Augmentation of osteoclast formation and its function in patients with IFN-g signaling abnormality

• Project/Area Number: 15K21189
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology; Orthopaedic surgery
• Research Institution: Hiroshima University
• Principal Investigator: Tsumura Miyuki 広島大学, 医歯薬保健学研究院(医), 研究員 (80646274)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: STAT1 / IFNGR1 / MSMD / 原発性免疫不全症 / 破骨細胞 / iPS細胞 / 食細胞異常 / 骨リモデリング / IFN-γ

Outline of Final Research Achievements

STAT1 plays an important role in host immune response against viral and intracellular pathogens by mediating IFN-α/β and IFN-γ signaling. Heterozygous loss-of-function mutations in IFNGR1 and STAT1 can be molecular cause of Mendelian Susceptibility to Mycobacterial Diseases (MSMD) in human. These pathogenic mutations exert a dominant-negative effect on IFN-γ-STAT1 signaling, leading to host susceptibility to mycobacteria. Chronic and multifocal osteomyelitis is one of the representative symptoms in patients with MSMD. The histopathology of biopsied specimen shows noncaseating granuloma with abundant number of osteoclasts. Osteoclasts, bone-resorbing multinuclear cells, are derived from myeloid/monocyte lineage. IFN-γ is known to be a strong inhibitor of osteoclastogenesis through the IFN-γ-STAT1 signaling in mice. In this study, we examined the effect of IFN-γ on the formation and function of osteoclast derived from using the patients with AD IFNGR1 or STAT1 deficiency.

Research Products

• [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] 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] Screening of MCAD deficiency in Japan: 16 years' experience of enzymatic and genetic evaluation (2016)
  • Author(s): Tajima G, Hara K, Tsumura M, Kagawa R, Okada S, Sakura N, Hata I, Shigematsu Y, Kobayashi M
  • Journal Title: Molecular Genetics and Metabolism Volume: 119 Issue: 4 Pages: 322-328
  • DOI: 10.1016/j.ymgme.2016.10.007
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Significance of ACADM mutations identified from newborn screening of MCAD deficiency in Japan (2016)
  • Author(s): Keiichi Hara, Go Tajima, Satoshi Okada, Miyuki Tsumura, Reiko Kagawa, Kenichiro Shirao, Yoshinori Ohno, Shin'ichiro Yasunaga, Motoaki Ohtsubo, Ikue Hata, Nobuo Sakura, Yosuke Shigematsu, Yoshihiro Takihara, Masao Kobayashi
  • Journal Title: Molecular Genetics and Metabolism Volume: 118 Issue: 1 Pages: 9-14
  • DOI: 10.1016/j.ymgme.2015.12.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Extrapulmonary tuberculosis mimicking Mendelian susceptibility to mycobacterial disease in a patient with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. (2016)
  • Author(s): Kataoka S, Muramatsu H, Okuno Y, Hayashi Y, Mizoguchi Y, Tsumura M, Okada S, Kobayashi M, Sano C, Sato H, Oh-Iwa I, Ito M, Kojima D, Hama A, Takahashi Y, Kojima S.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 137 Pages: 619-622
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer. (2016)
  • Author(s): Hayakawa S, Okada S, Tsumura M, Sakata S, Ueno Y, Imai K, Morio T, Ohara O, Chayama K, Kobayashi M.
  • Journal Title: J. Clin. Immunol.. Volume: 36 Issue: 1 Pages: 28-32
  • DOI: 10.1007/s10875-015-0221-x
  • Peer Reviewed
• [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
• [Presentation] Osteoclastogenesis is significantly enhanced in patients with MSMD through the impaired of IFN-γ-STAT1 signaling (2015)
  • Author(s): Miyuki Tsumura, Satoshi Okada, Masao Kobayashi.
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市白石区）
  • Year and Date: 2015-11-18
• [Presentation] Enhanced osteoclastogenesis is caused by the abnormal IFN-STAT1 signaling in MSMD patients (2015)
  • Author(s): Miyuki Tsumura, Osamu Hirata, Reiko Kagawa, Yoko Mizoguchi, Satoshi Okada, Masao Kobayashi.
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル、ホテル日航金沢、ホテル金沢、金沢市アートホテル、もてなしドーム（石川県金沢市）
  • Year and Date: 2015-10-16
• [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
  • Publisher: 科学評論社