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Pathophysiological role of B cell subtypes that change with age

Research Project

Project/Area Number 21H02753
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49070:Immunology-related
Research InstitutionKyushu University

Principal Investigator

Baba Yoshihiro  九州大学, 生体防御医学研究所, 教授 (20415269)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2023: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2022: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2021: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
KeywordsB細胞 / ABCs / 自己免疫疾患 / 免疫寛容 / アナジー / 老化 / 加齢
Outline of Research at the Start

年齢を重ねるごとに免疫機能が低下していく免疫老化は、感染症の重症化や免疫寛容維持機構の破綻による自己免疫疾患発症に密接に関係します。しかし、それら現象を支えるメカニズムは未だ解明されていません。特に、液性免疫の要となるB細胞に関する知見は非常に乏しいのが現状です。そこで本研究では、トランスクリプトーム解析と分子・細胞・個体レベルの機能解析により、B細胞の加齢に伴う多様性の変化と免疫老化誘導の鍵となるB細胞サブタイプの同定を試みます。そして、同定したB細胞サブタイプの機能と分化・活性化機序を解明し、免疫機能低下と自己免疫疾発症機構を理解することを到達目標とします。

Outline of Final Research Achievements

We have identified Fcrl5 as a gene that is highly expressed in CD11c+ age-associated B cells. We conducted an analysis using B cell-specific transgenic mice with Fcrl5 (Fcrl5-BTg), and the results showed that these mice spontaneously develop autoimmune diseases with age. Additionally, we found that imiquimod-induced SLE-like autoimmune disease was more severe in Fcrl5-BTg mice compared to wild-type mice. Mechanistically, using a B cell anergy model of HEL-BCR/sHEL, we discovered that increased expression of Fcrl5 led to anergy break. Given that Fcrl5 expression is normally low in asymptomatic B cells, the abnormally elevated Fcrl5 expression may disrupt B cell immune tolerance and contribute to the development of autoimmune diseases.

Academic Significance and Societal Importance of the Research Achievements

免疫老化の研究は、加齢の影響を大きく受ける臓器が胸腺であることから、T細胞老化の研究が精力的に行われている一方で、液性免疫を司るB細胞に関する知見は極めて乏しい。加齢に関連したB細胞サブタイプとして唯一報告されている加齢性B細胞は、その病原性や分化の仕組みは不明である。CD11c+加齢性B細胞に発現が高いFcrl5が、自己反応性B細胞の活性化を誘導することを示す我々の知見は、今後、自己免疫疾患の病態の理解や新規治療候補となる可能性がある。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (9 results)

All 2024 2023 2021 Other

All Int'l Joint Research (3 results) Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (1 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Int'l Joint Research] The University of Melbourne(オーストラリア)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Department of Pathology and Cell Biology/Columbia University(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Immunophenomics Centre(フランス)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Type I interferon promotes the fate of Toll-like receptor 9-stimulated follicular B cells to plasma cell differentiation.2024

    • Author(s)
      Higuchi R, Tanaka K, Saito Y, Murakami D, Nakagawa T, Nutt S.L, Ohkawa Y, Baba Y
    • Journal Title

      PNAS Nexus

      Volume: in press

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bruton’s tyrosine kinase inhibition limits endotoxic shock by suppressing IL-6 production by marginal zone B cells in mice2024

    • Author(s)
      Kawata Kazuhiko、Hatano Shinya、Baba Akemi、Imabayashi Keisuke、Baba Yoshihiro
    • Journal Title

      Frontiers in Immunology

      Volume: 15

    • DOI

      10.3389/fimmu.2024.1388947

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Upregulated Fcrl5 disrupts B cell anergy and causes autoimmune disease2023

    • Author(s)
      Chisato Ono, Shinya Tanaka, Keiko Myouzen, Takeshi Iwasaki, Mahoko Ueda, Yoshinao Oda, Kazuhiko Yamamoto, Yuta Kochi, Yoshihiro Baba
    • Journal Title

      Frontiers in Immunology

      Volume: 14 Pages: 01-14

    • DOI

      10.3389/fimmu.2023.1276014

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Generation and characterization of CD19-iCre mice as a tool for efficient and specific conditional gene targeting in B cells.2021

    • Author(s)
      Yasuda T, Saito Y, Ono C, Kawata K, Baba A, Baba Y.
    • Journal Title

      Sci. Rep.

      Volume: 11 Issue: 1 Pages: 5524-5524

    • DOI

      10.1038/s41598-021-84786-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ER membrane protein complex 1 interacts with STIM1 and regulates store-operated Ca2+ entry2021

    • Author(s)
      Kawata Kazuhiko、Baba Akemi、Shiota Masayuki、Wanibuchi Hideki、Baba Yoshihiro
    • Journal Title

      The Journal of Biochemistry

      Volume: 170 Issue: 4 Pages: 483-488

    • DOI

      10.1093/jb/mvab063

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 自己免疫疾患における病原性B細胞2023

    • Author(s)
      馬場義裕
    • Organizer
      第15回日本血液疾患免疫療法学会
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited

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Published: 2021-04-28   Modified: 2025-01-30  

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