Study on the mechanism of autoimmunity and malignancy developed in primary immunodeficiency

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591245
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MORIO Tomohiro Tokyo Medical and Dental University, 大学院・医歯学総合研究科, 准教授 (30239628)
• Project Period (FY): 2008 – 2010
• Keywords: 先天性免疫不全症 / 自己免疫疾患 / 悪性腫瘍 / DNA損傷修復 / 毛細血管拡張小脳失調症 / Mre11 / V(D)J再構成 / 免疫グロブリンクラススイッチ

Research Abstract

We studied on the mechanism of autoimmunity and malignancy frequently observed in patients with primary immunodeficiency (PID). Patients with impaired DNA damage response such as ataxia telangiectasia (AT) and Mre11 deficiency showed chromosomal abnormality caused by defect in DNA damage processing. AT patients showed defective T-cell development as well. T-cell anergy was not properly executed in lymphocytes from ICOS deficiency showing autoimmunity. Skewed TCR V repertoire usage was observed in ～50% of CVID patients. These findings suggest the presence of various mechanism underling autoimmune disorder and malignancy in PID patients.

Research Products

• [Journal Article] Analysis of mutations andrecombination activity inRAG-deficient patient. (2011)
  • Author(s): Asai E., Wada T., Sakakibara Y., Toga A., Toma T., Shimizu T., Imai K., Nonoyama S., Morio T., Kamachi Y., Ohara O., Yachie A.
  • Journal Title: Clin.Immunol 138 Pages: 172-177
• [Journal Article] AutoimmuneLymphoproliferative Syndrome Like Disease With Somatic KRAS Mutation. (2011)
  • Author(s): Takagi M, Shinoda K, Piao J, MitsuikiN, Takagi M, Matsuda K, Muramatsu H,Doisaki S, Nagasawa M, Morio T.,Kasahara Y, Koike K, Kojima S, Takao A,Mizutani S.
  • Journal Title: Blood 117 Pages: 2887-2890
• [Journal Article] 【内科疾患の診断基準病型分類・重症度】免疫・その他先天性免疫不全症候群 (2011)
  • Author(s): 森尾友宏
  • Journal Title: 内科 105 Pages: 1296-1300
• [Journal Article] Qualitative and quantitativedifferences in the intensity of Fas-mediated intracellular signals determine life and death in T cells. (2010)
  • Author(s): Shin MJ, Shim JH, Lee JY, Chae WJ, LeeHK, Morio T., Park JH, Chang EJ, Lee SK.
  • Journal Title: Int J.Hematol. 92 Pages: 262-270
• [Journal Article] Prominent eosinophilia but less eosinophil activation in a patientwith Omenn syndrome. (2010)
  • Author(s): Seki M., Kimura H., Mori A., Shimada A., Yamada Y., Maruyama K., Hayashi Y., Agematsu K., Morio T., Yachie A., Kato M.
  • Journal Title: Pediatr.Int. 52 Pages: e196-199
• [Journal Article] Successful cord blood transplantation for a CHARGE syndrome with CHD7 mutation showing DiGeorge sequence including hypoparathyroidism. (2010)
  • Author(s): Inoue H., Takada H., Kusuda T., Goto T., Ochiai M., Kinjo T., Muneuchi J., TakahataY., Takahashi N., Morio T., Kosaki K., Hara T.
  • Journal Title: Eur.J.Paedirtr. 169 Pages: 839-844
• [Journal Article] IkB regulates TH17 development by cooperating with ROR nuclear receptors. (2010)
  • Author(s): Okamoto K, Iwai Y, Ohhora M, YamamotoM, Morio T., Aoki K, Ohya K, Jetten AM,Akira S, Muta T, Takayanagi H.
  • Journal Title: Nature. 464 Pages: 1381-1385
• [Journal Article] X-linked thrombocytopenia (XLT) due to WAS mutations: Clinicalcharacteristics, long-term outcome,and treatment options. (2010)
  • Author(s): Albert MH, Bittner TC, Nonoyama S,Notarangelo LD, Burns S, Imai K, Espanol T, Fasth A, Pellier I, StraussG, Morio T., Gathmann B, Noordzij JG,Fillat C, Hoenig M, Nathrath M, MeindlA, Pagel P, Wintergerst U, Fischer A,Thrasher AJ, Belohradsky BH, Ochs HD.
  • Journal Title: Blood. 115 Pages: 3231-3238
• [Journal Article] Autopsystudy of cerebellar degeneration insiblings with ataxia-telangiectasia-like disorder. (2010)
  • Author(s): Oba D., Hayashi M., Minamitani M., HamanoS., Uchisaka N., Kikuchi A., Kishimoto H., Takagi M., Morio T., Mizutani S.
