Research on molecular mechanisms of break in immunological tolerance in disorders caused by single-gene defect

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390270
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• 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, 准教授 (30239628)
• Co-Investigator(Kenkyū-buntansha): OHARA Osamu かずさDNA研究所, ヒトゲノム研究部, 副所長 (20370926)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 分類不能免疫不全症 / 自己免疫疾患 / 免疫学的寛容 / レパートリー解析 / 責任遺伝子探索 / 次世代シークエンサー

Research Abstract

We set up a multiparameter flow cytometry for detailed immunophenotyping and KRECs/TRECs analysis for assessment of B and T cell neogenesis, respectively in order to delve into pathogenesis of autoimmunity developed in primary immunodeficiency (PID). We categorized the PID patients into several groups and also established a database for PID with autoimmunity. We developed an extensive method to analyze IgH and TCR repertoires using high-throughput next generation sequencing (NGS), and started measuring the repertoire in 10 patients. Through whole exome analysis (WEA) for more than 40 PID patients with autoimmunity, we identified a mutation in 5 patients. These include BTK, FANCA, LRBA, PIK3CD, and STAT1. Candidate genes (ranging one to six) were obtained by carrying out WEA for a patient and his/her family members in 5 patients.

Research Products

• [Journal Article] Rapid Detection of Intracellular p47phox and p67phox by Flow Cytometry; Useful Screening T ests for Chronic Granulomatous Disease (2013)
  • Author(s): Wada T, Muraoka M, T oma T, Imai T, Shigemura T, Agematsu K, Haraguchi K, Moriuchi H, Oh-Ishi T, Kitoh T, Ohara O, Morio T, Yachie A
  • Journal Title: J Clin Immunol Volume: 33 Pages: 857-864
  • Peer Reviewed
• [Journal Article] Aberrant glycosylation of IgA in Wiskott-Aldrich syndrome and X-liked thrombocytopenia (2013)
  • Author(s): Shimizu M, Kanegane H, Wada T, Motoyoshi Y, Morio T, Candotti F, Yachie A
  • Journal Title: J Allergy Clin Immunol Volume: 131 Pages: 587-590
  • Peer Reviewed
• [Journal Article] Calssification of common variable immunodeficiency by quantification of T cell receptor and Ig kappa-deleting recombination excision circles (2013)
  • Author(s): Kamae C, Nakagawa N, Sato H, Honma K, Mitsuiki N, Ohar a O. Kanegane H, Pasic S, Pan-Hammerstrom Q, van Zelm MC, Morio T, Imai K, Nonoyama S
  • Journal Title: J Allergy Clin Immunol Volume: 131 Pages: 1437-1440
  • Peer Reviewed
• [Journal Article] A novel Wiskott-Aldrich syndrome protein mutation in an infant with thrombotic thrombocytopenic purpura (2013)
  • Author(s): Kawasaki Y, T oyoda H, Otsuki S, Iwasa T, Iwamoto S, Azuma E, Itoh-Habe N, Wada H, Fujimura Y, Mor io T, Imai K, Mistusiki N, Ohara O, Komada Y
  • Journal Title: Eur J Haematol Volume: 290 Pages: 164-8
  • Peer Reviewed
• [Journal Article] Endocrine complications in primary immunodeficiency diseases in Japan (2012)
  • Author(s): Nozaki T, T akada H, Ishimura M, Ihara K, Imai K, Mor io T, Kobayashi M, Nonoyama S, Hara T
  • Journal Title: Clinical Endocrinol Volume: 77 Pages: 628-634
  • Peer Reviewed
• [Journal Article] Btk negatively regulates ROS production and stimulation-induced apoptosis in human neutrophils (2012)
  • Author(s): Honda F, Kano H, Kanegane H, Nonoyama S, Kim E-S, Lee S-K, Takagi M, mizutani S, Morio T
  • Journal Title: Nature Immunol Volume: 13 Pages: 369-378
  • Peer Reviewed
• [Journal Article] Transducible form of p47phox and p67phox compensate for defective NADPH oxidase activity in neutrophils of patients with chronic granulomatous disease (2012)
  • Author(s): Honda F, Hane Y, T oma T, Y achie A, Kim E-S, Lee S-K, T akagi M, Mizutani S, Morio T
  • Journal Title: Biochem Biophy s Res Comm Volume: 417 Pages: 162-168
  • Peer Reviewed
• [Journal Article] Functional characterization and targeted correction of A TM mutations identified in Japanese patients with ataxia-telangiectasia (2012)
  • Author(s): Nakamura K, Du L, Tunuguntla R, Fike F, Cavalieri S, Morio T, Mizutani S, Brusco A, Gatti RA
  • Journal Title: Hum Mutat Volume: 33 Pages: 198-208
  • Peer Reviewed
• [Journal Article] Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory (2012)
  • Author(s): Kaji T, Ishige A, Hikida M, T aka J, Hijikata A, Kubo M, Nagashima T, T akahashi Y, Kurosaki T, Okada M, Ohar a O, Rajewsky K, T akemori T
