元宏、土居岳彦、保科隆之、大賀正一、原 寿郎
  • Organizer: 第115回日本小児科学会学術集会
  • Place of Presentation: 福岡
• [Presentation] 組織球性壊死性リンパ節炎の病理と臨床 ～臨床的観点から～ (2012)
  • Author(s): 高田英俊
  • Organizer: 第44回日本小児感染症学会
  • Place of Presentation: 北九州
  • Invited
• [Presentation] 小児臓器移植および免疫不全状態児への予防接種ガイドライン ～原発性免疫不全患者へのワクチン接種～ (2012)
  • Author(s): 高田英俊
  • Organizer: 第44回日本小児感染症学会
  • Place of Presentation: 北九州
  • Invited
• [Presentation] 小児感染免疫 up-to-date 自然免疫機構
  • Author(s): 高田英俊
  • Organizer: 第44回日本小児感染症学会 ad hoc教育セミナー
  • Place of Presentation: 北九州
  • Invited
• [Book] 小児の臓器移植および免疫不全状態における予防接種ガイドライン2014 (2014)
  • Author(s): 高田英俊
  • Total Pages: 127
  • Publisher: 協和企画
• [Book] 小児の発熱A to Z 免疫不全症-自然免疫不全 (2012)
  • Author(s): 高田英俊
  • Total Pages: 255
  • Publisher: 診断と治療社
• [Book] 自己炎症性疾患・自然免疫不全症とその近縁疾患 Myddsome異常症（IRAK4およびMyD88欠損症） (2012)
  • Author(s): 高田英俊
  • Total Pages: 279
  • Publisher: 診断と治療社
• [Book] 自己炎症性疾患・自然免疫不全症とその近縁疾患 Mendel遺伝型マイコバクテリア易感染症（IL-12、IFN-系の異常） (2012)
  • Author(s): 高田英俊
  • Total Pages: 279
  • Publisher: 診断と治療社