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Identification of molecular characteristics of pathogenic autoantibody-producing cells

Research Project

Project/Area Number 16H05201
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionTohoku University

Principal Investigator

TAKAI Toshiyuki  東北大学, 加齢医学研究所, 教授 (20187917)

Research Collaborator Inui Masanori  
Itou Ari  
Endo Shota  
Su Mei-Tzu  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords免疫抑制 / 免疫チェックポイント / レセプター / 自己免疫疾患 / 免疫寛容 / 全身性エリテマトーデス / 皮膚筋炎 / LILRファミリー / 形質細胞 / 抗体療法 / 免疫抑制分子 / 自己抗体 / 病原性プラズマセル / 免疫抑制受容体
Outline of Final Research Achievements

In this study, first we have found that expression of leukocyte immunoglobulin-like receptor (LILR)B4, an inhibitory member of the human LILR family, is augmented in autoantibody-producing plasmablasts/plasma cells (PCs) of systemic lupus erythematosus (SLE) patients. However, the mechanism behind the upregulation of LILRB4 upon pathogenic antibody-secreting cells is yet to be known. To clarify the mechanism, next we have examined if glycoprotein 49B (gp49B), the murine counterpart of human LILRB4, is also elevated in autoantibody-producing cells in several SLE mouse models. We have found that gp49B is indeed expressed on PC of SLE-prone models but not of healthy C57BL/6 mice, and the level was positively correlated to the autoantibody IgG titer in serum. Gp49B genetic deletion, however, did not abolish the serum autoantibodies or fully ameliorate the lethal glomerulonephritis, indicating that gp49B is not the sole regulator of lupus but a pathogenic element in the disease.

Academic Significance and Societal Importance of the Research Achievements

SLEではステロイド剤と免疫抑制剤を併用することで短期生存率が著明に改善しているが特異性に乏しく,ステロイド長期投与による骨粗鬆症や感染症,動脈硬化性病変などは長期の生命予後,患者QOLを大きく低下させる。自己抗体のソースである汎B・活性化Bリンパ球を標的にした抗体療法の臨床試験が進められているが,リスク,ベネフィットのバランスに優れた薬剤の開発は成功していない。本研究は自己抗体を高産生するSLE病原性プラズマセル(PC)特異的に高発現する,リガンドが未同定のオーファン受容体LILRB4(B4)を見出した。これにより病原性PC特異的に治療する道筋が見えた。

Report

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

    (7 results)

All 2019 2017 2016

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results,  Acknowledgement Compliant: 2 results) Presentation (3 results) (of which Invited: 1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Gp49B is a pathogenic marker for autoantibody-producing plasma cells in lupus-prone BXSB/Yaa mice2019

    • Author(s)
      Wong Yi Li、Su Mei-Tzu、Sugahara-Tobinai Akiko、Itoi So、Kezuka Dai、Endo Shota、Inui Masanori、Takai Toshiyuki
    • Journal Title

      International Immunology

      Volume: 印刷中 Issue: 6 Pages: 397-406

    • DOI

      10.1093/intimm/dxz017

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] EXPLORING OF IMMUNE INHIBITORY RECEPTORS THAT CHARACTERIZE PATHOGENIC PLASMA CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS2017

    • Author(s)
      Takai T, Inui M.
    • Journal Title

      Japanese Journal of Allergology

      Volume: 66 Issue: 1 Pages: 27-31

    • DOI

      10.15036/arerugi.66.27

    • NAID

      130005394544

    • ISSN
      0021-4884, 1347-7935
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Tolerogenic immunoreceptor ILT3/LILRB4 paradoxically marks pathogenic auto-antibody-producing plasmablasts and plasma cells in non-treated SLE.2016

    • Author(s)
      Inui M, Sugahara-Tobinai A, Fujii H, Itoh-Nakadai A, Fukuyama H, Kurosaki T, Ishii T, Harigae H, Takai T.
    • Journal Title

      Int Immunol.

      Volume: Dec;28(12) Issue: 12 Pages: 597-604

    • DOI

      10.1093/intimm/dxw044

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Expression of gp49B on plasma cells from autoimmune-prone mice and its relevance to progression of autoimmune disease.2016

    • Author(s)
      Wong YiLi、Inui M、Takai T
    • Organizer
      第45回日本免疫学会学術集会
    • Place of Presentation
      沖縄コンベンションセンター(沖縄・宜野湾)
    • Year and Date
      2016-12-06
    • Related Report
      2016 Annual Research Report
  • [Presentation] Immunoregulatory receptor LILRB4 on plasmablasts is related to antoantibody production in SLE.2016

    • Author(s)
      乾匡範、藤井博司、伊藤亜里、石井智徳、髙井俊行
    • Organizer
      第45回日本免疫学会学術集会
    • Place of Presentation
      沖縄コンベンションセンター(沖縄・宜野湾)
    • Year and Date
      2016-12-05
    • Related Report
      2016 Annual Research Report
  • [Presentation] 全身性エリテマトーデスにおけるBリンパ球系細胞の抑制性受容体2016

    • Author(s)
      髙井俊行、乾匡範、飛内章子、伊藤亜里、藤井博司、石井智徳
    • Organizer
      第65回日本アレルギー学会学術大会
    • Place of Presentation
      東京国際フォーラム(東京)
    • Year and Date
      2016-06-18
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Patent(Industrial Property Rights)] 炎症性疾患のマーカー2016

    • Inventor(s)
      高井俊行,石井智徳,藤井博司,乾 匡範
    • Industrial Property Rights Holder
      高井俊行,石井智徳,藤井博司,乾 匡範
    • Industrial Property Rights Type
      特許
    • Filing Date
      2016-07-29
    • Related Report
      2016 Annual Research Report

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

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