アレルギー疾患関連遺伝子発現及び細胞機能の調節によるアレルギー応答制御

• Project/Area Number: 21591287
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Juntendo University
• Principal Investigator: 西山 千春 Juntendo University, 医学(系)研究科(研究院), 准教授 (20327836)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: アレルギー / 転写調節因子 / マスト細胞・好塩基球 / 樹状細胞 / PU.1 / GATA1 / 高親和性IgE受容体 / 遺伝子多型(SNP) / GATA-1 / 遺伝子多型(SNPs) / マスト細胞

Research Abstract

アレルギー・自己免疫疾患の治療、予防を最終目標に、免疫担当細胞の遺伝子発現や機能を制御する転写調節因子の働きを解析してきている。特に、I型アレルギー反応の制御を目指し、マスト細胞・好塩基球におけるIgE受容体構成分子の発現制御機構解析や、マスト細胞系列と樹状細胞系列の分岐を決定する分子として見出したPU.1の機能解析を進めている。
本年度は、マスト細胞特異的分子c-kitの発現制御機構解析によりGATA2がSp1を介してプロモーターを転写活性化する機構があることや、エピジェネティック遺伝子発現制御の研究からHDAC阻害剤がマスト細胞のアレルギー反応を抑制しながら感染に対する防御反応をむしろ亢進する作用を持つことなどを見出し、報告してきた。ごく最近では、Notchシグナルに応答してマスト細胞が、従来樹状細胞などの特定の抗原提示細胞に限られると考えられていたMHC class II発現を引き起こすこと、及びその分子機構について明らかにした。PU.1については、樹状細胞の機能や遺伝子発現調節に関わる分子機構を詳細に解析し、少なくとも抗原提示能の調節に重要な共刺激分子群CD80・CD86の発現に必須であり、樹状細胞の機能制御を介して、自己免疫疾患治療応用に展開できる可能性を見出した。
また、遺伝子多型と疾患の相関については、IgE受容体α鎖遺伝子プロモーター領域の多型がアトピー性皮膚炎や炎症性腸疾患と関連すること、TLR2プロモーター多型がアレルギー疾患と相関すること、などを日本人と欧州の異なる民族を母集団とした統計学的解析と分子生物学的解析を行い報告した。

Research Products

• [Journal Article] Notch1-mediated signaling induces MHC class II expression through the activation of class II transactivator promoter III in mast cells (2011)
  • Author(s): Nobuhiro Nakano, et al.
  • Journal Title: J.Biol.Chem. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Critical role of transcription factor PU.1 in the expression of CD80 and CD86 on dendritic cells (2011)
  • Author(s): Shunsuke Kanada, et al.
  • Journal Title: Blood Volume: (in press)
  • Peer Reviewed
• [Journal Article] Naturally occurring FCER1A N222K mutation-its ethnicity-dependent distribution and a role in atopic dermatitis (2011)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Mol.Immunol. Volume: (in press)
  • Peer Reviewed
• [Journal Article] An association of TLR2-16934A>T polymorphism and severity/phenotype of atopic dermatitis (2011)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: J.Eur.Acad.Dermatol.Venereol. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Very rare minor homozygous GG genotype of tissue factor +5466A>G mutation in a patient with two cryptogenic cerebovasucular ischemic events (2011)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Int.J.Cardiology Volume: (in press)
  • Peer Reviewed
• [Journal Article] GATA2 and Sp1 positively regulate the c-kit promoter in mast cells (2010)
  • Author(s): Keiko Maeda, et al.
  • Journal Title: J.Immunol. Volume: 185 Pages: 4252-4260
  • Peer Reviewed
• [Journal Article] Opposite effects of Trichostatin A on activation of mast cells by different stimulants (2010)
  • Author(s): Qing-hui Wang, et al.
