The discovery of the second case of human heme oxygenase-1 deficiency: biological evidence of HO-1 enzyme

• Project/Area Number: 23591531
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kanazawa University
• Principal Investigator: KOIZUMI SHOICHI 金沢大学, その他部局等, 名誉教授 (50019973)
• Co-Investigator(Renkei-kenkyūsha): YACHIE Akihiro 金沢大学, 医学系, 教授 (40210281) ; WADA Taizou 金沢大学, 医学系, 講師 (30313646) ; NISHIMURA Ryousei 金沢大学, 医学系, 講師 (50324116) ; SUGIMOTO Naotoshi 金沢大学, 医学系, 准教授 (80272954) ; OHTA Kunio 金沢大学, 医学系, 准教授 (00303280) ; NIIDA Yo 金沢大学, 金沢医科大学, 准教授 (40293344) ; SHIMIZU Masaki 金沢大学, 医学系, 講師 (10401902)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ヘムオキシゲナーゼ / ヘムオキシゲナーゼ１欠損症 / 炎症 / 血管炎 / 腎尿細管 / 溶血性貧血 / 血管内皮細胞 / ビリルビン代謝 / ヘムオキシゲナーゼ１欠損症、インド

Research Abstract

Heme oxygenase-1(HO-1) is the rate-limiting enzyme to metabolyze heme, showing antioxidant effects. In 1999, we reported the first case of human HO-1 deficiency. After the 2nd case was discovered in 2011, the 3 subsequent cases have been reported so far. All 5 patients with HO-1 deficiency were characterized by recalcitrant systemic inflammation, asplenia, microangiopathy and hypertention. Clinical data show hemolytic anemia with low serum bilirubin, thrombocytosis and evidences of renal tissue injury. From these data we would like to introduce HO-1 deficiency as a novel autoinflammatory disease.

Research Products

• [Journal Article] Long-term follow-up of a case of hypomagnesemia with secondary hypocalcemia caused by novel TRPM6 mutation. (2014)
  • Author(s): Shimizu M
  • Journal Title: Pediatric Nephrology Volume: 14
  • Peer Reviewed
• [Journal Article] Expansion of a liver-infiltrating cytotoxic T-lymphocyte clone in concert with the development of hepatitis-associated aplastic anemia (2013)
  • Author(s): Ikawa, Y., Nishimura, R., Kuroda, R., Mase, S., Araki R., Maeba, H., Wada, T., Toma, T., Koizumi, S., Yachie, A.
  • Journal Title: Brit J Haematol Volume: 161(4) Pages: 599-602
  • Peer Reviewed
• [Journal Article] An infant with recurrent convulsive seizures of 3 weeks duration: Questions (2013)
  • Author(s): Shimizu M
  • Journal Title: Pediatric Nephrology Volume: 13 Issue: 10 Pages: 1951-1951
  • DOI: 10.1007/s00467-013-2615-4
  • Peer Reviewed
• [Journal Article] Upregulation of aquaporin expression in the salivary glands of heat-acclimated rats (2013)
  • Author(s): Sugimoto, N., Matsuzaki, K., Ishibashi, H., Tanaka, M., Sawaki, T., Fujita, Y., Kawanami, T., Masaki, Y., Okazaki, T., Sekine, J., Koizumi, S., Yachie, A., Shido, O.
  • Journal Title: Scientific Reports Volume: 3 Pages: 1763-1763
  • Peer Reviewed
• [Journal Article] Targeted activation of PKAand Epac promotes glioblastoma regression in vitro (2013)
  • Author(s): Naotoshi Sugimoto
  • Journal Title: Mol Clin Oncol Volume: 1 Pages: 281-285
  • Peer Reviewed
• [Journal Article] Expansion of a liver-infiltrating cytotoxic T-lymphocyte clone in concert with the development of hepatitis-associated aplastic anemia. (2013)
  • Author(s): Ikawa Y
  • Journal Title: Brit J Haematol Volume: 161 Pages: 599-602
  • Peer Reviewed
• [Journal Article] Upregulation of aquaporin expression in the salivary glands of heat-acclimated rats. (2013)
  • Author(s): Sugimoto N
  • Journal Title: Scientific Reports Volume: 3 Pages: 1763-1763
  • Peer Reviewed
• [Journal Article] Compensated inflammation in systemic juvenile idiopathic arthritis : role of alternatively activated macrophages (2012)
  • Author(s): Shimizu M., Yachie, A.
