Analysis of abnormal STAT1 disorders using disease-specific iPS cells.

• Project/Area Number: 26670501
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Hiroshima University
• Principal Investigator: Kobayashi Masao 広島大学, 医歯薬保健学研究院, 教授 (00162016)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: STAT1 / iPS細胞 / 単球機能 / 破骨細胞 / 食細胞 / 原発性免疫不全症

Outline of Final Research Achievements

This study demonstrated the establishment of the disease-specific iPS cells from patients with STAT1 abnormalities which consist of loss of function (LOF) and gain of function (GOF). Monocytes were differentiated derived from STAT1-LOF iPS cells presented the abnormal phosphorylation of STAT1 in response to IFNg. However, the change of transcriptional activity was not observed in monocytes derived from iPS cells. Osteoclasts were differentiated from bone marrow cells in patients with STAT1-LOF. The number and the activity of osteoclasts in STAT1-LOF patients were prominent, resulting in the excessive bone absorption in patients. Similar abnormality was confirmed by monocytes derived from iPS cells. These results suggest that the disease-specific iPS cells from patients with STAT1 abnormalities may be useful for the analysis of pathogenesis of STAT1-LOF and STAT1-GOF.

Research Products

• [Journal Article] Impairment of IL-17A/F immunity to Candida and IFN-γ immunity to Mycobacterium in humans with inherited RORγT deficiency. (2015)
  • Author(s): Okada S, Markle JG, Deenick EK, Federico Mele F, Averbuch D, Kobayashi M, Abel L, Cooper AM, Notarangelo LD, Boisson-Dupuis S, Puel A, Sallusto F, Bustamante J, Tangye SG, Casanova JL
  • Journal Title: Science Volume: 349 Issue: 6248 Pages: 606-613
  • DOI: 10.1126/science.aaa4282
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mosaicism of an ELANE mutation in an asymptomatic mother in a familial case of cyclic neutropenia. (2015)
  • Author(s): Hirata O, Okada S, Ttsumura M, Karakawa S, Matsumura I, Kimura Y, Mihara T, Yasunaga S, Takihara Y, Ohara O, Kobayashi M
  • Journal Title: Journal of Clinical Immunology Volume: 2015 Issue: 5 Pages: 1-5
  • DOI: 10.1007/s10875-015-0165-1
  • Peer Reviewed / Open Access
• [Journal Article] Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia. (2015)
  • Author(s): Narita A, Muramatsu H, Sekiya Y, Okuno Y, Sakaguchi H, Nishio N, Yoshida N, Wang X, Xu Y, Kawashima N, Doisaki S, Hama A, Takahashi Y, Kudo K, Moritake H, Kobayashi M, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Kojima S; Japan Childhood Aplastic Anemia Study Group.
  • Journal Title: Haematologica. Volume: 100 Issue: 12 Pages: 1546-1552
  • DOI: 10.3324/haematol.2015.132530
  • Peer Reviewed / Open Access
• [Journal Article] STAT3 is a critical cell intrinsic regulator of human unconventional T cell numbers and function. (2015)
  • Author(s): Wilson RP, Ives ML, Rao G, Lau A, Payne K, Kobayashi M, Holland SM, Casanova JL, Uzel G, Ma CS, Tangye SG, Deenick EK
  • Journal Title: Journal of Experimental Medicine Volume: 212 Issue: 6 Pages: 855-864
  • DOI: 10.1084/jem.20141992
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. (2015)
  • Author(s): Ma CS, Wong N, Tangye SG, et al.
  • Journal Title: J Allergy Clin Immunol Volume: 136 Issue: 4 Pages: 993-1006
  • DOI: 10.1016/j.jaci.2015.05.036
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The International Immune Tolerance Induction Study and its follow-up study on Japanese hemophilia A patients with inhibitors. (2015)
  • Author(s): Yoshioka A, Ishii E, Ueno T, Usami I, Kobayashi M, Kobayashi R, Sotomatsu M, Shirahata A, Suzuki T, Taki M, Ishida Y, Matsushita T, Shima M, Nogami K, Sakai M, Kigasawa H, Fukutake K
  • Journal Title: Int J Hematol. Volume: 101(4) Issue: 4 Pages: 362-8
  • DOI: 10.1007/s12185-015-1734-z
  • Peer Reviewed / Open Access
• [Journal Article] HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis. (2014)
