自己識別機構の破綻をきたす免疫不全症の病態解明と原因遺伝子同定

2011 Fiscal Year Annual Research Report

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 22021049
• Research Institution: National Defense Medical College
• Principal Investigator: 野々山 恵章 防衛医科大学校, 医学教育部・医学科専門課程, 教授 (40280961)
• Co-Investigator(Kenkyū-buntansha): 大嶋 宏一 京都大学, iPS細胞研究所, 特定研究員 (60525377) ; 今井 耕輔 東京医科歯科大学, 大学院・医歯学総合研究科, 准教授 (90332626) ; 長瀬 隆弘 (財)かずさDNA研究所, ヒトゲノム研究部, 室長 (10211442)
• Keywords: 免疫学 / 遺伝子 / 移植・再生医療 / 発生・分化 / 感染症

Research Abstract

T細胞、B細胞新生能のマーカーであるTREC,KRECを、微量の乾燥濾紙血からrealtimePCRで定量的に測定する技術を確立した。T細胞分化障害である重症複合型免疫不全症(SCID)ではTRECが陰性になり、B細胞分化障害である伴性劣性無γ-グロブリン血症(XLA)ではKRECが陰性になることを見出し、現行の新生児スクリーニングで採取される微量の乾燥濾紙血(ガスリー血)で、両疾患をスクリーニング出来ることも示した。ATM,DiGeorge症候群,Rac2欠損症などの原発性免疫不全症でもTREC/KRECが陰性になることを見出した。原因不明の免疫不全症であるCommon variable immunodeficiency(CVID)がTREC,KRECの発現パターンにより4群に分けられ、自己免疫疾患、悪性腫瘍の発生などの合併症の発生頻度、重症度と相関することを示した。
また原発性免疫不全症のデータベース(Primary Immunodeficiency Database in Japan,PIDJ)を構築した。
PIDJを利用し、樹状細胞欠損症が28名存在することを見出し、Exome解析により、患者全エクソンの遺伝子配列を次世代シークエンサーで解読し変異を解析した。その結果6人で樹状細胞欠損症の原因遺伝が転写因子GATA2の異常であることを新規に見出した。さらに、患者T細胞はIL-4,IL-17産生が著明に低下していて、Th2,Th17細胞への分化にGATA2が必須であること、また、T細胞新生能のマーカーであるTRECが、解析可能であった4患者全員で低下し、T細胞の初期分化にGATA2が重要な役割を果たしていることを示した。以上、免疫系で自己認識に深く関与する抗原提示において重要な役割を果たしている樹状細胞が欠損している疾患を見出し、その原因遺伝子を同定した。