  • Journal Title: Cytokine Volume: 60(1) Pages: 226-232
  • Peer Reviewed
• [Journal Article] Phosphodiesterase inhibitors suppress Lactobacillus casei cell wall-induced NF-kB and MAPK activation, and cell proliferation through a protein kinase A- or exchange protein activated by cAMP-dependent signal pathway. (2012)
  • Author(s): Saito T, Sugimoto N, Ohta K, Shimizu T, Phtani K, Nakayama Y, Nakanuma T, Hitomi Y, Nakamura H, Koizumi S, Yachie A.
  • Journal Title: The Scientific World Journal Volume: 2012 Pages: 8-8
  • Peer Reviewed
• [Journal Article] Cellular Heat Acclimation Regulates Cell Growth, Cell Morphology, Mitogen-activated Protein Kinase Activation, and Expression of Aquaporins in Mouse Fibroblast Cells. (2012)
  • Author(s): N Sugimoto, O Shido, K Matsuzaki, T Ohno-Shosaku, Y Hitomi, M Tanaka, T Sawaki, Y Fujita, T Kawanami, Y Masaki, T Okazaki, H Nakamura, S Koizumi, A Yachie, H Umehara
  • Journal Title: Cell Physiol Biochem Volume: 30 Pages: 450-457
  • Peer Reviewed
• [Journal Article] Human Heme oxygenase (HO)-1 deficiency presenting with hemolysis, nephritisand asplenia (2011)
  • Author(s): Radhakrishnan,N., Yadav,S.P., Sachdeva,A., Pruthi,P.K., Sawhney,S., Piplani,T., Wada,T., Yachie,A.
  • Journal Title: J Pediatr Hematol Oncol Volume: 33(1) Pages: 74-78
  • Peer Reviewed
• [Journal Article] Urinary heme oxygenase-1 as a sensitive indicator of tubulointerstitial inflammatory damage in various renal diseases (2011)
  • Author(s): Yokoyama, T., Shimizu, M., Ohta, K., Yuno, T., Okajima, M., Wada, T., Toma, T., Koizumi, S., Yachie, A.
  • Journal Title: Am J Nephrol Volume: 33 Pages: 414-420
  • Peer Reviewed
• [Journal Article] Human heme oxygenase (HO)-1 deficiency presenting with hemolysis, nephritisand asplenia. (2011)
  • Author(s): Nita Radhakrishnan, S Prakash Yadav, Taizo Wada, Akihiro Yachie
  • Journal Title: J Pediatr Hematol Oncol Volume: 33 Pages: 74-81
  • Peer Reviewed
• [Journal Article] Activation of tumor suppressor protein PTEN and induction of apoptosis are involved in cAMP-mediated inhibition of cell number in B92 glial cells. (2011)
  • Author(s): Naotoshi Sugimoto, Shinji Miwa, Takako Ohno-Shosaku, Hiroyuki Tsuchiya, Yoshiaki Hitomi, Hiroyuki Nakamura, Katsuro Tomita, Akihiro Yachie, Shoichi Koizumi
  • Journal Title: Neuroscience Letters Volume: 497 Pages: 55-59
  • NAID: 120003141599
  • Peer Reviewed
• [Journal Article] Urinary Heme Oxygenase-1 as a Sensitive Indicator of Tubulointerstitial Inflammatory Damage in Various Renal Diseases. (2011)
  • Author(s): Yokoyama T, Shimizu M, OhtaK, Yuno T, Okajima M, WadaT, Toma T, Koizumi S, Yachie A:
  • Journal Title: Am J Nephrol Volume: 33 Pages: 414-420
  • Peer Reviewed
• [Journal Article] Aplastic anemia successfully treated with rituximab: the possible role of aplastic anemia-associated autoantibodiesas a marker for response (2011)
  • Author(s): Hiroyuki Takamatsu, Hiroshi Yagasaki, Yoshiyuki Takahashi, Asahito Hama, Yutaka Saikawa,Akihiro Yachie, Shoichi Koizumi, Seiji Kojima, Shinji Nakao
  • Journal Title: European Journal of Haematology Volume: 86 Pages: 541-545
  • Peer Reviewed
• [Journal Article] Long-term follow-up of a case of hypomagnesemia with secondary hypocalcemia caused by novel TRPM6 mutation
  • Author(s): Shimizu, M., Niida, Y., Koizumi, S., Yachie, A.
