ＫＲＥＣ／ＴＲＥＣによる先天性免疫不全症スクリーニング法開発と病態解析への応用

2012 Fiscal Year Annual Research Report

• Project/Area Number: 22390213
• Research Institution: 防衛医科大学校
• Principal Investigator: 野々山 恵章 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, 医学教育部医学科専門課程, 教授 (40280961)
• Co-Investigator(Kenkyū-buntansha): 小原 收 公益財団法人かずさＤＮＡ研究所, ヒトゲノム研究部, 副所長 (20370926) ; 大嶋 宏一 京都大学, 学内共同利用施設等, 研究員 (60525377) ; 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): 2010-04-01 – 2013-03-31
• Keywords: 免疫学 / 遺伝子 / 移植・再生医療 / 発生・分化 / 感染症

Research Abstract

先天性免疫不全症の新生児スクリーニングの開発と病態解明を目的に以下の研究を行った。
a) TREC/KREC 測定による免疫不全症新生児スクリーニング法の確立
TREC(T cell receptor recombination circles)とKREC (Kappa-chain recombination excision circles)は、Ｔ細胞新生、Ｂ細胞新生の良いマーカーである。新生児乾燥濾紙血のTREC/KRECを測定した結果、健常新生児では全員でTREC/KRECがともに陽性、T細胞欠損患者ではTRECが陰性、Ｂ細胞欠損患者ではKRECが陰性であった。Ataxia telangiectasiaではKRECが全員陰性であった。以上、先天性免疫不全症新生児スクリーニング法を開発した。
b) TREC/KREC測定による免疫不全症の病態解明
先天性免疫不全症の中で最も頻度の高いCommon variable immunodeficiency (CVID,分類不能型免疫不全症)患者４０例でTREC, KRECの測定を行った。その結果、A群(TREC(+), KREC(+)), B群(TREC(+),KREC(-))、C群(TREC(-), KREC(+))、D群(TREC(-), KREC(-))の４群に分かれることを見出した。４群で臨床症状および生命予後が有意に異なること、γグロブリン定期補充で予後が良い群、造血幹細胞移植が必要な群が鑑別でき、TREC/KREC測定により免疫不全症の病態に即した治療法が選択できることを示した。さらに、A群にB細胞の抗体産生細胞への分化障害があるTACI異常症、ICF症候群、D群にRAG異常症、GATA2異常症、C群にFANCE異常症を見出すことが出来た。すなわちTREC/KRECが病態解明につながり、診断に有用である事を明らかにした。