  • Journal Title: FEBS Lett. Volume: 584 Pages: 2315-2320
  • Peer Reviewed
• [Journal Article] Establishment of a simple detection system for blood group ABO-specific transferase activity in DNA-transfected cells (2010)
  • Author(s): Chiyomi Nishiyda, et al.
  • Journal Title: Legal Med. Volume: 12 Pages: 172-176
  • Peer Reviewed
• [Journal Article] Suppressive effects of transcription factor GATA-1 on cell type-specific gene expression in dendritic cells (2010)
  • Author(s): Naomi Shimokawa, et al.
  • Journal Title: Immunogenetics Volume: 62 Pages: 421-429
  • Peer Reviewed
• [Journal Article] An association between functional FcεRIα polymorphisms and total serum IgE levels in patients with inflammatory bowel disease (2010)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Scand.J.Gastroenterology Volume: 45 Pages: 766-767
  • Peer Reviewed
• [Journal Article] FcεRIα gene (FCER1A) promoter polymorphisms and total serum IgE levels in Japanese atopic dermatitis patients (2010)
  • Author(s): Yusuke Niwa, et al.
  • Journal Title: Int.J.Immunogenetics Volume: 37 Pages: 139-141
  • Peer Reviewed
• [Journal Article] Tissue factor-1208D>I polymorphism is associated with D-dimer levels in patients with inflammatory bowel disease (2010)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Inflamm.Bowel Dis. Volume: 16 Pages: 1095-1096
  • Peer Reviewed
• [Journal Article] Tissue factor +5466A>G and-1208D>I genetic polymorphisms and severity of rheumatoid arthritis (2010)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Clin.Chem.Lab.Med. Volume: 48 Pages: 423-425
  • Peer Reviewed
• [Journal Article] Suppressive effects of transcription factor GATA-1 on cell type-specific gene expression in dendritic cells (2010)
  • Author(s): Naomi Shimokawa, et al.
  • Journal Title: Immunogenetics (in press)
  • Peer Reviewed
• [Journal Article] An association between functional FcepsilonRIalpha polymorphisms and total serum IgE levels in patients with inflammatory bowel disease (2010)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Scand.J.Gastroenterology (in press)
  • Peer Reviewed
• [Journal Article] FcepsilonRIalpha gene(FCER1A)promoter polymorphisms and total serum IgE levels in Japanese atopic dermatitis patients (2010)
  • Author(s): Yusuke Niwa, et al.
  • Journal Title: Int.J.Immunogenetics (in press)
  • Peer Reviewed
• [Journal Article] Tissue factor-1208D>I polymorphism is associated with D-dimer levels in patients with inflammatory bowel disease (2010)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Inflamm.Bowel.Dis. (in press)
  • Peer Reviewed
• [Journal Article] Very rare minor homozygous GG genotype of tissue factor +5466A>G mutation in a patient with two cryptogenic cerebovascular ischemic events (2010)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Int.J.Cardiology (in press)
  • Peer Reviewed
• [Journal Article] Tissue factor +54466A>G and -1208D>I genetic polymorphisms and severity of rheumatoid arthritis (2009)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Clin.Chem.Lab.Med. 48 Pages: 423-425
  • Peer Reviewed
• [Journal Article] Interaction of functional FCER2 promoter polymorphism and phenotype-associated haplotypes (2009)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Tissue Antigens 74 Pages: 534-538
  • Peer Reviewed
• [Journal Article] FcepsilonRIalpha gene-18483A>C polymorphism affects transcriptional activity through YY1 binding (2009)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Immunogenetics 61 Pages: 649-655
  • Peer Reviewed
• [Journal Article] Involvement of PU.1 in the transcriptional regulation of TNF-alpha (2009)
  • Author(s): Fukai Tatsuo, et al.
  • Journal Title: Biochem.Biophys.Res.Commun. 388 Pages: 102-106
  • Peer Reviewed
• [Journal Article] Tissue factor genetic polymorphisms and haplotypes in Japanese population (2009)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Atherosclerosis 207 Pages: 344-345
  • Peer Reviewed
• [Journal Article] Discovery of proteinaceous N-modification in lysine biosynthesis of Thermus thermophilus (2009)
  • Author(s): Akira Horie, et al.