  • Journal Title: Pediatric Nephrology Volume: (in press)
  • Peer Reviewed
• [Presentation] Protective role of host mast cells against acute graft-versus-host disease (2013)
  • Author(s): Araki,R., Nishimura, R., Maeba, H., Kuroda, R., Fujii, T., Mase, S., Koizumi, S., Yachie, A.
  • Organizer: 55th Annual Meeting of American Society of Hematology
  • Place of Presentation: New Orleans (USA)
• [Presentation] IFN-gamma-mediated elimination of host DCs by cytokine induced killer cells leads to less GVHD (2013)
  • Author(s): Mase,S., Nishimura, R., Kuroda, R., Fujii,T., Araki, R., Maeba, H., Koizumi, S., Yachie, A.
  • Organizer: 55th Annual Meeting of American Society of Hematology
  • Place of Presentation: New Orleans (USA)
• [Presentation] Monitoring of CD4+ T-cell receptor repertoire helps manage the patients with prolonged GVHD (2013)
  • Author(s): Kuroda, R., Nishimura, R., Mase, S., Fujii, T., Araki, R., Maeba, H., Koizumi, S., Yachie, A.
  • Organizer: 55th Annual Meeting of American Society of Hematology
  • Place of Presentation: New Orleans Convention Center (USA)
• [Presentation] Accurate Detection Of Renal Involvement In Pediatric Patients With Acute Lymphoblastic Leukemia By Utilizing 3D-Reconstruction Models Of Enhanced CT and Its Clinical Implications (2013)
  • Author(s): Raita Araki
  • Organizer: the 55th ASH Annual Meeting
  • Place of Presentation: New Orleans, USA
• [Presentation] Both Host-Type and Donor-Type Mast Cells Protect Against Acute Graft-Versus-Host Disease (2013)
  • Author(s): Hideaki Maeba
  • Organizer: the 55th ASH Annual Meeting
  • Place of Presentation: New Orleans, USA
• [Presentation] Natural Course Of Serum Ferritin In Childhood Cancer Survivors: Need For Iron Removal Therapy? (2013)
  • Author(s): Rie Kuroda
  • Organizer: the 55th ASH Annual Meeting
  • Place of Presentation: New Orleans, USA
• [Presentation] Allogeneic Cytokine-Induced Killer Cells Eliminate Host Dendritic Cells Due To The Enhanced Killing Activity By IFN-Gamma, Leading To Less Graft-Versus-Host Disease (2013)
  • Author(s): Toshihiro Fujiki
  • Organizer: the 55th ASH Annual Meeting
  • Place of Presentation: New Orleans, USA
• [Presentation] Protective role of host mast cells against acute graft-versus-host disease (2013)
  • Author(s): Araki R
  • Organizer: 日本血液学会
  • Place of Presentation: 札幌、ロイトン札幌
• [Presentation] IFN-gamma-mediated elimination of host DCs by cytokine induced killer cells leads to less GVHD (2013)
  • Author(s): Mase S
  • Organizer: 日本血液学会
  • Place of Presentation: 札幌、ロイトン札幌
• [Presentation] Monitoring of CD4+ T-cell receptor repertoire helps manage the patients with prolonged GVHD (2013)
  • Author(s): Kuroda R
  • Organizer: 日本血液学会
  • Place of Presentation: 札幌、ロイトン札幌
• [Presentation] Heme oxygenase-1 deficiency : a novel autoinflammatory disease, associated with systemic inflammation, accelerated tissue injury and endothelial dysfunction (2012)
  • Author(s): Yachie, A., Yokoyama, T., Shimizu, M., Ohta, K., Toma, T., Wada, T., Radhakrishnan, N., Sachdeva, A., Yadav, S.P.
  • Organizer: 15th Biennial Meeting of the European Society of Immunodeficiencies (ESID 2012)
  • Place of Presentation: Florence Convention Center (Italy)
• [Presentation] Allogeneic cytokine-induced killer cells kill dendritic cells efficiently resulting in less graft-versus-host disease (2012)
  • Author(s): Mase,S., Kuroda,R., Maeba,H., Araki,R., Fujiki,T., Koizumi,S., Yachie,A., Nishimura,R.