Current Status of Research Progress

Reason

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Factors Associated with Steroid Phobia in Caregivers of Children with Atopic Dermatitis. (2013)
  • Author(s): Kojima R, Fujiwara T, Matsuda A, Narita M, Matsubara O, Nonoyama S, Ohya Y, Saito H, Matsumoto K.
  • Journal Title: Pediatr Dermatol. Volume: 30 Pages: 29-35
  • DOI: 10.1111/j.1525-1470.2012.01808.x
  • Peer Reviewed
• [Journal Article] Salivary Cortisol Response to Stress in Young Children with Atopic Dermatitis. (2013)
  • Author(s): Kojima R, Matsuda A, Nomura I, Matsubara O, Nonoyama S, Ohya Y, Saito H, Matsumoto K.
  • Journal Title: Pediatr Dermatol. Volume: 22 Pages: 17-22
  • DOI: 10.1111/j.1525-1470.2012.01808.x
  • Peer Reviewed
• [Journal Article] Neonatal herpes encephalitis caused by a virologically confirmed acyclovir resistant herpes simplex virus type 1. (2013)
  • Author(s): Kakiuchi S, Nonoyama S, Wakamatsu H, Kogawa K, Wang L, Kinoshita-Yamaguchi H, Takayama-Ito M, Lim CK, Inoue N, Mizuguchi M, Igarashi T, Saijo M.
  • Journal Title: J. Clin. Microbiol. Volume: 51 Pages: 356-359
  • DOI: 10.1128/JCM.02247-12
  • Peer Reviewed
• [Journal Article] Impaired KLHL3-Mediated Ubiquitination of WNK4 Causes Human Hypertension. (2013)
  • Author(s): Wakabayashi M, Mori T, Isobe K. Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Matsuo H, Murata T, Nomura S, Asano T, Kawaguchi H, Nonoyama S, Rai T, Sasaki S, Uchida S.
  • Journal Title: Cell Reports. Volume: 3 Pages: 858-868
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  • Peer Reviewed
• [Journal Article] Kasabach-Merritt Phenomenon: A Report of 11 Cases From a Single Institution. (2013)
  • Author(s): Yasui N, Koh K, Kato M, Park MJ, Tomizawa D, Oshima K, Uchisaka N, Gocho Y, Arakawa A, Seki M, Oguma E, Kishimoto H, Watanabe S, Kikuchi A, Hanada R.
  • Journal Title: J Pediatr Hematol Oncol. Volume: in press Pages: in press
  • Peer Reviewed
• [Journal Article] Robust and Highly-Efficient Differentiation of Functional Monocytic Cells from Human Pluripotent Stem Cells under Serum- and Feeder Cell-Free Conditions. (2013)
  • Author(s): Yanagimachi MD, Niwa A, Tanaka T, Honda-Ozaki F, Nishimoto S, Murata Y, Yasumi T, Ito J, Tomida S, Oshima K, Asaka I, Goto H, Heike T, Nakahata T, Saito MK.
  • Journal Title: PLoS One. Volume: 8 Pages: e59243
  • DOI: 10.1371/journal.pone.0059243
  • Peer Reviewed
• [Journal Article] Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia. (2013)
  • Author(s): Yoshimi A, Kamachi Y, Kojima S and et al.
  • Journal Title: Pediatr Blood Cancer. Volume: 60 Pages: 836-841
  • DOI: 10.1002/pbc.24359
  • Peer Reviewed
• [Journal Article] Successful Treatment of Diffuse Large B-Cell Lymphoma in a Patient With Ataxia Telangiectasia Using Rituximab. (2013)
  • Author(s): Machida S, Tomizawa D, Tamaichi H, Okawa T, Endo A, Imai K, Nagasawa M, Morio T, Mizutani S, Takagi M.
  • Journal Title: Pediatr Hematol Oncol. Volume: in press Pages: in press
  • Peer Reviewed
• [Journal Article] Successful bone marrow transplantation with reduced intensity conditioning in a patient with delayed-onset adenosine deaminase deficiency. (2013)
  • Author(s): Kanegane H, Taneichi H, Nomura K, Wada T, Yachie A, Imai K, Ariga T, Santisteban I, Hershfield MS, Miyawaki T.
  • Journal Title: Pediatr Transplant. Volume: 71 Pages: E29-E32
  • DOI: 10.1111/j.1399-3046.2012.01762.x
  • Peer Reviewed
• [Journal Article] Hyper-eosinophilia in 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. Volume: 54 Pages: 543-546
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  • 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. Volume: 32 Pages: 411-420
  • DOI: 10.1007/s10875-011-9638-z
  • Peer Reviewed
• [Journal Article] Functional STAT3 deficiency compromises the generation of human T follicular helper cells. (2012)
  • Author(s): Ma CS, Avery DT, Tangye SG and et al.
  • Journal Title: Blood Volume: 26;119 Pages: 3997-4008
  • DOI: 10.1182/blood-2011-11-392985
  • 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. Volume: 26;13 Pages: 369-378
  • DOI: 10.1038/ni.2234
  • 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. Volume: 76 Pages: 1501-1508
  • 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. Volume: 171 Pages: 1273-1276
  • DOI: 10.1007/s00431-012-1715-7.
  • Peer Reviewed
• [Journal Article] Clinical profile and genetic basis of Wiskott-Aldrich syndrome at Chandigarh, north India. (2012)
  • Author(s): Suri D, Singh S, Sehgal S and et al.