  • Journal Title: Acta Neuropathol. 119 Pages: 513-520
• [Journal Article] Fatal degeneration of specialized cardiac muscle associated with chronic activeEpstein-Barr virus infection. (2009)
  • Author(s): Hasegawa D., Kaji M., Takeda H., KawasakiK., Takahashi H., Ochiai H., Morio T., Omori Y., Yokozaki H., Kosaka Y.
  • Journal Title: PediatrInt. 51 Pages: 846-848
• [Journal Article] Immunologically silent cancer clone transmission from mother to offspring. (2009)
  • Author(s): Isoda T., Ford A., Tomizawa D., van DelftF., De Castro DG., Mitsuiki N., Score J., Taki T., Takagi M., Morio T., Saji H., Greaves M., Mizutani S.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 106 Pages: 178821788-178821785
• [Journal Article] Phenotypic Variations between Affected Siblings with Ataxia-Telangiectasia: Ataxia-Telangiectasia in Japan. (2009)
  • Author(s): Morio T., Takahashi N., Watanabe F., HondaF., Sato M., Takagi M., Imadome KI., Miyawaki T., Delia D., Nakamura K., GattiRA., Mizutani S.
  • Journal Title: Int.J.Hematol. 90 Pages: 455-462
• [Journal Article] Two brothers with ataxia-telangiectasia-like disorder with lung adenocarcinoma. (2009)
  • Author(s): Uchisaka N., Takahashi N., Sato M., Kikuchi A., Mochizuki S., Imai K., Nonoyama S., Ohara O., Watanabe F., Mizutani S., Hanada R., Morio T.
  • Journal Title: J.Pediatr. 155 Pages: 435-438
• [Journal Article] Bilateral anterior granulomatous keratouveitis with sunset glow fundus in a patient with autoiommune polyglandular syndrome. (2009)
  • Author(s): Futagami Y., Sugita S., Fujimaki T., Yokoyama T., Morio T., Mochizuki M.
  • Journal Title: Ocul Immunol Inflamm. 17 Pages: 88-90
• [Journal Article] Impaired CD4 and CD8 effector function and decreased memory T-cell populations in ICOS deficient patients. (2009)
  • Author(s): Takahashi N., Matsukoto K., Saito H., Nanki T., Miyasaka N., Kobata T., Azuma M., Lee S-K., Mizutani S., Morio T.
  • Journal Title: J.Immunol. 182 Pages: 5515-5527
• [Journal Article] Rapid diagnosis of ataxia-telangiectasia by flow cytometric monitoring of DNA damage-dependent ATM phosphorylation. (2009)
  • Author(s): Honda M., Takagi M., Chessa L., Morio T., Mizuatni S.
  • Journal Title: Leukemia. 23 Pages: 409-414
• [Journal Article] 免疫低下に伴うMAC感染症に合併した呼吸器クリプトスポリジウム症の1例 (2009)
  • Author(s): 所正治, HusseinAmjad I.A., 田中身和, 山口智博, 森尾友宏, 佐藤隆介, 水谷修紀
  • Journal Title: Clinical Parasitology 19 Pages: 55-58
• [Journal Article] V(D)J 再構成および免疫グロブリンクラススイッチにおけるATM の役割 (2009)
  • Author(s): 森尾友宏
  • Journal Title: 臨床免疫・アレルギー科 51 Pages: 154-161
• [Journal Article] ウイルス感染の排除機構と免疫記憶 (2009)
  • Author(s): 森尾友宏
  • Journal Title: 小児内科 41 Pages: 970-975
• [Journal Article] Vesical varices and telangiectasias in a patient with ataxia telangiectasia. (2008)
  • Author(s): Suzuki K., Tsugawa K., Oki E., Morio T., Ito E., Tanaka H.