Research Products

• [Journal Article] Hyper-eosinophilia granular acute B-cell lymphoblastic leukemia with myeloid antigen expression (2012)
  • Author(s): Kobayashi D, Kogawa K, Imai K, Tanaka T, Sada A, Nonoyama S
  • Journal Title: Pediatr Int
  • Peer Reviewed
• [Journal Article] Clinical and genetic characteristics of XIAP deficiency in Japan (2012)
  • Author(s): Yang X, Kanegane H, Nishida N, Imamura T, Hamamoto K, Miyashita R, Imai K, Nonoyama S, Sanayama K, Yamaide A, Kato F, Nagai K, Ishii E, Zelm M, Latour S, Zhao X, Miyawaki T
  • Journal Title: J Clin Immunol
  • Peer Reviewed
• [Journal Article] Functional STAT3 deficiency compromises IL-12-dependent generation of human T-follicular helper cells (2012)
  • Author(s): Ma CS, Avery DT, Chan A, Batten M, Bustamante J, Boisson-Dupuis S, Arkwright PD, Minegishi Y, Nonoyama S, French MA, Choo S, Peake J, Wong M, Cook MC, Fulcher DA, Casanova JL, Deenick EK, Tangye SG
  • Journal Title: Blood
  • Peer Reviewed
• [Journal Article] The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils (2012)
  • Author(s): Honda F, Kano H, Kanegane H, Nonoyama S, Kim ES, Lee SK, Takagi M, Mizutani S, Morio T
  • Journal Title: Nat Immunol
  • Peer Reviewed
• [Journal Article] Missense Mutations of the BMPR1B (ALK6) Gene in Childhood Idiopathic Pulmonary Arterial Hypertension (2012)
  • Author(s): Chida A, Shintani M, Nakayama T, Furutani Y, Hayama E, Inai K, Saji T, Nonoyama S, Nakanishi T
  • Journal Title: Circ J
  • Peer Reviewed
• [Journal Article] GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia (2012)
  • Author(s): Ishida H, Imai K, Homma K, Tamura S, Imamura T, Itoh M, Nonoyama S
  • Journal Title: Eur J Pediatr
  • Peer Reviewed
• [Journal Article] Clinical profile and genetic basis of Wiskott-Aldrich syndrome at Chandigarh, north India (2012)
  • Author(s): Suri D, Singh S, Rawat A, Gupta A, Kamae C, Honma K, Nakagawa N, Imai K, Nonoyama S, Oshima K, Mitsuiki N, Ohara O, Bilhou-Nabera C, Proust A, Ahluwalia J, Dogra S, Saikia B, Walker Minz R, Sehgal S
  • Journal Title: Asian Pac J Allergy Immunol Volume: 30 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Factors Associated with Steroid Phobia in Caregivers of Children with Atopic Dermatitis (2012)
  • Author(s): Kojima R, Fujiwara T, Matsuda A, Narita M, Matsubara O, Nonoyama S, Ohya Y, Saito H, Matsumoto K
  • Journal Title: Pediatr Dermatol
  • Peer Reviewed
• [Journal Article] Endocrine complications in primary immunodeficiency diseases in Japan (2012)
  • Author(s): Nozaki T, Takada H, Ishimura M, Ihara K, Imai K, Morio T, Kobayashi M, Nonoyama S, Hara T
  • Journal Title: Clin Endocrinol
  • Peer Reviewed
• [Journal Article] Survey of Japanese infants younger than 3 months who were treated with oseltamivir for influenza : Safety of oseltamivir treatment (2012)
  • Author(s): Morioka I, Nonoyama S, Tanaka-Taya K, Ihara T, Sugaya N, Ueta I, Kumagai T, Okada K, Hosoya M, Okabe N, Morishima T
  • Journal Title: Scand J Infect Dis
  • Peer Reviewed
• [Journal Article] Multiple reversions of an IL2RG mutation restore T cell function in an X-linked severe combined immunodeficiency patient (2012)
  • Author(s): Kawai T, Saito M, Nishikomori R, Yasumi T, Izawa K, Murakami T, Okamoto S, Mori Y, Nakagawa N, Imai K, Nonoyama S, Wada T, Yachie A, Ohmori K, Nakahata T, Heike T
  • Journal Title: J Clin Immunol
  • Peer Reviewed
• [Journal Article] Outcomes of Childhood Pulmonary Arterial Hypertension in BMPR2 and ALK1 Mutation Carriers (2012)
  • Author(s): Chida A, Shintani M, Yagi H, Fujiwara M, Kojima Y, Sato H, Imamura S, Yokozawa M, Onodera N, Horigome H, Kobayashi T, Hatai Y, Nakayama T, Fukushima H, Nishiyama M, Doi S, Ono Y, Yasukouchi S, Ichida F, Fujimoto K, Ohtsuki S, Teshima H, Kawano T, Nomura Y, Gu H, Ishiwata T, Furutani Y, Inai K, Saji T, Matsuoka R, Nonoyama S, Nakanishi T
  • Journal Title: Am J Cardiol
  • Peer Reviewed
• [Journal Article] Early and rapid detection of X-linked lymphoproliferative syndrome with SH2D1A mutations by flow cytometry (2011)
  • Author(s): Zhao M, Kanegane H, Kobayashi C, Nakazawa Y, Ishii E, Kasai M, Terui K, Gocho Y, Imai K, Kiyasu J, Nonoyama S, Miyawaki T
  • Journal Title: Cytometry B Clin Cytom Volume: 80 Pages: 8-13
  • Peer Reviewed
• [Journal Article] Contribution of Sarcoplasmic Reticulum Ca2+Release and Ca2+ Transporters on Sarcolemmal Channels to Ca2+ Transient in Fetal Mouse Heart (2011)
  • Author(s): Takizawa M, Ishiwata T, Kawamura Y, Kanai T, Kurokawa T, Nishiyama M, Ishida H, Asano Y, Nonoyama S
  • Journal Title: Pediatr Res Volume: 69 Pages: 306-311
  • Peer Reviewed
• [Journal Article] Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells (2011)
  • Author(s): Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, Agematsu K, Yamada M, Kawamura N, Ariga T, Tsuge I, Nonoyama S, Karasuyama H, Minegishi Y