  • Organizer: 38th Annual meeting of the European group for blood and marrow transplantation (EBMT)
  • Place of Presentation: Geneva Convention Center (Switzerland)
• [Presentation] Evaluating Prolonged Gvhd Based On Monocyte and T-Cell Activation, Leads to Early Detection of Immunological Changes Before Gvhd Exacerbations (2012)
  • Author(s): Rie Kuroda, Toshihiro Fujiki, Shintaro Mase, Raita Araki, Hideaki Maeba, Shoichi Koizumi, Akihiro Yachie, and Ryosei Nishimura
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: Atlanta, USA
• [Presentation] Allogeneic Cytokine-Induced Killer Cell-Dependent Eimination of Host Dendritic Cells Leads to Less Graft-Versus-Host Disease. (2012)
  • Author(s): Shintaro Mase, Hideaki Maeba, Toshihiro Fujiki, Rie Kuroda, Raita Araki, Shoichi Koizumi, Akihiro Yachie, and Ryosei Nishimura
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: Atlanta, USA
• [Presentation] Only High Concentration of Immunoglobulin Inhibits Activation of Lymphocytes: Potential Use of Immunoglobulin for Preventing Gvhd (2012)
  • Author(s): Hideaki Maeba, Rie Kuroda, Toshihiro Hujiki, Shintaro Mase, Raita Araki, Shoichi Koizumi, Akihiro Yachie, and Ryosei Nishimura
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: Atlanta, USA
• [Presentation] Regulatory Role of Host IL-17 Via Control of Host Macrophage Activation Contributes to Less Acute Gvhd (2012)
  • Author(s): Rie Kuroda, Katsuaki Sato, Hideaki Maeba, Toshihiro Fujiki, Shintaro Mase, Raita Araki, Kazuhito Naka, Makoto Naito, Yoichiro Iwakura, Akihiro Yachie, Shoichi Koizumi, and Ryosei Nishimur
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: Atlanta, USA
• [Presentation] Superior Immunomodulatory Effects of Cultured Mast Cells: Potent Strategy for Treatment of Gvhd (2012)
  • Author(s): Raita Araki, Hideaki Maeba, Rie Kuroda, Toshihiro Fujiki, Shintaro Mase, Shoichi Koizumi, Akihiro Yachie, and Ryosei Nishimura
  • Organizer: 55th American Society of Hematology Annual Meeting
  • Place of Presentation: Atlanta, USA
• [Presentation] Allogeneic cytokine-induced killer cells kill dendritic cells efficiently resulting in less graft-versus-host disease (2012)
  • Author(s): Shintaro Mase, Rie Kuroda, Hideaki Maeba, Raita Araki, Toshihiro Fujiki, Shoichi Koizumi, Akihiro Yachie and Ryosei Nishimura
  • Organizer: 38th Annual meeting of the European group for blood and marrow transplantation
  • Place of Presentation: Geneva, Switzerland
• [Presentation] Potent strategy for treatment of GVHD utilizing cultured mast cells. (2012)
  • Author(s): Araki R, Nishimura R, Maeba H, Fijiki T, Masae S, Kuroda R, Yachie A
  • Organizer: 第７４回日本血液学会
  • Place of Presentation: 国立京都国際会館
• [Presentation] 培養肥満細胞を用いたGVHD治療への基礎的検討 (2012)
  • Author(s): 荒木来太、西村良成、前馬秀昭、黒田梨絵、藤木俊寛、馬瀬新太郎、谷内江昭宏
  • Organizer: 第５４回日本小児血液・がん学会
  • Place of Presentation: パシフィコ横浜会議センター
• [Presentation] 末梢血リンパ球、単球活性化同時解析を用いた移植後病態解析；血便症例を例にあげて (2012)
  • Author(s): 黒田梨絵、西村良成、馬瀬新太郎、前馬秀昭、荒木来太、藤木俊寛、谷内江昭宏
  • Organizer: 第５４回日本小児血液・がん学会
  • Place of Presentation: パシフィコ横浜会議センター
• [Presentation] A genetic variation in the heme oxygenase-1 gene predicts the outcome of HLA-fully-matched unrelated bone marrow transplantation (2011)
  • Author(s): Morishita,E., Maruyama,K., Takami,A., Onizuka,M., Kawase,T., Morishima,Y., Fukuda,T., Kodera,Y., Ohtake,S., Yachie,A., Nakao,S.