  • Journal Title: Ped.Nephrol. 23 Pages: 1005-1008
• [Journal Article] Ataxia telangiectasiaの臨床的特徴全国調査から明らかになったこと (2008)
  • Author(s): 森尾友宏
  • Journal Title: 小児科臨床 61 Pages: 1805-1810
• [Journal Article] 【原発性免疫不全症候群】Ataxia telangiectasia (2008)
  • Author(s): 森尾友宏
  • Journal Title: アレルギー・免疫 15 Pages: 1370-1377
• [Presentation] 造血細胞移植後の体系的免疫能評価法 (2011)
  • Author(s): 森尾友宏
  • Organizer: 第33回日本造血細胞移植学会総会
  • Place of Presentation: 愛媛
  • Year and Date: 2011-03-09
• [Presentation] Btk Controls ROS Production and Apoptosis in Human Neutrophils.XIVth meeting of the European Society for Immunodeficiencies.Isutanbul (2010)
  • Author(s): Morio T
  • Organizer: Republic of Turkey
  • Year and Date: 20101006-20101009
• [Presentation] Impaired CD4 and CD8 Effector Function and Decreased MemoryT-cell Populations in ICOS-deficient Patients. (2010)
  • Author(s): Morio T, Terada N, Nanki T, Miyasaka N, Kobata T, Matsumoto K, Azuma M, Mizutani S
  • Organizer: 14th International Congressof Immunology 2010
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-20100827
• [Presentation] IκBζ is required for the transcriptional program in Th17 development. (2010)
  • Author(s): Okamoto K, Iwai Y, Oh-hora M, Yamamoto M, Morio T, Jetten AM, Akira S, Muta T, Takayanag H.
  • Organizer: 14th International Congress of Immunology 2010
  • Place of Presentation: Kobe,Japan
  • Year and Date: 20100822-20100827
• [Presentation] Functional analysis of Fas-mediated activation signaling pathways in Tcells. (2010)
  • Author(s): Shin M J, Shim J, Lee J, Chae W, Lee H, Morio T, Park J H, Chang E, Lee S.
  • Organizer: 14th International Congress of Immunology 2010
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-20100827
• [Presentation] Btk controls ROS production and apoptosis in human neutrophil. (2010)
  • Author(s): Honda F, Ikeda Y, Takahashi1 N, Lee S, Mizutani S, Morio T
  • Organizer: 14th International Congress of Immunology 2010
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-20100827
• [Presentation] 日本における先天性免疫不全症に対する臍帯血移植成績 (2010)
  • Author(s): 森尾友宏、富澤大輔、梶原道子、水谷修紀、熱田由子、加藤剛二、原寿郎、加藤俊一
  • Organizer: 第113回日本小児科学会学術集会
  • Place of Presentation: 岩手
  • Year and Date: 20100423-20100425
• [Presentation] Common variable immunodeficiency (CVID): Molecular basis of immune dysfunction. (2010)
  • Author(s): 森尾友宏
  • Organizer: The 2nd Symposium for PID in Asia
  • Place of Presentation: Chiba
  • Year and Date: 20100204-20100205
• [Presentation] 分類不能型免疫不全症の全国調査と亜群同定 (2010)
  • Author(s): 森尾友宏
  • Organizer: 第3回日本免疫不全症研究会
  • Place of Presentation: 東京
  • Year and Date: 2010-01-30
• [Presentation] Btkによる好中球活性酸素産生及びアポトーシスの制御 (2009)
  • Author(s): 本田冨美子、水谷修紀、Sang-Kyou Lee、森尾友宏
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 20091202-20091204
• [Presentation] Basic to Clinical:Artemis/Cernnunos/Lig4 deficiency (2009)
  • Author(s): 森尾友宏、水谷修紀
  • Organizer: 第51回日本小児血液学会
  • Place of Presentation: 千葉
  • Year and Date: 20091127-20091129
• [Presentation] Btkによる好中球活性酸素産生及びアポトーシスの制御 (2009)
  • Author(s): 本田冨美子、水谷修紀、Sang-Kyou Lee、森尾友宏
  • Organizer: 第37回日本臨床免疫学会総会
  • Place of Presentation: 東京
  • Year and Date: 20091113-20091114
• [Presentation] ROS-induced DNA damage response. (2009)
  • Author(s): 森尾友宏
  • Organizer: The 66th KSBMB Annual Meeting2009
  • Place of Presentation: COEX, Korea
  • Year and Date: 20090512-20090513
• [Presentation] 当科における同種造血幹細胞移植(1995-2007年)の検討 (2009)
  • Author(s): 長澤正之、小野敏明、遠藤明史、青木由貴、磯田健志、富澤大輔、高木正稔、梶原道子、森尾友宏、水谷修紀
  • Organizer: 第112回日本小児科学会学術総会
  • Place of Presentation: 奈良
