Identification of novel differentiation factors in immune system using iPS cells derived from primary immunodeficiencies.

• Project/Area Number: 26293250
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Defense Medical College
• Principal Investigator: NONOYAMA Shigeaki 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究, その他部局等, 教授 (40280961)
• Co-Investigator(Kenkyū-buntansha): 今井 耕輔 東京医科歯科大学, 医歯(薬)学総合研究科, 准教授 (90332626)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2014: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 免疫学 / 発生・分化 / 移植・再生医療 / 細胞・組織 / 遺伝子

Outline of Final Research Achievements

iPS cells derived from patients with primary immunodeficiencies were established including GATA 2 deficiency, Wiskott-Aldrich syndrome, Chediak-Higashi syndrome, and Reticular Dysgenesis. Differentiation defects of iPS cells derived from the diseases were examined using an in vitro differentiation system. It was found that GATA 2 deficiency has impaired differentiation into hematopoietic progenitor cells, Wiskott-Aldrich syndrome has impaired differentiation into platelets, and Reticular Dysgenesis has impaired metabolism in hematopoietic progenitor cells. The causative gene mutations were corrected in iPS cells by genome editing, and RNA sequence was performed during differentiation process. A group of genes differently expressed were found. This result gives important clues for identification of differentiation factors.

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] Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint. (2016)
  • Author(s): Cantaert T, Schickel J, Bannock, Ng Y, Massad C, Delmotte F, Yamakawa N, Glauzy S, Chamberlain N, Kinnunen T, Menard L, Lavoie A, Walter J, Notarangelo L, Bruneau J, Al-Herz W, Kilic S, Ochs H, Cunningham-Rundles C, Burg M, Kuijpers T, Kracker S, Kaneko H, Sekinaka Y, Nonoyama S, Durandy A, and Meffre E.
  • Journal Title: J Clin Invest. Volume: 126 Issue: 11 Pages: 4289-4302
  • DOI: 10.1172/jci84645
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. (2016)
  • Author(s): Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, Espinosa Rosales FJ, Hammarström L, Nonoyama S, Quinti I, Routes JM, Tang ML, Warnatz K.
  • Journal Title: J Allergy Clin Immunol Pract. Volume: 4 Issue: 1 Pages: 38-59
  • DOI: 10.1016/j.jaip.2015.07.025
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PTEN mutation can cause Activated PI3 Kinase Delta Syndrome (APDS)-like immunodeficiency. (2016)
  • Author(s): Tsujita Y, Mitsui-Sekinaka K, et al.
  • Journal Title: J Allergy Clin Immunol Volume: -
  • Peer Reviewed
• [Journal Article] Hematopoietic Stem Cell Transplantation for X-Linked Thrombocytopenia With Mutations in the WAS gene. (2015)
  • Author(s): Oshima K, Imai K, Albert M.H, Bittner T.C, Strauss G, Filipovich A.H, Morio T, Kapoor N, Dalal J, Schultz K.R, Casper J.T, Notarangelo L.D, Ochs H.D, Nonoyama S.
  • Journal Title: J Clin Immunol Volume: 35 Issue: 1 Pages: 15-21
  • DOI: 10.1007/s10875-014-0105-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RAG1 Deficiency May Present Clinically as Selective IgA Deficiency. (2015)
  • Author(s): Kato T, Crestani E, Kamae C, Honma K, Yokosuka T, Ikegawa T, Nishida N, Kanegane H, Wada T, Yachie A, Ohara O, Morio T, Notarangelo LD, Imai K, Nonoyama S.
  • Journal Title: J Clin Immunol. Volume: 35(3) Issue: 3 Pages: 280-8
  • DOI: 10.1007/s10875-015-0146-4
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features and hematopoietic stem cell transplantation for CD40 ligand deficiency in Japan (2015)
  • Author(s): Mitsui-Sekinaka K, Imai K, Sato H, Tomizawa D, Kajiwara M, Nagasawa M, Morio T, Nonoyama S
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: - Issue: 4 Pages: 1018-1024
  • DOI: 10.1016/j.jaci.2015.02.020
  • Peer Reviewed / Acknowledgement Compliant
• [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] Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome. (2015)
  • Author(s): Kreins A.Y, Ciancanelli M.J, Boisson-Dupuis S, et al.
  • Journal Title: J Exp Med. Volume: 212 Issue: 10 Pages: 1641-1662
  • DOI: 10.1084/jem.20140280
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance. (2015)
  • Author(s): Cantaert T, Schickel JN, Bannock JM, Ng YS, Massad C, Oe T, Wu R, Lavoie A, Walter JE, Notarangelo LD, Al-Herz W, Kilic SS, Ochs HD, Nonoyama S, Durandy A, Meffre E.
  • Journal Title: Immunity Volume: 17; 43 Issue: 5 Pages: 884-95
  • DOI: 10.1016/j.immuni.2015.10.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chronic Granulomatous Disease: Two Decades of Experience From a Tertiary Care Centre in North West India. (2014)
  • Author(s): Rawat A
  • Journal Title: J Clin Immunol. Volume: 34 Issue: 1 Pages: 58-67
  • DOI: 10.1007/s10875-013-9963-5
  • Peer Reviewed
• [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] Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. (2014)
  • Author(s): Al-Herz W
  • Journal Title: Front Immunol. Volume: 5 Pages: 162-162
  • DOI: 10.3389/fimmu.2014.00162
  • Peer Reviewed
• [Journal Article] Analysis of somatic hypermutation in the IgM switch region in human B cells. (2014)
  • Author(s): Horiuchi K
  • Journal Title: J Allergy Clin Immunol. Volume: 134 Issue: 2 Pages: 411-419
  • DOI: 10.1016/j.jaci.2014.02.043
  • Peer Reviewed
• [Journal Article] Cord blood transplantation is associated with rapid B cell neogenesis compared with bone marrow transplantation (2014)
  • Author(s): Nakatani K, Imai K, Shigeno M, Sato H, Tezuka M, Okawa T, Mitsuiki N, Isoda T, Tomizawa D, Takagi M, Nagasawa M, Kajiwara M, Yamamoto M, Arai A, Miura O, Kamae C, Nakagawa N, Honma K, Nonoyama S, Mizutani S, Morio T.
  • Journal Title: Bone Marrow Transplantation Volume: 49 Issue: 9 Pages: 1155-1161
  • DOI: 10.1038/bmt.2014.123
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hyper-IgE syndrome with a novel STAT3 mutation-a single center study from India. (2014)
  • Author(s): Saikia B
  • Journal Title: Asian Pac J Allergy Immunol. Volume: 32 Issue: 4 Pages: 321-327
  • DOI: 10.12932/ap0456.32.4.2014
  • Peer Reviewed
• [Journal Article] ICON: The Early Diagnosis of Congenital Immunodeficiencies. (2014)
  • Author(s): Routes J
  • Journal Title: J Clin Immunol. Volume: 34 Issue: 4 Pages: 398-424
  • DOI: 10.1007/s10875-014-0003-x
  • Peer Reviewed
• [Remarks] 原発性免疫不全症のデータベース
  • URL: http://pidj.rcai.riken.jp/index.html