Elucidation of molecular mechanism of cytopenia associated with immunodeficiency/immune disorder

• Project/Area Number: 26293244
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Morio Tomohiro 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (30239628)
• Co-Investigator(Kenkyū-buntansha): 小原 收 公益財団法人かずさDNA研究所, 技術開発研究部, 副所長・部長 (20370926)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2016: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
• Keywords: 遺伝子 / 免疫学 / 臨床 / アレルギー

Outline of Final Research Achievements

We hypothesized that cytopenia in common variable immunodeficiency (CVID) could be due to 1) autoantibody, 2) hemophagocytosis, 3) differentiation blockade, and 4) increased cell death of a particular lineage. We looked at the involvement of each machinery in different CVID patients and elucidated the following. 1) IgH repertoire was skewed and the size of SHM was reduced in activated PI3Kδ syndrome. 2) IFN-g production was augmented in some of STAT1-GOF-CMCD patients. 3) Common lymphoid precursors were reduced in newly identified B cell deficiency due to heterologous mutation of IKZF1. 4) T cells were activated and induced to cell death in TNFAIP3 (A20) deficiency. Through whole exome analysis on samples from CVID patients with cytopenia, we have identified two novel genes and have carried out functional analysis using model cell systems.

Research Products

• [Journal Article] Ataxia-telangiectasia: Immunodeficiency and survival. (2017)
  • Author(s): 1.van Os NJ, Jansen AF, van Deuren M, Haraldsson A, van Driel NT, Etzioni A, van der Flier M, Haaxma CA, Morio T, Rawat A, Schoenaker MH, Soresina A, Taylor AM, van de Warrenburg BP, Weemaes CM, Roeleveld N, Willemsen MA.
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  • Peer Reviewed / Open Access
• [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] Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan. (2017)
  • Author(s): 3.Ono S, Okano T, Hoshino A, Yanagimachi M, Hamamoto K, Nakazawa Y, Imamura T, Onuma M, Niizuma H, Sasahara Y, Tsujimoto H, Wada T, Kunisaki R, Takagi M, Imai K, Morio T, Kanegane H.
  • Journal Title: J Clin Immunol. Volume: 37 Issue: 1 Pages: 85-91
  • DOI: 10.1007/s10875-016-0348-4
  • Peer Reviewed / Open Access
• [Journal Article] Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome. (2017)
  • Author(s): Takagi M, Ogata S, Ueno H, Yoshida K, Yeh T, Hoshino A, Piao J, Yamashita M, Nanya M, Okano T, Kajiwara M, Kanegane H, Muramatsu H, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Bando Y, Kato M, Hayashi Y, Miyano S, Imai K, Ogawa S, Kojima S, Morio T.
  • Journal Title: J Allergy Clin Immunol. Volume: - Issue: 6 Pages: 31286-6
  • DOI: 10.1016/j.jaci.2016.09.038
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel compound heterozygous mutations in a Japanese girl with Janus kinase 3 deficiency. (2016)
  • Author(s): 5.Sato T, Okano T, Tanaka-Kubota M, Kimura S, Miyamoto S, Ono S, Yamashita M, Mitsuiki N, Takagi M, Imai K, Kajiwara M, Ebato T, Ogata S, Oda H, Ohara O, Kanegane H, Morio T.
  • Journal Title: Pediatr Int. Volume: 58 Issue: 10 Pages: 1076-1080
  • DOI: 10.1111/ped.13070
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of second transplantation and donor lymphocyte infusion for donor mixed chimerism after allogeneic stem cell transplantation for nonmalignant diseases. (2016)
  • Author(s): 6.Umeda K, Adachi S, Tanaka S, Miki M, Okada K, Hashii Y, Inoue M, Cho Y, Koh K, Goto H, Kajiwara R, Hyakuna N, Kato K, Morio T, Yabe H.