  • Year and Date: 20090417-20090419
• [Presentation] ICOS欠損症におけるT 細胞機能異常 (2009)
  • Author(s): 森尾友宏
  • Organizer: 第2回日本免疫不全症研究会
  • Place of Presentation: 東京
  • Year and Date: 2009-01-31
• [Presentation] Mre11遺伝子変異を認めAtaxia telangiectasia like disorderと診断した肺腺癌の小児兄弟例 (2008)
  • Author(s): 内坂直樹、菊地陽、望月慎史、外山大輔、山西未穂、荒川ゆうき、花田良二、高橋尚美、渡邊文晶、佐藤正樹、森尾友宏、水谷修紀
  • Organizer: 第50回日本小児血液学会総会・第24回日本小児がん学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 20081114-20081116
• [Presentation] フローサイトメトリーを用いたDNA損傷の定量化と毛細血管拡張性小脳失調症診断方法の確立 (2008)
  • Author(s): 本田真由子、高木正稔、森尾友宏、水谷修紀
  • Organizer: 第50回日本小児血液学会総会・第24 回日本小児がん学会学術集会
  • Place of Presentation: 千葉
  • Year and Date: 20081114-20081116
• [Presentation] 造血細胞移植後ex vivo 増幅CD4T 細胞輸注療法 (2008)
  • Author(s): 森尾友宏
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 20081010-20081012
• [Presentation] Stability of Artemis protein is regulated by Hsp72. (2008)
  • Author(s): Watanabe F, Morio T, Ogigami N, Kiyono T,Domenico Delia, Mizutani S
  • Organizer: Ataxia telangiectasia workshop 2008
  • Place of Presentation: Otsu, Shiga
  • Year and Date: 20080422-20080425
• [Presentation] Generation of DNA double-stranded breaks in stalled DNA replication forks:anessential stepinitiated by Artemis toward a second wave of DNA damage response and ATM activation. (2008)
  • Author(s): Unno J, Takagi M, Watanabe F, Sato M, Takahashi N, Morio T, Teraoka H, Mizutani S
  • Organizer: Ataxia telangiectasia workshop 2008
  • Place of Presentation: Otsu, Shiga
  • Year and Date: 20080422-20080425
• [Presentation] Ataxia-Telangiectasia in Japan:Phenotypic variations in affected siblings with Ataxia-Telangiectasia. (2008)
  • Author(s): Morio T, Watanabe F, Takahashi N, Sato M, Sato R, Takagi M, Imadome K, Miyawaki T, Domenico Delia, Nakamura K, Richard Gatti, Mizutani S
  • Organizer: Ataxia telangiectasia workshop 2008
  • Place of Presentation: Otsu,Shiga
  • Year and Date: 20080422-20080425
• [Presentation] Identification of Novel Mutation in Japanese Patients with Ataxia Telangiectasia;Absence of Founder Mutations. (2008)
  • Author(s): Nakamura K, Morio T, Mizutani S, Richard A Gatti.
  • Organizer: Ataxia telangiectasia workshop 2008
  • Place of Presentation: Otsu,Shiga
  • Year and Date: 20080422-20080425
• [Presentation] Regulation of Artemis/ATM-related DNA damage response network. (2008)
  • Author(s): Mizutani S, Unno J, Watanabe F, Takagi M, Morio T, Teraoka H, Domenico D.
  • Organizer: Ataxia telangiectasia workshop 2008
  • Place of Presentation: Otsu,Shiga
  • Year and Date: 20080422-20080425
• [Presentation] Ataxia telangiectasia (2008)
  • Author(s): 森尾友宏
  • Organizer: Involement of ATM in immunodeficiency and leukemogenesis Symposium on Recent Advances in Cell Function and Defense Mechanisim
  • Place of Presentation: Yonsei Univeristy, Seoul,Korea
  • Year and Date: 2008-04-18
• [Presentation] Immunodefiencies with impaired DNA damage response. (2008)
  • Author(s): 森尾友宏
  • Organizer: Recent Advances in DNA Damage Response
  • Place of Presentation: Yonsei Univeristy, Seoul, Korea
  • Year and Date: 2008-04-18
• [Book] 免疫不全症(新版臨床免疫学第二版) (2009)
  • Author(s): 森尾友宏(分担執筆)
  • Total Pages: 168-175
  • Publisher: 講談社
• [Book] 免疫(病気が見えるvol 6 免疫・膠原病・感染症) (2009)
  • Author(s): 森尾友宏(分担監修)
  • Total Pages: 1-31
• [Book] 先天性免疫不全症(ハリソン内科学第3版)(原著第17版) (2009)
  • Author(s): 森尾友宏(分担訳者)
• [Book] 遺伝病に対して何ができるだろうか?(症例でわかる新しい臨床遺伝学)第14章 (2008)
  • Author(s): 森尾友宏(分担訳者)
  • Total Pages: 353-381,406-407
  • Publisher: メディカル・サイエンス・インターナショナル
• [Remarks] ホームページ等