アレルギー性接触皮膚炎感作に必要な非感染性自然免疫活性化経路

• Project Area: Homeostatic inflammation: Molecular basis and dysregulation
• Project/Area Number: 24117714
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Saga University
• Principal Investigator: 原 博満 佐賀大学, 医学部, 准教授 (20392079)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000); Fiscal Year 2013: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2012: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: CARD9 / アレルギー / 接触皮膚炎 / 樹状細胞 / ITAM / 自然免疫 / シグナリング / 接触性皮膚炎 / Syk

Research Abstract

リコンビナントITAMR-Ig蛋白のライブラ リーを作製し、これを用いて、contact sensitizerであるTNCB、DNCB、フィTC、oxazoloneに結合活性を有する受容体を探索した。その結果、これらのうち複数のcontact sensitizerに結合活性を示しDAP12と会合するITAMRを２つ見いだした（それぞれCSR-A、CSR-Bとする）。
次に、 ITAMシグナルにより活性化するNFATプロモーターの制御下にGFPリポーター遺伝子を発現するT細胞株(43-1）に、CSR-AおよびCSR-Bと、これらの得られた候補受容体とDAP12を共発現させた細胞を作製し、プレートコートしたcontact sensitizeで刺激して、候補受容体の活性化能を検証した。その結果、CSR-AはDNFBを除くcontact sensitizerにより活性化され、一方、CSR-BはTNCBとoxazoloneにより活性化され、NFATの活性化およびサイトカイン（IL-2）産生を誘導することが判った。

Current Status of Research Progress

Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] An ITAM-Syk-CARD9 signaling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells. (2014)
  • Author(s): S Yasukawa, Y Miyazaki, C Yoshii, M Nakaya, N Ozaki, S Toda, E Kuroda, K-I Ishibashi, T Yasuda, Y Natsuaki, F Mi-ichi, E Iizasa, T Nakahara, M Yamazaki, K Kabashima, Y Iwakura, Ti Takai, T Saito, T Kurosaki, B Malissen, N Ohno, M Furue, H Yoshida, and H Hara
  • Journal Title: Nature Communications Volume: 5
  • Peer Reviewed
• [Journal Article] 接触アレルゲンによる自然免疫活性化機構 (2013)
  • Author(s): 原博満、安川晋輔
  • Journal Title: 感染・炎症・免疫 Volume: 43 Pages: 285-295
• [Presentation] Analysis for the role of Syk-CARD9-regulated IL-1 secretion pathway in DCs in contact hypersensitivity by the mixed-chimera diphtheria toxin receptor (DTR)-mediated conditional cell knockout (MixC-Treck) method, a novel method for conditional gene targeting in mice. (2013)
  • Author(s): H. Hara, S. Yasukawa, Y. Natsuaki, K. Kabashima, M. Furue and H. Yoshida
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張
• [Presentation] Essential role of ITAM-Syk-IL-1 axis in skin dendritic cells for the sensitization of allergic contact dermatitis. (2013)
  • Author(s): H. Hara, S. Yasukawa, M. Furue and H. Yoshida:
  • Organizer: International Congress of Immunology
  • Place of Presentation: Milano, Italy
• [Presentation] IL-1 released by skn dendritic cells activated through Syk and CARD9 pathway is essential for the sensitization of allergic contact dermatitis. (2013)
  • Author(s): Hiromitsu Hara, Shinsuke Yasukawa, Masutaka Furue, Hiroki Yoshida
  • Organizer: IMMUNOLOGY 2013 AAI Annual Meeting
  • Place of Presentation: Honolulu, Hawaii
• [Presentation] Innate immune activation through ITAM- Syk-CARD9 signaling coupling to NLRP3 inflammasome is essential for the development of allergy to contact sensitizers. (2012)
  • Author(s): 安川晋輔
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2012-12-05
• [Presentation] Contact allergy to chemical sensitizers requires innate immune activation by coupling of the ITAM-Syk-CARD9 pathway and NLRP3 inflammasome. (2012)
  • Author(s): 原博満
  • Organizer: IEIIS2012, Homeostatic inflammation symposium
  • Place of Presentation: 学術総合センター（東京）
  • Year and Date: 2012-10-23
• [Presentation] INNATE IMMUNE ACTIVATION THROUGH ITAM-SYK-CARD9 SIGNALING COUPLING TO INFLAMMASOME IS ESSENTIAL FOR THE DEVELOPMENT OF CONTACT ALLERGY TO ORGANIC CHEMICAL ALLERGENS. (2012)
  • Author(s): 原博満
  • Organizer: 10th Joint meeting of International Cytokine Society and International Society of Interferon and Cytokine Research
  • Place of Presentation: Geneve, Switzerland
  • Year and Date: 2012-09-11
• [Presentation] Role of Card9-mediated signaling in contact hypersensitivity (2012)
  • Author(s): 安川晋輔
  • Organizer: 2nd Eastern Asia Dermatology Congress
  • Place of Presentation: Beijing, China
  • Year and Date: 2012-06-13