  • Journal Title: Pediatr Blood Cancer. Volume: 63 Issue: 12 Pages: 2221-2229
  • DOI: 10.1002/pbc.26141
  • Peer Reviewed / Open Access
• [Journal Article] Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. (2016)
  • Author(s): Tsujita Y, et al.
  • Journal Title: J Allergy Clin Immunol. Volume: 138 Issue: 6 Pages: 1672-1680
  • DOI: 10.1016/j.jaci.2016.03.055
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype: an international survey of 276 patients from 169 kindreds (2016)
  • Author(s): Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, Ouachee-Chardin M, Fouyssac F, Girisha KM, Etzioni A, Van Montfrans J, Camcioglu Y, Kerns LA, Belohradsky B, Blanche S, Bousfiha A, Rodriguez-Gallego C, Meyts I, Kisand K, Reichenbach J, et al.
  • Journal Title: Blood Volume: 127 Issue: 25 Pages: 3154-64
  • DOI: 10.1182/blood-2015-11-679902
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 複合免疫不全症や分類不能免疫不全症における自己免疫疾患 (2016)
  • Author(s): 星野顕宏, 森尾友宏
  • Journal Title: Keynote R・A Volume: 4 Pages: 104-107
  • Peer Reviewed
• [Journal Article] 感染・免疫・アレルギー PAPA症候群(化膿性関節炎・壊疽性膿皮症・ざ瘡症候群) (2016)
  • Author(s): 熊木恵里, 森尾友宏
  • Journal Title: 小児科診療 Volume: 79 Pages: 335-335
  • Peer Reviewed
• [Journal Article] iPS細胞による原発性免疫不全症の治療戦略 (2016)
  • Author(s): 森尾友宏
  • Journal Title: 炎症と免疫 Volume: 24 Pages: 86-90
  • Peer Reviewed
• [Journal Article] Allogeneic stem cell transplantation for X-linked agammaglobulinemia using reduced intensity conditioning as a model of the reconstitution of humoral immunity. (2016)
  • Author(s): Ikegame K, Imai K, Yamashita M, Hoshino A, Kanegane H, Morio T, Kaida K, Inoue T, Soma T, Tamaki H, Okada M, Ogawa H.
  • Journal Title: J Hematol Oncol. Volume: 9 Pages: 9-9
  • Peer Reviewed / Open Access
• [Journal Article] The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. (2016)
  • Author(s): Gamez-Diaz L, August D, Stepensky P, Revel-Vilk S, Seidel MG, Mituiki N, Morio T, Worth AJ, Blessing J, Van de Veerdonk F, Feuchtinger T, Kanariou M, Schmitt-GA Jung S, Seneviratne S, Burns S, Belohradsky BH, Rezaei N, Bakhtiar S, Speckmann C, Jordan M, Grimbacher B.
  • Journal Title: J. Allergy Clin. Immunol. Volume: 137 Pages: 223-230
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 Pages: 28-32
  • Peer Reviewed / Open Access
• [Journal Article] Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency. (2015)
  • Author(s): Tamura S, Higuchi K, Tamaki M, Inoue C,Awazawa R,Mitsuki N,Nakazawa Y,Mishima H,Takahashi K, Kondo O,Imai K, Morio T, Ohara O, Ogi T, Furukawa F, Inoue M, Yoshiura K, Kanazawa N.
  • Journal Title: Clin. Immunol. Volume: 160 Pages: 255-260
  • Peer Reviewed / Open Access
• [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 Pages: 280-8
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features and hematopoietic stem cell transplantations 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: J Allergy Clin Immunol. Volume: 136 Pages: 1018-24
  • Peer Reviewed / Open Access
• [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] Mutations in Bruton's tyrosine kinase impair IgA responses. (2015)
  • Author(s): Mitsuiki N, Yang X, S, Bartol SJ, Grosserichter-Wagener C, Kosaka Y, Takada H, Imai K, Kanegane H, Mizutani S, van der Burg M, van Zelm MC, Ohara O, Morio T.
