Novel therapeutic target molecules in Sjogren's syndrome: NR4A2 and DPP4

• Project/Area Number: 16K20934
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Collagenous pathology/Allergology; Pathobiological dentistry/Dental radiology
• Research Institution: University of Tsukuba
• Principal Investigator: Takahashi Hiroyuki 筑波大学, 附属病院, 病院講師 (10770745)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: シェーグレン症候群 / Th17細胞 / T細胞 / 内科 / 免疫学 / 遺伝子 / 歯学

Outline of Final Research Achievements

To clarify a role of NR4A2 and DPP4 in the pathogenesis of Sjogren’s syndrome (SS), 1) I examined mRNA expression of NR4A2 and DPP4 in labial salivary glands (LSGs) of SS, IgG4-related disease (IgG4-RD) and healthy controls (HC) by qPCR and the protein expression in the LSGs by immunofluorescence staining (IF), and 2) performed functional analysis of the gene using peripheral CD4+ T cells of SS patients. 1) NR4A2 was significantly higher in LSGs of SS than controls, while DPP4 was not. IF revealed higher NR4A2 in CD4+ T cells and IL-17-producing cells in LSGs of SS compared with IgG4-RD. 2) Peripheral CD4+ T cells showed significantly increased NR4A2 mRNA and Th17 polarization in SS compared with HC. Nuclear NR4A2 in Th17-polarized CD4+ T cells was significantly higher in SS than in HC. Importazole, inhibiting nuclear NR4A2, suppressed Th17 polarization and IL-21 mRNA in CD4+ T cells under Th17-polarizing conditions. Thus, NR4A2 could contribute to enhanced Th17 polarization in SS.

Research Products

• [Journal Article] cDNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjogren's syndrome (2017)
  • Author(s): Takahashi H, Tsuboi H, Asashima H, Hirota T, Kondo Y, Moriyama M, Matsumoto, Nakamura S, Sumida T.
  • Journal Title: Clinical & Experimental Immunology Volume: 190 Issue: 1 Pages: 96-109
  • DOI: 10.1111/cei.13000
  • Peer Reviewed / Open Access
• [Presentation] A potential role of NR4A2 overexpression in CD4+ T cells in the pathogenesis of Sjogren’s syndrome. (2018)
  • Author(s): Takahashi H, Tsuboi H, Asashima H, Kudo H, Ono Y, Abe S, Kondo Y, Matsumoto I, Sumida T
  • Organizer: The 14th International Symposium on Sjogren’s syndrome (Washington DC, USA), 2018
  • Int'l Joint Research
• [Presentation] シェーグレン症候群患者のCD4陽性T細胞におけるNR4A2発現亢進とTh17分化 (2018)
  • Author(s): 高橋広行、坪井洋人、浅島弘充、近藤裕也、松本功、住田孝之
  • Organizer: 第62回日本リウマチ学会総会・学術集会
• [Presentation] DNA microarray analysis of labial salivary glands in patients with Sjogren's syndrome: comparison with IgG4-related disease (2017)
  • Author(s): Hiroyuki Takahashi, Hiroto Tsuboi, Hiromitsu Asashima, Tomoya Hirota, Yuya Kondo, Isao Matsumoto and Takayuki Sumida
  • Organizer: 第61回日本リウマチ学会総会・学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2017-04-20
• [Presentation] DNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjogren’s syndrome. (2017)
  • Author(s): Takahashi H, Tsuboi H, Asashima H, Hirota T, Kondo Y, Matsumoto I, Sumida T
  • Organizer: The 7th East Asian Group of Rheumatology (Tokyo), 2017
  • Int'l Joint Research
• [Presentation] シェーグレン症候群患者のCD4陽性T細胞におけるNR4A2発現亢進とTh17分化 (2017)
  • Author(s): 高橋広行、坪井洋人、浅島弘充、近藤裕也、森山雅文、松本功、中村誠司、住田孝之
  • Organizer: 第26回日本シェーグレン症候群学会学術集会
• [Presentation] DNAマイクロアレイによるシェーグレン症候群の唾液腺における遺伝子発現解析 (2017)
  • Author(s): 高橋広行、坪井洋人、浅島弘充、近藤裕也、松本功、住田孝之
  • Organizer: 第45回日本臨床免疫学会総会
• [Presentation] DNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjogren’s syndrome. (2017)
  • Author(s): Takahashi H, Tsuboi H, Asashima H, Kudo H, Ono Y, Abe S, Kondo Y, Matsumoto I, Sumida T
  • Organizer: 2017 American College of Rheumatology, Annual Meeting (San Diego, USA)
  • Int'l Joint Research
• [Presentation] DNA microarray analysis of labial salivary glands in patients with Sjogren’s syndrome: comparison with IgG4-related disease (2016)
  • Author(s): Hiroyuki Takahashi, Hiroto Tsuboi, Hiromitsu Asashima, Tomoya Hirota, Yuya Kondo, Isao Matsumoto and Takayuki Sumida
  • 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（沖縄県宜野湾市）
  • Year and Date: 2016-12-06
• [Presentation] DNAマイクロアレイによるシェーグレン症候群の唾液腺における遺伝子発現解析 (2016)
  • Author(s): 高橋広行、坪井洋人、中井雄治、浅島弘充、廣田智哉、近藤裕也、古川祥子、森山雅文、松本功、吉原俊雄、中村誠司、阿部啓子、住田孝之
  • Organizer: 第25回日本シェーグレン症候群学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2016-09-09
• [Book] 分子リウマチ (2017)
  • Author(s): 高橋広行、坪井洋人、住田孝之
  • Total Pages: 58
  • Publisher: 先端医学社
  • ISBN: 9784865502787