  • Journal Title: Nat.Chem.Biol. 5 Pages: 673-679
  • Peer Reviewed
• [Journal Article] Roles of PU.1 in monocyte- and mast cell-specific gene regulation : PU.1 transactivates CIITA pIV in cooperation with IFN-gamma (2009)
  • Author(s): Tomonobu Ito, et al.
  • Journal Title: Int.Immunol. 21 Pages: 803-816
  • Peer Reviewed
• [Journal Article] Tissue factor(TF)+5466A>G polymorphism predicts plasma TF levels in subjects with cryptogenic ischemic stroke (2009)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Thromb.Haemost. 102 Pages: 173-175
  • Peer Reviewed
• [Journal Article] FCER1A genetic variability and serum IgE levels (2009)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Allergy 64 Pages: 1383-1383
  • Peer Reviewed
• [Journal Article] Human umbilical cord epithelial cells express Notch ligands Delta1 and Jagged 1 (2009)
  • Author(s): William Ng, et al.
  • Journal Title: J.Dermatol.Sci. 54 Pages: 131-134
  • Peer Reviewed
• [Journal Article] Functional analysis of a polymorphism in the promoter region of the IL-12/-23p40 gene (2009)
  • Author(s): Naomi Shimokawa, et al.
  • Journal Title: Clin.Exp.Allergy 39 Pages: 228-235
  • Peer Reviewed
• [Journal Article] Genetic variability of high-affinity IgE receptor alpha-subunit(Fcepsilon RIalpha) (2009)
  • Author(s): Daniel Potaczek, et al.
  • Journal Title: Immunol.Res. 45 Pages: 75-84
  • Peer Reviewed
• [Journal Article] Notch signaling confers antigen-presenting cell functions on mast cells (2009)
  • Author(s): Nobuhiro Nakano, et al.
  • Journal Title: J.Allergy Clin.Immunol. 123 Pages: 74-81
  • Peer Reviewed
• [Presentation] 小児アレルギー疾患における末梢血好塩基球および樹状細胞の高親和性IgE受容体(FcεRI)発現の検討 (2010)
  • Author(s): 鈴木竜洋
  • Organizer: 第47回日本小児アレルギー学会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2010-12-04
• [Presentation] Cyclooxygenase-2 inhibition restores UVB-mediated down-regulation of Darier disease-related gene (2010)
  • Author(s): 上條麻弥
  • Organizer: 日本研究皮膚科学会第35回年次学術大会
  • Place of Presentation: 和歌山県民文化会館(和歌山)
  • Year and Date: 2010-12-03
• [Presentation] Critical role of a transcription factor PU.1 in the cell-type specific gene expression of dendritic cells (2010)
  • Author(s): 北村奈緒
  • Organizer: 日本研究皮膚科学会第35回年次学術大会
  • Place of Presentation: 和歌山県民文化会館(和歌山)
  • Year and Date: 2010-12-03
• [Presentation] 高親和性IgE受容体(FcεRI)発現に関わる遺伝子多型 (2010)
  • Author(s): 西山千春
  • Organizer: 第60回日本アレルギー学会秋季学術大会
  • Place of Presentation: 東京国際フォーラム(東京)
  • Year and Date: 2010-11-27
• [Presentation] マスト細胞の成熟に寄与する遺伝子Tescalcinの解析 (2010)
  • Author(s): 中野信浩
  • Organizer: 第60回日本アレルギー学会秋季学術大会
  • Place of Presentation: 東京国際フォーラム(東京)
  • Year and Date: 2010-11-27