  • Journal Title: Int J Hematol. Volume: 101(3) Issue: 3 Pages: 305-13
  • DOI: 10.1007/s12185-015-1732-1
  • Peer Reviewed / Open Access
• [Journal Article] Wiskott-Aldrich syndrome in a girl caused by heterozygous WASP mutation and extremely skewed X-chromosome inactivation: a novel association with maternal uniparental isodisomy 6 (2015)
  • Author(s): Takimoto T, Takada H, Ishimura M, Kirino M, Hata K, Ohara O, Morio T, Hara T
  • Journal Title: Neonatology Volume: 107 Issue: 3 Pages: 185-190
  • DOI: 10.1159/000370059
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells. (2014)
  • Author(s): Park T, Park S, Cho J, Moon J, Kim N, Park K, Seong RH, Lee S, Morio T, Bothwell AL, Lee S.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 111(52) Issue: 52 Pages: 18673-8
  • DOI: 10.1073/pnas.1413687112
  • Peer Reviewed / Open Access
• [Journal Article] Hematopoietic Stem Cell Transplantation for X-Linked Thrombocytopenia With Mutations in the WAS gene. (2014)
  • Author(s): Oshima K, Imai K, Albert MH, Bittner TC, Strauss G, Filipovich AH, Morio T, Kapoor N, Dalal J, Schultz KR, Casper JT, Notarangelo LD, Ochs HD, Nonoyama S.
  • Journal Title: Clin Immunol. Volume: Epub ahead of print
  • Peer Reviewed
• [Journal Article] Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody (2014)
  • Author(s): Yamazaki Y, Yamada M, Kawai T, Morio T, Onodera M, Ueki M, Watanabe N, Takada H, Takezaki S, Chida N, Kobayashi I, Ariga T.
  • Journal Title: J Immunol. Volume: 193(10) Pages: 4880-7
  • Peer Reviewed / Open Access
• [Journal Article] Transcription activator-like effector nuclease-mediated transduction of exogenous gene into IL2RG locus. (2014)
  • Author(s): Matsubara Y, Chiba T, Kashimada K, Morio T, Takada S, Mizutani S, Asahara H.
  • Journal Title: Sci Rep. Volume: 4 Pages: 5043-5043
  • Peer Reviewed / Open Access
• [Journal Article] Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency (2014)
  • Author(s): Endo A, Watanabe K, Ohye T, Suzuki K, Matsubara T, Shimizu N, Kurahashi H, Yoshikawa T, Katano H, Inoue N, Imai K, Takagi M, Morio T, Mizutani S
  • Journal Title: Clin Infect Dis Volume: 59 Issue: 4 Pages: 545-548
  • DOI: 10.1093/cid/ciu323
  • Peer Reviewed / Open Access
• [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] BCG vaccination in patients with severe combined immunodeficiency: Complications, risks, and vaccination policies. (2014)
  • Author(s): Marciano BE, Huang CY, Joshi G, Rezaei N, Carvalho BC, Allwood Z, Ikinciogullari A, Reda SM, Gennery A, Thon V, Espinosa-Rosales F, Al-Herz W, Porras O, Shcherbina A, Szaflarska A, Kiliç S, Franco JL, Gómez Raccio AC, Roxo P Jr and et.al.