  • Journal Title: J Exp Med Volume: 208 Pages: 235-249
  • Peer Reviewed
• [Journal Article] Quantification of κ-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects (2011)
  • Author(s): Nakagawa N, Imai K, Kanegane H, Sato H, Yamada M, Kondoh K, Okada S, Kobayashi M, Agematsu K, Takada H, Mitsuiki N, Oshima K, Ohara O, Suri D, Rawat A, Singh S, Pan-Hammarstrom Q, Hammarstrom L, Reichenbach J, Seger R, Ariga T, Hara T, Miyawaki T, Nonoyama S
  • Journal Title: J Allergy Clin Immunol Volume: 128 Pages: 223-225
  • Peer Reviewed
• [Journal Article] Severe human herpesvirus 6 associated encephalopathy in three children : Analysis of cytokine profiles and the carnitine palmitoyltransferase 2 gene (2011)
  • Author(s): Matsumoto H, Hatanaka D, Ogura Y, Chida A, Nakamura Y, Nonoyama S
  • Journal Title: Pediatr Infect Dis J Volume: 30 Pages: 999-1001
  • Peer Reviewed
• [Journal Article] Nationwide Survey of Patients with Primary Immunodeficiency Diseases in Japan (2011)
  • Author(s): Ishimura M, Takada H, Doi T, Imai K, Sasahara Y, Kanegane H, Nishikomori R, Morio T, Heike T, Kobayashi M, Ariga T, Tsuchiya S, Nonoyama S, Miyawaki T, Hara T
  • Journal Title: J Clin Immunol Volume: 31 Pages: 968-976
  • Peer Reviewed
• [Journal Article] Primary Immunodeficiency Diseases : an update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency (2011)
  • Author(s): Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, Etzioni A, Fischer A, Franco JL, Geha RS, Hammarstrom L, Nonoyama S, Notarangelo LD, Ochs HD, Puck JM, Roifman C, Seger R, Tang MLK
  • Journal Title: Front Immun Volume: 2 Pages: 54
  • Peer Reviewed
• [Journal Article] Quantification of human herpesvirus-6 (HHV-6) DNA in a cord blood transplant recipient with chromosomal integration of HHV-6 (2011)
  • Author(s): Kobayashi D, Kogawa K, Imai K, Tanaka T, Hiroi S, Satoh H, Tanaka-Taya K, Nonoyama S
  • Journal Title: Transpl Infect Dis Volume: 13 Pages: 650-653
  • Peer Reviewed
• [Journal Article] Ulinastatin, a Urinary Trypsin Inhibitor, for the Initial Treatment of Patients with Kawasaki (2011)
  • Author(s): Kanai T, Ishiwata T, Kobayashi T, Sato H, Takizawa M, Kawamura Y, Tsujimoto H, Nakatani K, Ishibashi N, Nishiyama M, Hatai Y, Asano Y, Kobayashi T, Takeshita S, Nonoyama S
  • Journal Title: Circulation Volume: 124 Pages: 2822-2828
  • Peer Reviewed
• [Journal Article] Cardiopulmonary arrest caused by craniometaphyseal dysplasia (2011)
  • Author(s): Chida A, Yanagawa Y, Matsumoto H, Nonoyama S
  • Journal Title: Indian J Pediatr Volume: 78 Pages: 1010-1012
  • Peer Reviewed
• [Journal Article] Analysis of mutations and recombination activity in RAG-deficient patients (2011)
  • Author(s): Asai E, Wada T, Sakakibara Y, Toga A, Toma T, Shimizu T, Nampoothiri S, Imai K, Nonoyama S, Morio T, Muramatsu H, Kamachi Y, Ohara O, Yachie A
  • Journal Title: Clin Immunol Volume: 138 Pages: 172-177
  • Peer Reviewed
• [Journal Article] Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein (2011)
  • Author(s): Murata Y, Yasumi T, Shirakawa R, Izawa K, Sakai H, Abe J, Tanaka N, Kawai T, Oshima K, Saito M, Nishikomori R, Ohara O, Ishii E, Nakahata T, Horiuchi H, Heike T
  • Journal Title: Blood Volume: 118 Pages: 1225-1230
  • Peer Reviewed
• [Journal Article] Clinical and host genetic characteristics of Mendelian susceptibility to mycobacterial diseases in Japan (2011)
  • Author(s): Hoshina T, Takada H, Sasaki-Mihara Y, Kusuhara K, Oshima K, Okada S, Kobayashi M, Ohara O, Hara T
  • Journal Title: J Clin Immunol Volume: 31 Pages: 309-314
  • Peer Reviewed
• [Journal Article] A novel serum-free monolayer culture for orderly hematopoietic differentiation of human pluripotent cells via mesodermal progenitors (2011)
  • Author(s): Niwa A, Heike T, Umeda K, Oshima K, Kato I, Sakai H, Suemori H, Nakahata T, Saito MK.Jul
  • Journal Title: PLoS One Volume: 6 Pages: e22261
  • Peer Reviewed
• [Journal Article] High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome : results of an International Multicenter Collaborative Study (2011)
  • Author(s): Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K, Ohara O, Nishikomori R, Morimoto T, Kambe N, Goldbach-Mansky R, Aksentijevich I, de Saint Basile G, Neven B, van Gijn M, Frenkel J, Arostegui JI, Yague J, Merino R, Ibanez M, Pontillo A, Takada H, Imagawa T, Kawai T, Yasumi T, Nakahata T, Heike T
  • Journal Title: Arthritis Rheum Volume: 63 Pages: 3625-3632
  • DOI: doi:10.1002/art.30512
  • Peer Reviewed
• [Journal Article] Novel mutations of MVK gene in Japanese family members affected with hyperimmunoglobulinemia D and periodic fever syndrome (2011)
  • Author(s): Mizuno T, Sakai H, Nishikomori R, Oshima K, Ohara O, Hata I, Shigematsu Y, Ishige T, Tamura K, Arakawa H
  • Journal Title: Rheumatol Interest
  • Peer Reviewed
• [Remarks]
  • URL: http://pidj.rcai.riken.jp/