Functional analysis of phospholipase D4 for autoimmune diseases

• Project/Area Number: 16K09891
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Kyoto University
• Principal Investigator: Shuji Akizuki 京都大学, 医学研究科, 特定病院助教 (50626637)
• Co-Investigator(Kenkyū-buntansha): 寺尾 知可史 国立研究開発法人理化学研究所, 生命医科学研究センター, 副チームリーダー (60610459)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ホスホリパーゼD4 / 関節リウマチ / 自己免疫疾患 / 全身性エリテマトーデス / B細胞 / 全ゲノム関連解析 / 膠原病学 / 免疫学

Outline of Final Research Achievements

Phospholipase D4 is one of the disease susceptibility genes of rheumatoid arthritis (RA), but its detailed function is unknown. Applicants have shown that PLD4 deficient mutant mice develop B lymphocyte count abnormalities and germinal center hyperplasia, hypergammaglobulinemia, autoantibodies such as anti-DNA antibodies, glomerulonephritis, In addition, whole genome association analysis of SLE showed that it has a high frequency of PLD4 gene polymorphisms identical to RA. These results indicate that PLD4 plays an important role in maintaining B cell homeostasis and immune tolerance in the immune system, and is universally involved in systemic autoimmune diseases beyond biological species.

Academic Significance and Societal Importance of the Research Achievements

本研究は多因子疾患である膠原病の発病原因となる遺伝要因を全ゲノム関連解析で特定し、特に機能未知な遺伝子に着目し解析することで新規の病態理解の手掛かりを探索した。本研究の結果、ホスホリパーゼD4がB細胞免疫の免疫寛容に関わることが明らかとなり、将来の治療標的の可能性も含め、臨床応用への基盤構築が達成されたと考えらえる。

Research Products

• [Journal Article] PLD4 is a genetic determinant to systemic lupus erythematosus and involved in murine autoimmune phenotypes (2019)
  • Author(s): Akizuki S, Ishigaki K, Kochi Y, Law SM, Matsuo K, Ohmura K, Suzuki A, Nakayama M, Iizuka Y, Koseki H, Ohara O, Hirata J, Kamatani Y, Matsuda F, Sumida T, Yamamoto K, Okada Y, Mimori T, Terao C.
  • Journal Title: Annals of the Rheumatic Diseases Volume: 78 Issue: 4 Pages: 509-518
  • DOI: 10.1136/annrheumdis-2018-214116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Genetic mutation of phospholipase D4 disturbs the homeostasis and immunological tolerance of B cells in mice (2016)
  • Author(s): Shuji AKizuki
  • Organizer: The 13th International Workshop of Autoantibodies and Autoimmunity
  • Place of Presentation: The Westin Miyako, Kyoto
  • Year and Date: 2016-10-11
  • Int'l Joint Research