  • Journal Title: J Allergy Clin Immunol. Volume: 133(4) Issue: 4 Pages: 1134-41
  • DOI: 10.1016/j.jaci.2014.02.028
• [Presentation] 原発性免疫不全症 (2016)
  • Author(s): 森尾友宏
  • Organizer: 第44回日本臨床免疫学会総会（ビギナーズセミナー）
  • Place of Presentation: 東京都新宿区（京王プラザホテル ）
  • Year and Date: 2016-09-08
• [Presentation] 免疫不全症から学ぶIBDの病態 (2016)
  • Author(s): 森尾友宏
  • Organizer: 第7回日本炎症性腸疾患学会学術集会（特別講演）
  • Place of Presentation: 京都府 京都市左京区（国立京都国際会館）
  • Year and Date: 2016-07-10
• [Presentation] 膠原病・リウマチ性疾患と間違えやすい原発性免疫不全症 (2016)
  • Author(s): 森尾友宏
  • Organizer: 第60回日本リウマチ学会総会学術集会（教育研修講演）
  • Place of Presentation: 神奈川県横浜市西区（パシフィコ横浜）
  • Year and Date: 2016-04-23
• [Presentation] 原発性免疫不全症の遺伝子解析：その成果と限界 (2015)
  • Author(s): 森尾友宏
  • Organizer: 第43回日本臨床免疫学会（ワークショップ）
  • Place of Presentation: 神戸（神戸国際会議場）
  • Year and Date: 2015-10-23
• [Presentation] 稀少性免疫難病の診断と治療 (2015)
  • Author(s): 森尾友宏
  • Organizer: 日本人類遺伝学会第60回大会（特別講演）
  • Place of Presentation: 東京（京王プラザホテル）
  • Year and Date: 2015-10-15
  • Invited
• [Presentation] 免疫不全症・異常症におけるリンパ球亜群解析 (2014)
  • Author(s): 森尾友宏
  • Organizer: ヒューマンイムノロジーフォーラム2014
  • Place of Presentation: 新・都ホテル（京都）
  • Year and Date: 2014-12-13
• [Presentation] 血液疾患を合併する原発性免疫不全症-単一遺伝子疾患から血液疾患の分子病態解析へ (2014)
  • Author(s): 森尾友宏
  • Organizer: 第102回近畿血液学地方会
  • Place of Presentation: テイジンホール（大阪）
  • Year and Date: 2014-11-08
• [Presentation] 感染防御におけるサイトカインの働き (2014)
  • Author(s): 森尾友宏
  • Organizer: 第46回日本小児感染症学会総会・学術集会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2014-10-18
• [Presentation] 原発性免疫不全症における遺伝子解析 (2014)
  • Author(s): 森尾友宏
  • Organizer: 第42回日本臨床免疫学会総会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2014-09-26
• [Presentation] 原発性免疫不全症からみるCommon Disease: 病態解析及び治療の最近の進歩 (2014)
  • Author(s): 森尾友宏
  • Organizer: 第42回日本臨床免疫学会総会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2014-09-25
• [Presentation] 免疫応答の遮断により惹起される感染症：背景の理解から臨床 (2014)
  • Author(s): 森尾友宏
  • Organizer: 第6回KOCS小児リウマチ研究会
  • Place of Presentation: ホテルレオパレス博多（博多）
  • Year and Date: 2014-05-31
  • Invited
• [Presentation] Overview2 ヒトリンパ球解析の現状と展望 (2014)
  • Author(s): 森尾友宏
  • Organizer: 第58回日本リウマチ学会総会（シンポジウム（ヒト免疫とリウマチ性疾患））
  • Place of Presentation: グランドプリンスホテル新高輪（東京）
  • Year and Date: 2014-04-26
• [Book] 医学のあゆみ「多パラメータ解析による免疫担当細胞亜群同定と機能解析」 (2015)
  • Author(s): 森尾友宏、高島健浩、今井耕輔
  • Publisher: 医歯薬出版株式会社
• [Book] はじめに－感染症の歴史と免疫不全症の概念の変遷 (2014)
  • Author(s): 森尾友宏
  • Publisher: 東京医学社
• [Book] 小児内科「成人にいたった免疫不全症」 (2014)
  • Author(s): 森尾友宏
  • Publisher: 東京医学社
• [Book] リウマチ科「原発性免疫不全症の分子的背景と免疫異常」 (2014)
  • Author(s): 高島健浩，森尾友宏
  • Publisher: 科学評論社
• [Book] 小児内科「自然免疫と発熱」 (2014)
  • Author(s): 森尾友宏
  • Publisher: 東京医学社
• [Book] 小児内科「原発性免疫不全症における消化管感染症」 (2014)
  • Author(s): 森尾友宏
  • Publisher: 東京医学社