• [Presentation] 樹状細胞の遺伝子発現における転写調節因子PU.1の役割 (2010)
  • Author(s): 北村奈緒
  • Organizer: 第60回日本アレルギー学会秋季学術大会
  • Place of Presentation: 東京国際フォーラム(東京)
  • Year and Date: 2010-11-26
• [Presentation] 小児アレルギー疾患の末梢血好塩基球および樹状細胞における高親和性IgE受容体(FcεRI)発現の検討 (2010)
  • Author(s): 鈴木竜洋
  • Organizer: 第60回日本アレルギー学会秋季学術大会
  • Place of Presentation: 東京国際フォーラム(東京)
  • Year and Date: 2010-11-25
• [Presentation] Effect of Cyclooxygenase-2 on human ATP2A2 gene in keratinocyte (2010)
  • Author(s): 上條麻弥
  • Organizer: The First Eastern Asia Dermatology Congress
  • Place of Presentation: ホテルニューオータニ博多(福岡)
  • Year and Date: 2010-09-30
• [Presentation] マスト細胞の成熟及び抗原提示能獲得へのNotch受容体の寄与 (2010)
  • Author(s): 中野信浩
  • Organizer: 日本農芸化学会2010年度(平成22年度)大会
  • Place of Presentation: 東京大学駒場キャンパス(東京)
  • Year and Date: 2010-03-30
• [Presentation] The role of transcription factor PU.1 in the regulation of MHCclassII and CD11c expression in dendritic cells (2009)
  • Author(s): 北村奈緒
  • Organizer: 研究皮膚科学会2009年度大会
  • Place of Presentation: JALリゾートホテル(福岡)
  • Year and Date: 2009-12-03
• [Presentation] マスト細胞機能の獲得におけるNotchレセプターの役割 (2009)
  • Author(s): 中野信浩
  • Organizer: 第39回日本免疫学会総会・学術集会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2009-12-02
• [Presentation] マスト細胞におけるc-kit分子の発現調節機構について (2009)
  • Author(s): 前田啓子
  • Organizer: 第59回日本アレルギー学会秋季学術大会
  • Place of Presentation: 秋田キャッスルホテル・秋田ビューホテル・(秋田)
  • Year and Date: 2009-10-31
• [Presentation] Ethnicity-oriented mutational analysis of FECR1A 3'-UTR (2009)
  • Author(s): Daniel Potaczek
  • Organizer: 第59回日本アレルギー学会秋季学術大会
  • Place of Presentation: 秋田キャッスルホテル・秋田ビューホテル・(秋田)
  • Year and Date: 2009-10-31
• [Presentation] マスト細胞の形質獲得における各種Notchリガンドの役割 (2009)
  • Author(s): 中野信浩
  • Organizer: 第59回日本アレルギー学会秋季学術大会
  • Place of Presentation: 秋田キャッスルホテル・秋田ビューホテル・(秋田)
  • Year and Date: 2009-10-31
• [Presentation] 樹状細胞のMHCクラスII、 CD11c発現における転写調節因子PU.1の役割 (2009)
  • Author(s): 北村奈緒
  • Organizer: 第59回日本アレルギー学会秋季学術大会
  • Place of Presentation: 秋田キャッスルホテル・秋田ビューホテル・(秋田)
  • Year and Date: 2009-10-29
• [Book] 知っておかなければならないアレルギー疾患の基礎知識・FcεRIα遺伝子の発現調節 (2010)
  • Author(s): 西山千春
  • Total Pages: 7
  • Publisher: 株式会社 医薬ジャーナル社(アレルギー・免疫)
• [Book] FcεRIα鎖の発現調節 (2009)
  • Author(s): 西山千春
  • Total Pages: 6
  • Publisher: 科学評論社(臨床免疫・アレルギー科)
• [Remarks]
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/atopy_center/kenkyu_nishiyama.htm
• [Remarks]
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/atopy_center/keireki_nishiyama.html
• [Remarks]
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/atopy_center/kenkyu_nishiyama.htm
• [Remarks]
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/atopy_center/keireki_nishiyama.html