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2023 Fiscal Year Annual Research Report

Pathological characterization of inflammatory bowel disease based on primary immunodeficiency

Research Project

Project/Area Number 20K08718
Research InstitutionWakayama Medical University

Principal Investigator

田村 志宣  和歌山県立医科大学, 医学部, 准教授 (10364085)

Project Period (FY) 2020-04-01 – 2024-03-31
Keywords原発性免疫不全症 / 炎症性腸疾患 / DNAリガーゼIV / 遺伝子再構成障害 / LIG4症候群 / Th1細胞 / IFN-γ / TCRレパトア解析
Outline of Annual Research Achievements

本研究では、DNA損傷修復に関わるDNAリガーゼIV(LIG4)の低形成性変異を導入したマウス(Lig4W447Cホモ変異マウス)に生じた炎症性腸疾患の分子基盤、細胞生物学的基盤を明らかにすることを目的とした。これまでに、Lig4W447Cホモ変異マウスにおいて、DNA損傷修復障害、獲得免疫不全が生じること、さらには、IFN-γを産生するTh1細胞を主体とする炎症性腸疾患を発症することを見出した。今年度は、このホモ変異マウスに生じたユニークな炎症病態の解析を継続し、いくつかの結果を得ることができた。

1)Lig4W447Cホモ変異マウスとRag2欠損マウス(リンパ球欠失マウス)とのダブル変異マウスを作成した。このダブル変異マウスでは、完全に炎症を消去でき、長期生存した。Lig4W447Cホモ変異マウスの腸炎はリンパ球依存性であることを見出した。
2)Lig4W447Cホモ変異マウスの腸炎発症には、IFN-γが鍵となるサイトカインと考えられた。そこで、IFN-γ欠損マウスを作成し、Lig4W447Cホモ変異マウスとのダブル変異マウスを作成した。このダブル変異マウスでは、Lig4W447Cホモ変異マウスと同じく、大腸を含めた全身性の炎症が認められた。一方、FACS解析やRNA-Seq解析より、この炎症はTh17細胞がドミナントな表現型であった。IFN-γを欠損させることで、炎症病態がTh1型からTh17型に移行することを見出した。
3)野生型マウスとLig4W447Cホモ変異マウスの脾臓で、シングルセル解析とTCRレパトア解析を行った。シングルセル解析より、変異マウスでは、IFN-γを産生するTh1細胞がドミナントであることを見出し。さらに、TCRレパトア解析より、ホモ変異マウスでは、TCR遺伝子のclonotypeの著明な減少とoligoclonalなTCRの候補を見出した。

  • Research Products

    (13 results)

All 2024 2023

All Journal Article (7 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 7 results,  Open Access: 4 results) Presentation (6 results) (of which Int'l Joint Research: 5 results)

  • [Journal Article] Predictive Model for Occurrence of Febrile Neutropenia after Chemotherapy in Patients with Diffuse Large B-Cell Lymphoma: A Multicenter, Retrospective, Observational Study2024

    • Author(s)
      Morimoto Masaya、Yokoya Yuma、Yoshida Kikuaki、Kosako Hideki、Hori Yoshikazu、Mushino Toshiki、Tamura Shinobu、Ito Reiko、Koyamada Ryosuke、Yamashita Takuya、Mori Shinichiro、Mori Nobuyoshi、Ohde Sachiko
    • Journal Title

      Hematology Reports

      Volume: 16 Pages: 76-88

    • DOI

      10.3390/hematolrep16010008

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Post-infarction Left Ventricular Free Wall Rupture Diagnosed by Contrast-Enhanced Computed Tomography: A Case Report2024

    • Author(s)
      Morimoto Yuya、Tamura Shinobu、Kawashima Shuji、Inoue Shigeaki
    • Journal Title

      Cureus

      Volume: 16 Pages: e52127

    • DOI

      10.7759/cureus.52127

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Clinicopathological analysis of CD47 and signal regulatory protein alpha expression in myeloid sarcoma patients: CD47 expression is a favourable prognostic factor2023

    • Author(s)
      Tanaka Ken、Miyoshi Hiroaki、Kawamoto Keisuke、Shimasaki Yasumasa、Nakashima Kazutaka、Imamoto Teppei、Yamada Kyohei、Takeuchi Mai、Moritsubo Mayuko、Furuta Takuya、Kohno Kei、Tamura Shinobu、Sonoki Takashi、Ohshima Koichi
    • Journal Title

      Pathology

      Volume: 56 Pages: 81-91

    • DOI

      10.1016/j.pathol.2023.10.007

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Clinical Characteristics and Diagnostic Prediction of Severe Fever with Thrombocytopenia Syndrome and Rickettsiosis in the Co-Endemic Wakayama Prefecture, Japan2023

