Analysis of the autoimmune phenomena that are controlled by Shp-1 in dendritic cells

• Project/Area Number: 16K09887
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Gunma University
• Principal Investigator: KANEKO YORIAKI 群馬大学, 医学部附属病院, 講師 (00334095)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 自己免疫疾患 / シェーグレン症候群 / 樹状細胞 / Shp-1 / 自己免疫性唾液腺炎 / マクロファージ / 実験腎炎 / 自己免疫

Outline of Final Research Achievements

We generated a conditional knockout mouse (Shp-1 CKO) to analyze a cytoplasmic tyrosine phosphatase Shp-1. This knockout strain specifically lacks Shp-1 in dendritic cells (DCs). Aged Shp-1 CKO secreted less salivary fluid than control mice in response to pilocarpine stimulation. Histological analysis revealed periductal foci increased in the salivary glands of Shp-1 CKO. The numbers of the cells infiltrating into the glands of Shp-1 CKO were measured by flow cytometry, and we found T and B cells increased markedly in the glands.

Academic Significance and Societal Importance of the Research Achievements

Shp-1 CKOは加齢に伴いIgGやC3の沈着を伴う自己免疫性の腎炎を発症し、Th1タイプの免疫応答が強いことは、すでに報告している。そして、本研究課題を通じて、老齢となったShp-1 CKOが、外分泌腺を標的とする自己免疫性の臓器障害を呈することも明らかとなった。ヒトのシェーグレン症候群(SjS)は、唾液や涙液の分泌低下など外分泌腺障害を呈する自己免疫性疾患であり、腺外症状としての自己免疫性腎炎も主要な症候である。従って、Shp-1 CKOはSjSの有用な動物モデルの１つとなる可能性が考えられた。

Research Products

• [Journal Article] SIRPα+dendritic cells regulate homeostasis of fibroblastic reticular cells via TNF receptor ligands in the adult spleen (2017)
  • Author(s): Saito Yasuyuki、Respatika Datu、Komori Satomi、Washio Ken、Nishimura Taichi、Kotani Takenori、Murata Yoji、Okazawa Hideki、Ohnishi Hiroshi、Kaneko Yoriaki、Yui Katsuyuki、Yasutomo Koji、Nishigori Chikako、Nojima Yoshihisa、Matozaki Takashi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 114 Issue: 47
  • DOI: 10.1073/pnas.1711345114
  • Peer Reviewed / Int'l Joint Research
• [Presentation] CD11c-specific ablation of the protein tyrosine phosphatase Shp-1 induces autoimmune sialadenitis: Is it a new model mouse for Sjoegren's syndrome? (2018)
  • Author(s): Kinoshita Masato, Kaneko Yoriaki, Watanabe Mitsuharu, Ohishi Yuko, Shrestha Shreya, Suwa Junya, Saito Yasuyuki, Ohnishi Hiroshi, Nojima Yoshihisa, Matozaki Takashi, and Hiromura Keiju
  • Organizer: The 47th Annual Meeting of The Japanese Society for Immunology
• [Presentation] CD11c-Specific Ablation of SHP-1 Results in Renal Fibrosis with Age (2018)
  • Author(s): Watanabe Mitsuharu, Kaneko Yoriaki, Kinoshita Masato, Ohishi Yuko, Sakairi Toru, Ikeuchi Hidekazu, Nojima Yoshihisa, and Hiromura Keiju
  • Organizer: Kidney Week 2018
  • Int'l Joint Research
• [Presentation] 樹状細胞特異的にShp-1を欠損する遺伝子改変マウスにおける自己免疫性唾液腺炎の解析 (2018)
  • Author(s): 木下雅人, 金子和光, 渡辺光治, 大石裕子, 諏訪絢也, 中里見征央, 坂入徹, 池内秀和, 前嶋明人, 野島美久, 廣村桂樹
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] Dendritic cell-specific ablation of the protein tyrosine phosphatase Shp-1 induces autoimmune sialadenitis characterized by infiltration of CD4+ T cells and B cells (2017)
  • Author(s): KINOSHITA Masato, KANEKO Yoriaki, WATANABE Mitsuharu,OHISHI Yuko, SAITO Yasuyuki, OHNISHI Hiroshi, NOJIMA Yoshihisa, MATOZAKI Takashi, HIROMURA Keiju
  • Organizer: The 46th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Accumulation of dysregulated renal mononuclear phagocytes (rMoPh) and Th1 cells in the kidney of CD11c-specific Shp-1 knockout mice (2016)
  • Author(s): WATANABE Mitsuharu, KANEKO Yoriaki, HIROMURA Keiju, KINOSHITA Masato, OHISHI Yuko, SAITO Yasuyuki, OHNISHI Hiroshi, MATOZAKI Takashi, NOJIMA Yoshihisa
  • Organizer: The 45th Annual Meeting of The Japanese Society for Immunology
  • Place of Presentation: OKINAWA
  • Year and Date: 2016-12-07
• [Presentation] Shp-1 in dendritic cells controls the development of memory-phenotype CD8+ T cells (2016)
  • Author(s): OHISHI Yuko, KANEKO Yoriaki, WATANABE Mitsuharu, KINOSHITA Masato, HIROMURA Keiju, SAITO Yasuyuki, OHNISHI Hiroshi, MATOZAKI Takashi, NOJIMA Yoshihisa
  • Organizer: The 45th Annual Meeting of The Japanese Society for Immunology
  • Place of Presentation: OKINAWA
  • Year and Date: 2016-12-05