  • Author(s): Morishima T, Watanabe K, Niwa A, Hirai H, Saida S, Tanaka T, Kato I, Umeda K, Hiramatsu H, Saito MK, Matsubara K, Adachi S, Kobayashi M, Nakahata T, Heike T
  • Journal Title: Haematologica Volume: 99(1) Issue: 1 Pages: 19-27
  • DOI: 10.3324/haematol.2013.083873
  • Peer Reviewed / Open Access
• [Journal Article] Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. (2014)
  • Author(s): Mizoguchi Y, Tsumura M, Okada S, Hirata O, Minegishi S, Imai K, Hyakuna N, Muramatsu H, Kojima S, Ozaki Y, Imai T, Takeda S, Okazaki T, Ito T, Yasunaga S, Takihara Y, Bryant VL, Kong XF, Cypowyj S, Boisson-Dupuis S, Puel A, Casanova JL, Morio T, Kobayashi M.
  • Journal Title: J. Leukoc. Biol. Volume: 95 Issue: 4 Pages: 667-76
  • DOI: 10.1189/jlb.0513250
  • Peer Reviewed / Open Access
• [Journal Article] Detection of <I>Mucor velutinosus</I> in a Blood Culture After Autologous Peripheral Blood Stem Cell Transplantation : A Pediatric Case Report (2014)
  • Author(s): Joichi Y, Chijimatsu I, Yarita K, Kamei K, Miki M, Onodera M, Harada M, Yokozaki M, Kobayashi M, Ohge H
  • Journal Title: Medical Mycology Journal Volume: 55 Issue: 2 Pages: E43-E48
  • DOI: 10.3314/mmj.55.E43
  • NAID: 130004567865
  • ISSN: 2185-6486, 2186-165X
  • Peer Reviewed
• [Journal Article] A 2-year-old Japanese girl with TNF receptor-associated periodic syndrome: A case report of the youngest diagnosed proband in Japan (2014)
  • Author(s): Yasumura J, Wago M, Okada S, Nishikomori R, Takei S, Kobayashi M
  • Journal Title: Modern Rheumatology Volume: 20 Pages: 1-4
  • Peer Reviewed
• [Presentation] Impairment of IL-17 immunity to Candida and IFNγ immunity to Mycobacterium in humans with bi-allelic Rorc mutations. (2015)
  • Author(s): Okada S, Markle J, Kobayashi M, Bustamante J, Casanova JL
  • Organizer: The 57th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] MSMD Patients with IFN-γ-STAT1 Signaling Defect Present Enhanced Osteoclastogenesis and Bone Resorption. (2015)
  • Author(s): Nishimura S, Tsumura M, Hirata O, Reiko Kagawa, Mizoguchi Y, Okada S, Kobayashi M
  • Organizer: The 57th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] A comparison of myelopoiesis from induced pluripotent stem cells with a mutation in ELANE between cyclic neutropenia and sever congenital neutropenia. (2015)
  • Author(s): Saito S, Nishimura S, Tsumra M, Mizoguchi Y, Sakata S, Furue A, Kobayashi M
  • Organizer: The 57th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] 好中球異常症：診断と造血幹細胞移植 (2015)
  • Author(s): 小林正夫
  • Organizer: 第77回日本血液学会教育講演
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
  • Invited
• [Presentation] STAT1 gain-of-function in patients with chronic mucocutaneous candidiasis can be detected by the excessive phosphorylation of STAT1 in peripheral blood monocytes. (2014)
  • Author(s): Yoko Mizoguchi, Satoshi Okada, Miyuki Tsumura, Osamu Hirata, Shizuko Minegishi, Jean-Laurent Casanova, Tomohiro Morio, Masao Kobayashi
  • Organizer: The 56th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Excessive Nitric Oxide production of CGD neutrophils induces the down-regulation of NOS3 and EDN1 expression in human endothelial cells. (2014)
  • Author(s): Akari N. Utsunomiya, Miyuki Tsumura, Norioki Ohno, Mizuka Miki, Hiroshi Kawaguchi, Kazuhiro Nakamura and Masao Kobayashi
  • Organizer: The 56th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Early elimination of Factor VIII inhibitor by ITI with high dose immunoglobulin in hemophilia A children (2014)
  • Author(s): Yoko Mizoguchi, Aya Furue, Ikue Chijimatsu, Mizuka Miki, Keita Tomioka, Nakao Konishi, Atsushi Ono, Hiroshi Kawaguchi, Kazuhiro Nakamura and Masao Kobayashi
  • Organizer: WORLD FEDERATION OF HEMOPHILIA, 2014 World Congress
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2014-05-11 – 2014-05-15