  • Journal Title: Asian Pac J Allergy Immunol. Volume: 30 Pages: 71-78
  • 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. Volume: 77 Pages: 628-634
  • DOI: 10.1111/j.1365-2265.2012.04390.x
  • 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. Volume: 44 Pages: 605-609
  • DOI: 10.3109/00365548.2012.669844
  • 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. Volume: 32 Pages: 690-697
  • DOI: 10.1007/s10875-012-9684-1
  • Peer Reviewed
• [Journal Article] Outcomes of ChildhoodPulmonary Arterial Hypertension in BMPR2 and ALK1 Mutation Carriers. (2012)
  • Author(s): Chida A, Shintani M, Nakanishi T and et al.
  • Journal Title: Am J Cardiol. Volume: 110 Pages: 586-593
  • DOI: 10.1016/j.amjcard.2012.04.035
  • Peer Reviewed
• [Journal Article] Delayed onset adenosine deaminase deficiency associated with acute disseminated encephalomyelitis. (2012)
  • Author(s): Nakaoka H, Kanegane H, Taneichi H, Miya K, Yang X, Nomura K, Takezaki S, Yamada M, Ohara O, Kamae C, Imai K, Nonoyama S, Wada T, Yachie A, Hershfield MS, Ariga T, Miyawaki T.
  • Journal Title: Int J Hematol. Volume: 95 Pages: 692-696
  • DOI: 10.1007/s12185-012-1055-4
  • Peer Reviewed
• [Journal Article] A dual reporter splicing assay using HaloTag-containing proteins. Curr Chem Genomics. (2012)
  • Author(s): Oshima K, Nagase T, Imai K, Nonoyama S, Obara M, Mizukami T, Nunoi H, Kanegane H, Kuribayashi F, Amemiya S, Ohara O.
  • Journal Title: Curr Chem Genomics. Volume: 6 Pages: 27-37
  • DOI: 10.2174/1875397301206010027
  • Peer Reviewed
• [Journal Article] Matched sibling donor stem cell transplantation for Fanconi anemia patients with T-cell somatic mosaicism. (2012)
  • Author(s): Yabe M, Shimizu T, Morimoto T, Koike T, Takakura H, Tsukamoto H, Muroi K, Oshima K, Asami K, Takata M, Yamashita T, Kato S, Yabe H.
  • Journal Title: Pediatr Transplant Volume: 16 Pages: 340-345
  • DOI: 10.1111/j.1399-3046.2012.01669.x
  • Peer Reviewed
• [Journal Article] Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery. (2012)
  • Author(s): Tanaka T, Takahashi K, Saito MK and et al.
  • Journal Title: Blood Volume: 120 Pages: 1299-1308
  • DOI: 10.1182/blood-2012-03-417881
  • Peer Reviewed
• [Journal Article] A novel Wiskott-Aldrich syndrome protein mutation in an infant with thrombotic thrombocytopenic purpura. (2012)
  • Author(s): Kawasaki Y, Toyoda H, Otsuki S, Iwasa T, Iwamoto S, Azuma E, Itoh-Habe N, Wada H, Fujimura Y, Morio T, Imai K, Mitsuiki N, Ohara O, Komada Y.
  • Journal Title: Eur J Haematol. Volume: 90 Pages: 164-168
  • DOI: 10.1111/ejh.12057
  • Peer Reviewed
• [Presentation] Clinical features and immunological abnormalities of GATA2 deficiency in JAPAN. (2012)
  • Author(s): Honma K, Imai K, Kamae C, Ishida H, Ito Y, Kojima S, Yokosuka T, Kanegane H, Morio T, Sasahara Y, Fujiwara T, Harigae H, Hashii Y, Ohara O, Nonoyama S.
  • Organizer: 15th Biennial Meeting of the European Society of Immunodeficiencies (ESID2012)
  • Place of Presentation: Florence, Italy.
  • Year and Date: 20121003-20121006
• [Presentation] Classification of common variable immunodeficiency by quantification of T cell receptor recombination excision circles (TREC) and Ig kappa-deleting recombination excision circles (KREC). (2012)
  • Author(s): Kamae C, Nakagawa N, Sato H, Honma K, Mitsuiki N, Ohara O, Kanegane H, Pasic S, Pan-Hammarström Q, MC van Zelm, Morio T, Imai K, Nonoyama S.
  • Organizer: 15th Biennial Meeting of the European Society of Immunodeficiencies (ESID2012)
  • Place of Presentation: Florence, Italy.
  • Year and Date: 20121003-20121006
• [Presentation] Genetic analysis for 207 cases with primary immunodeficiency (PID) consulted to a single center through PID network in Japan (PIDJ) in 5 years (2007-2011). (2012)
  • Author(s): Mitsuiki N, Oshima K, Imai K, Ohara O, Morio T, Mizutani S.
  • Organizer: 15th Biennial Meeting of the European Society of Immunodeficiencies (ESID2012)
  • Place of Presentation: Florence, Italy.
  • Year and Date: 20121003-20121006
• [Presentation] 次世代シークエンサーにより、原因遺伝子の同定に至ったCVIDの1例 (2012)
  • Author(s): 釜江智佳子、満生紀子、小原明、野口恵美子、久保田健夫、本間健一、小原收、今井耕輔、野々山恵章
  • Organizer: 第3回関東甲越免疫不全症研究会
  • Place of Presentation: 東京
  • Year and Date: 2012-09-22
• [Book] 小児科診療 (2013)
  • Author(s): 今井耕輔
  • Total Pages: 9
  • Publisher: PIDJと原発性免疫不全の新生児スクリーニング
• [Book] 臨床血液 (2012)
  • Author(s): 今井耕輔
  • Total Pages: 9
  • Publisher: 原発性免疫不全症の遺伝子診断・治療
• [Book] 臨床免疫・アレルギー科 (2012)
  • Author(s): 今井耕輔
  • Total Pages: 11
  • Publisher: 原発性免疫不全症の最新国際分類
• [Remarks] 原発性免疫不全症候群 医療関係者サイト
  • URL: http://pidj.rcai.riken.jp/