    • Author(s)
      Teramoto Kan、Tamura Shinobu、Yoshida Kikuaki、Inada Yukari、Yamashita Yusuke、Morimoto Masaya、Mushino Toshiki、Koreeda Daisuke、Miyamoto Kyohei、Komiya Nobuhiro、Nakano Yoshio、Takagaki Yusaku、Koizumi Yusuke
    • Journal Title

      Medicina

      Volume: 59 Pages: 2024~2024

    • DOI

      10.3390/medicina59112024

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Angioimmunoblastic T-Cell Lymphoma after Treatment of Classic Hodgkin Lymphoma: A Case Report2023

    • Author(s)
      Tanaka Ken、Miyoshi Hiroaki、Yamashita Yusuke、Iwamoto Ryuta、Yokoya Yuma、Tochino Yuichi、Arakawa Fumiko、Tamura Shinobu、Murata Shin-Ichi、Sonoki Takashi、Ohshima Koichi
    • Journal Title

      Hematology Reports

      Volume: 15 Pages: 662~669

    • DOI

      10.3390/hematolrep15040067

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Administration of combined venetoclax and azacitidine in a patient with acute myeloid leukemia and multiple comorbidities undergoing dialysis: A case report2023

    • Author(s)
      Akagi Yuina、Yamashita Yusuke、Kosako Hideki、Furuya Yoshiaki、Hosoi Hiroki、Mushino Toshiki、Murata Shogo、Nishikawa Akinori、Tamura Shinobu、Nakao Taisei、Sonoki Takashi
    • Journal Title

      eJHaem

      Volume: 4 Pages: 841~843

    • DOI

      10.1002/jha2.732

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Coagulation potentials of plasma‐derived factors VIIa and X mixture (Byclot<sup>?</sup>) evaluated by global coagulation assay in patients with acquired haemophilia A2023

    • Author(s)
      Takeyama Masahiro、Furukawa Shoko、Ogiwara Kenichi、Tamura Shinobu、Ohno Hitoshi、Higasa Satoshi、Shimonishi Naruto、Nakajima Yuto、Onishi Tomoko、Nogami Keiji
    • Journal Title

      Haemophilia

      Volume: 30 Pages: 249~252

    • DOI

      10.1111/hae.14902

    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Mutant mice carrying a novel hypomorphic mutation of the DNA ligase IV gene show Th1-skewing intestinal inflammations with severe adaptive immunodeficiency2023

    • Author(s)
      Yamashita Y, Kato T, Kosako H, Iwabuchi S, Sasaki I, Kanazawa N, Hemmi H, Hashimoto S, Sonoki T, Tamura S, Kaisho T
    • Organizer
      12th International Society of Systemic Autoinflammatory Diseases Meeting
    • Int'l Joint Research
  • [Presentation] LIG4 syndrome mutation can lead to Th1-skewing intestinal inflammation in mice2023

    • Author(s)
      Tamura S, Yamashita Y, Kato T, Kosako H, Iwabuchi S, Sasaki I, Hemmi H, Hashimoto S, Kaisho T
    • Organizer
      2nd International Symposium of Clinical Immunology Meeting
    • Int'l Joint Research
  • [Presentation] Hypomorphic mutation in a DNA damage repair system causes Th1-skewing intestinal inflammation with severe combined immunodeficiency2023

    • Author(s)
      Tamura S, Yamashita Y, Kato T, Kosako H, Iwabuchi S, Sasaki I, Hemmi H, Hashimoto S, Kaisho T
    • Organizer
      29th International Symposium on Molecular Cell Biology of Macrophages
    • Int'l Joint Research
  • [Presentation] Impaired DNA double-strand break repair can drive innate immunity response in mice2023

    • Author(s)
      Tamura S, Kosako H, Yamashita Y, Kato T, Tabata S, Iwabuchi S, Tanaka K, Nakashima K, Sasaki I, Ohshima K, Hashimoto S, Sonoki T, Kaisho T
    • Organizer
      13th JSH International Symposium
    • Int'l Joint Research
  • [Presentation] A novel Lig4 hypomorphic mutation in mice can lead to intestinal inflammation evoked by skewing Th12023

    • Author(s)
      Yamashita Y, Kosako H, Kato T, Tabata S, Iwabuchi S, Tanaka K, Nakashima K, Sasaki I, Ohshima K, Hashimoto S, Sonoki T, Kaisho T, Tamura S
    • Organizer
      13th JSH International Symposium
  • [Presentation] Asciminib Induces Anti-Myeloma Effects Through Terminal Unfolded Protein Response2023

    • Author(s)
      Kosako H, Yamashita Y, Morita S, Iwabuchi S, Tamura S, Hashimoto S, Sonoki T
    • Organizer
      13th JSH International Symposium
    • Int'l Joint Research

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Published: 2024-12-25  

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