  • Organizer: 53rd Annual Meeting of American Society of Hematology
  • Place of Presentation: San Diego Convention Center (USA)
• [Presentation] Only Dendritic Cells, but Not Lymphocytes, Acquired Tolerogenicity by PUVA-Treatment by Upregulation of Indoleamine 2,3-Dioxygenase (IDO) (2011)
  • Author(s): Hideaki Maeba, Rie Kuroda, Yo Niida, Shintaro Mase, Raita Araki, Toshihiro Fujiki, Akihiro Yachie, Shoichi Koizumi, Ryosei Nishimura
  • Organizer: 54th Annual Meeting of the American Society of Hematology (ASH)
  • Place of Presentation: San Diego Convention Center (USA)
• [Presentation] Both Tissue-Derived and Bone Marrow-Derived Host IL-17 Producing Cells Are Required for Preventing Acute Graft-Versus-Host Disease (2011)
  • Author(s): Rie Kuroda, Hideaki Maeba, Katsuaki Sato, Kazuhito Naka, Shintaro Mase, Raita Araki, Toshihiro Fujiki, Yoichiro Iwakura, Akihiro Yachie, Shoichi Koizumi, Ryosei Nishimura
  • Organizer: 54th Annual Meeting of the American Society of Hematology (ASH)
  • Place of Presentation: San Diego Convention Center (USA)
• [Presentation] Attempting to Classify Prolonged Graft-Versus-Host-Disease According to Monocyte Activation Status in Addition to T-Cell (2011)
  • Author(s): ie Kuroda, Hideaki Maeba, Shintaro Mase, Raita Araki, Toshihiro Fujiki, Shoichi Koizumi, Akihiro Yachie, Ryosei Nishimura
  • Organizer: 54th Annual Meeting of the American Society of Hematology (ASH)
  • Place of Presentation: San Diego Convention Center (USA)
• [Presentation] 全身性若年性特発性関節炎におけるHO-1の役割とバイオマーカーとしての有用性
  • Author(s): 清水正樹、谷内江昭宏
  • Organizer: 第８回HO研究フォーラムKyoto
  • Place of Presentation: 京都府立医科大学青蓮会館（京都府）
• [Presentation] マクロファージ活性化症候群におけるHO-1の役割
  • Author(s): 清水正樹、横山忠史
  • Organizer: 第５５回日本リウマチ学会総会・学術集会、第２０回国際リウマチシンポジウム
  • Place of Presentation: 神戸国際会議場、神戸ポートピアホテル（兵庫県）
• [Presentation] Distinct role of IL-17 after HSCT: Protection from acute GVHD, while exacerbation of chronic GVHD.
  • Author(s): Kuroda R, Maeba H, Sato K, Naka K, Araki R, Mase S, Fujiki T, Iwakura Y, Koizumi S, Yachie A, Nishimura R.
  • Organizer: 第７３回日本血液学会
  • Place of Presentation: 名古屋国際会議場（愛知県）
• [Presentation] Attempting to classify prolonge GVHD according to monocyte activation status in addition to T-cell.
  • Author(s): Kuroda R, Nishimura R, Maeba H, Araki R, Mase S, Fujiki T, Koizumi S, Yachie A
  • Organizer: 第７３回日本血液学会
  • Place of Presentation: 名古屋国際会議場（愛知県）
• [Presentation] PUVA-treated dendritic cells have strong tolerogenic function by upregulation of IDO.
  • Author(s): Maeba H, Kuroda R, Niida Y, Araki R, Mase S, Fujiki T, Koizumi S, Yachie A, Nishimura R
  • Organizer: 第７３回日本血液学会
  • Place of Presentation: 名古屋国際会議場（愛知県）
• [Remarks]
  • URL: http://web.kanazawa-u.ac.jp/~med2
• [Remarks] 金沢大学小児科
  • URL: http://web.kanazawa-u.ac.jp/~med2
• [Remarks] 金沢大学小児科
  • URL: http://web.kanazawa-u,ac,jp/~med2
• [Remarks]
  • URL: http://web.kanazawa-u.ac.jp/~med2,
• [Remarks]
  • URL: http://kodomokokoro.w3.kanazawa-u.ac.jp/