  • Journal Title: J Exp Med Volume: 209 Pages: 2079-97
  • Peer Reviewed
• [Journal Article] Chronic mucocutaneous candidiasis caused by a gain-of-function mutation in the STAT1 DNA-binding domain (2012)
  • Author(s): Takezaki S, Y amada M, Kato M, Park MJ, Maruyama K, Yamazaki Y, Chida N, Ohar a O, Kobayashi I, Ariga T
  • Journal Title: J Immunol Volume: 189 Pages: 1521-6
  • Peer Reviewed
• [Journal Article] Detection of base substitution-type somatic mosaicism of the NLRP3 gene with >99.9% statistical confidence by massively parallel sequencing (2012)
  • Author(s): Izawa K, Hijikata A, T anaka N, Kawai T, Saito MK, Goldbach-Mansky R, Aksentijevich I, Y asumi T, Nakahata T, Heike T, Nishikomori R, Ohar a O
  • Journal Title: DNA Res Volume: 19 Pages: 143-52
  • Peer Reviewed
• [Journal Article] Nationwide Survey of Patients with Primary Immunodeficiency Diseases in Japan (2011)
  • Author(s): Ishimura M, T akada H, Doi T, Imai K, Sasahara Y, Kanegane H, Nishikomori R, Mor io T, Heike T, Kobayashi M, Ariga T, T suchiya S, Nonoyama S, Miyawaki T, Hara T
  • Journal Title: J Clin Immunol Volume: 31 Pages: 968-76
  • Peer Reviewed
• [Journal Article] Outcome of unrelated umbilical cord blood transplantation in 88patients with primary immunodeficiency in Japan (2011)
  • Author(s): Mor io T, Atsuta Y, T omizawa D, Nagamura-Inoue T, Kato K, Ariga T, Kawa K, Koike K, T auchi H, Kajiwara M, Hara T, Kato S
  • Journal Title: Br J Haematol Volume: 154 Pages: 363-372
  • Peer Reviewed
• [Journal Article] ADA-SCID with 'W AZA-ARI' mutations that synergistically abolished ADA protein stability (2011)
  • Author(s): Okura Y, Y amada M, Kobayashi I, Santisteban I, Arredondo-Santisteban G, Kato Z, Iguchi A, Y oshida M, Ohar a O, Nakagawa N, Imai K, Hershfield MS, Ariga T
  • Journal Title: Br J Haematol Volume: 153 Pages: 675-6
  • Peer Reviewed
• [Journal Article] Miyawaki T , Nonoyama S. Quantification of κ-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation effects (2011)
  • Author(s): Nakagawa N, Imai K, Kanegane H, Sato H, Y amada M, Kondoh K, Okada S, Kobayashi M, Agematsu K, T akada H, Mitsuiki N, Oshima K, Ohar a O, Suri D, Rawat A, Singh S, Nakagawa N, Imai K, Kanegane H, Sato H, Y amada M, Kondoh K, Okada S, Kobayashi M, Agematsu K, T akada H, Mitsuiki N, Oshima K, Ohar a O, Suri D, Rawat A, Singh S
  • Journal Title: J Aller gy Clin I mmunol Volume: 128 Pages: 223-225
  • Peer Reviewed
• [Presentation] 悪性腫瘍を合併する免疫不全症 (2013)
  • Author(s): 森尾友宏
  • Organizer: 第54回日本小児血液・がん学会学術集会 (シンポジウム)
  • Place of Presentation: 福岡
  • Year and Date: 20131129-1201
• [Presentation] 免疫不全症候群から学ぶ human immunology (2013)
  • Author(s): 森尾友宏
  • Organizer: 第41回日本臨床免疫学会総会(シンポジウム)
  • Place of Presentation: 山口
  • Year and Date: 20131127-29
• [Presentation] 分類不能型免疫不全症(CVID)の多彩な病像と分子基盤 (2013)
  • Author(s): 森尾友宏
  • Organizer: 第75会回日本血液学会学術集会
  • Place of Presentation: 北海道
  • Year and Date: 20131011-13
• [Presentation] Cord blood transplantation for primary immunodeficiency in Japan (2013)
  • Author(s): Morio T
  • Organizer: AsiaCORD2013
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20130419-20
• [Presentation] 易感染性, 自己免疫, 悪性腫瘍の分子基盤としての原発性免疫不全症 (2013)
  • Author(s): 森尾友宏
  • Organizer: 平成25年度遺伝子病制御研究所研究集会
  • Place of Presentation: 北海道
  • Year and Date: 2013-10-25
• [Presentation] Primary Immunodeficiencies due the Defect in Signaling Molecules (2012)
  • Author(s): T Morio
  • Organizer: 2012 KSMCB Annual Meeting
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20121010-12
• [Presentation] 細胞内寄生菌にたいする感染防御機構 (2012)
  • Author(s): 森尾友宏
  • Organizer: 第44回日本小児感染症学会総会・学術集会
  • Place of Presentation: 北九州
  • Year and Date: 2012-11-23
• [Presentation] 先天性免疫不全症および血液系腫瘍において診断の手がかりとなる皮膚病変と, 診断への道筋 (2012)
  • Author(s): 森尾友宏
  • Organizer: 第36回日本小児皮膚科学会学術大会 (シンポジウム)
  • Place of Presentation: 前橋市
  • Year and Date: 2012-07-15
• [Presentation] 分類不能型免疫不全症の病態解明へのアプローチ (2011)
  • Author(s): 森尾友宏
  • Organizer: 第39回日本臨床免疫学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-09-17
• [Presentation] 原発性免疫不全症候群 (2011)
  • Author(s): 森尾友宏
  • Organizer: 第114回日本小児科学会学術集会 教育セミナー
  • Place of Presentation: 東京
  • Year and Date: 2011-08-12
• [Book] カラー版内科学 (2012)
  • Author(s): 森尾友宏 : (分担執筆) 補体欠損症, 門脇孝, 永井良三編
  • Total Pages: 1333-4
  • Publisher: 西村書店