Investigation for pathogenesis of primary immunodeficiencies caused by PIP3-related deficiencies and its application to the development of new therapies

• Project/Area Number: 20K22916
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: National Defense Medical College
• Principal Investigator: Kanako Sekinaka 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 小児科学, 救急調整官 (00871344)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: PIP3 / APDS / PIK3CD / PIK3R1 / PTEN / FOXO1 / ERK / AKT-FOXO1シグナル伝達経路 / Bim / p27Kip1 / PID

Outline of Research at the Start

原発性免疫不全症APDS (Activated PI3K-Delta syndrome；活性化PI3Kδ症候群)は、PIP3(Phosphatidylinositol 3,4,5-triphosphate）過剰により、下流のAKT, mTOR, S6の恒常的リン酸化亢進が起こり発症する。これまでに、APDSの新規原因遺伝子PTENを世界で初めて同定し、免疫不全発症にAKT-FOXO1シグナル伝達経路が関与すること、リンパ組織増殖にERK経路の異常活性化が関与することを見出した。本研究では、(1) APDSにおける免疫異常発症機序の解明、 (2) APDSの病態に応じた新規治療法の開発を目指す。

Outline of Final Research Achievements

APDS (Activated PI3K-Delta syndrome) is a primary immunodeficiency characterized by increased susceptibility to infection, enlarged lymphoid tissue, defective antibody production, and lymphopenia. APDS is considered to have a pathology based on the overexpression of PIP3 through overactivation of the PI3K signaling pathway and the constant phosphorylation of AKT/mTOR/S6 downstream of PIP3. We analyzed samples from APDS patients with PIK3CD or PIK3R1 mutations and APDS-L patients with PTEN mutations and revealed that AKT-FOXO1 signaling pathway is involved in immunodeficiency and that abnormal activation of ERK signaling pathway is involved in lymphoid tissue proliferation.

Academic Significance and Societal Importance of the Research Achievements

APDS患者は原発性免疫不全症患者の中でも大きな割合を占めることが明らかになってきたが、APDS, APDS-Lにおける免疫異常（免疫不全およびリンパ組織増殖）の発症機序は不明であり、いまだに適切な治療法は確立されていない。本研究により、AKT-FOXO1シグナル伝達経路が免疫不全に、リンパ組織増殖にERK経路の異常活性化が関与することが示された。これらの成果をもとに、詳細な疾患分類や新規治療薬の開発につなげていくことが今後の目標である。

Research Products

• [Journal Article] The Primary Immunodeficiency Database in Japan (2022)
  • Author(s): Mitsui-Sekinaka Kanako、Sekinaka Yujin、Endo Akifumi、Imai Kohsuke、Nonoyama Shigeaki
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 805766-805766
  • DOI: 10.3389/fimmu.2021.805766
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Courses of IKAROS and CTLA4 Deficiencies: A Systematic Literature Review and Retrospective Longitudinal Study (2022)
  • Author(s): Hoshino A, Toyofuku E, Mitsuiki N, Yamashita M, Okamoto K, Yamamoto M, Kanda K, Yamato G, Keino D, Yoshimoto-Suzuki Y, Kamizono J, Onoe Y, Ichimura T, Nagao M, Yoshimura M, Tsugawa K, Igarashi T, Mitsui-Sekinaka K, Sekinaka Y, Doi T, Yasumi T, Nakazawa Y, Takagi M, Imai K, Nonoyama S, Morio T, Latour S, Kanegane H.
  • Journal Title: Frontiers in Immunology Volume: 12 Pages: 784901-784901
  • DOI: 10.3389/fimmu.2021.784901
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical and Immunological Analyses of Ten Patients with MIRAGE Syndrome. (2021)
  • Author(s): Mitsui-Sekinaka K, Narumi S, Sekinaka Y, Uematsu K, Yoshida Y, Amano N, Shima H, Hasegawa T, Nonoyama S.
  • Journal Title: J Clin Immunol. Volume: 41 Issue: 3 Pages: 709-711
  • DOI: 10.1007/s10875-020-00964-7
  • Peer Reviewed / Open Access