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The emergence of self-reactive B cells through somatic mutation and dysfunctional immune tolerance of peripheral B cells in a BCR-knock in mouse model

Research Project

Project/Area Number 16K08837
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Immunology
Research InstitutionOsaka University

Principal Investigator

Sakakibara Shuhei  大阪大学, 免疫学フロンティア研究センター, 寄附研究部門助教 (10618838)

Research Collaborator KIKUTANI Hitoshi  
IKAWA Masato  
SATO Yukoh  
ALIEL-HUSSIEN Marwa  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords自己免疫疾患 / 自己抗体 / B細胞 / 全身性エリテマトーデス / 免疫寛容 / B細胞 / 免疫学
Outline of Final Research Achievements

In acute systemic lupus erhthematosus (SLE), pathogenic autoantibodies are produced by self-reactive B cells that acquire somatic mutations to augment their reactivity. However, germline-encoded, low-affinity precursors for pathogenic autoantibody-producing cells have not been characterized. In this study, we generated site-directed knock-in mice of germline-encoded, low-affinity anti-DNA BCR and characterized the precursor B cells of pathogenic anti-DNA autoantibody-producing cells in vivo. Our analysis demonstrated that low-affinity anti-ssDNA B cells from the KI mice were not functionally anergic. Nonetheless, the KI B cells failed to differentiate into germinal center B cells, undergo somatic hypermutation and clonal expansion. Therefore, low-affinity anti-ssDNA B cells are suppressed by a tolerance checkpoint at germinal centers.

Academic Significance and Societal Importance of the Research Achievements

全身性エリテマトーデス(SLE)に代表される自己免疫疾患の多くは根治が困難であり、解決すべき問題は多い。本研究で示されたように、胚中心反応には弱親和性抗ssDNA B細胞を抑制する免疫寛容機構がある。その一方で、多くのSLEモデルマウスでは自発的な胚中心形成が顕著であり、それに由来する自己抗体がSLE様症状を誘引する。従って、胚中心でのB細胞免疫寛容はさほど厳格ではなく、自己反応性B細胞をとりまく環境や状況によっては機能しないことが明確とななった。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report

Research Products

(7 results)

All 2019 2018 2016

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Allergic conversion of protective mucosal immunity against nasal bacteria in patients with chronic rhinosinusitis with nasal polyposis.2019

    • Author(s)
      Takeda K, Sakakibara S, Yamashita K, Motooka D, Nakamura S, El Hussien MA, Katayama J, Maeda Y, Nakata M, Hamada S, Standley DM, Hayama M, Shikina T, Inohara H, Kikutani H.
    • Journal Title

      Journal of Allergy and Clinical Immunology

      Volume: 143 Pages: 1163-1175

    • DOI

      10.1016/j.jaci.2018.07.006

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Bystander inhibition of humoral immune responses by Epstein-Barr virus LMP1.2018

    • Author(s)
      Tsai C.-Y., Sakakibara S., Yasui T., Minamitani T., Okuzaki D., and Kikutani H.
    • Journal Title

      International Immunology

      Volume: 30(12) Pages: 579-590

    • DOI

      10.1093/intimm/dxy053

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Clonal evolution and antigen recognition of anti-nuclear antibodies in acute systemic lupus erythematosus.2018

    • Author(s)
      Sakakibara S., Arimori T., Yamashita K., et al
    • Journal Title

      Ann Rheum Dis.

      Volume: 7 Pages: 1507-1515

    • DOI

      10.1038/s41598-017-16681-y

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Development and activation of B cells expressing germline precursor of SLE-derived highaffinity anti-DNA antibody in knock-in mice2018

    • Author(s)
      Ali El Hussien Marwa., Sakakibara S., Kikutani H
    • Organizer
      第47回日本免疫学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Structural Basis of Antigen Recognition by Anti-dsDNA Antibodies Isolated from Systemic Lupus Erythematosus Patients2016

    • Author(s)
      榊原 修平
    • Organizer
      第45回 日本免疫学会
    • Place of Presentation
      沖縄 沖縄コンベンションセンター
    • Year and Date
      2016-12-05
    • Related Report
      2016 Research-status Report
  • [Presentation] Antigen-specific maturation of autoantibodies in systemic lupus erythematosus2016

    • Author(s)
      榊原 修平
    • Organizer
      International Congress of Immunology 2016
    • Place of Presentation
      オーストラリア メルボルン メルボルンコンベンション&エキシビジョンセンター
    • Year and Date
      2016-08-12
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] 全身性エリテマトーデス由来抗DNA抗体の構造学的解析から見た自己反応性B細胞の親和性成熟2016

    • Author(s)
      榊原 修平
    • Organizer
      自己免疫研究会
    • Place of Presentation
      東京 京王プラザホテル
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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