The role of exosome-derived from human T-cell leukemia virus type 1 (HTLV-1) infected cells in the pathogenesis of HTLV-1-positive rheumatoid arthritis.

• Project/Area Number: 17K09979
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: University of Miyazaki
• Principal Investigator: Umekita Kunihiko 宮崎大学, 医学部, 准教授 (20506084)
• Co-Investigator(Kenkyū-buntansha): 岡山 昭彦 宮崎大学, 医学部, 教授 (70204047)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: エクソソーム / ヒトT細胞白血病ウイルス / 関節リウマチ / ヒトT細胞白血病ウイルス（HTLV-1) / パターン認識受容体 / ヒトT細胞性白血病ウイルス（HTLV-1） / リウマチ学

Outline of Final Research Achievements

The aim of this study is to investigate the role of exosomes-derived from HTLV-1 infected cells in the inflammatory responses of rheumatoid arthritis synovial fibroblasts (RASFs). The expression of cytokines mRNA in RASFs was increased by exosomes and inflammatory cytokines such as IFNγ and TNFα. The silencing of both RIG-I and its cooperative binding protein using siRNA decreased the expression of cytokines mRNA in RASFs which were stimulated by exosomes and IFNγ. These results suggested that exosomes-derived from HTLV-1 infected cells may act as inflammatory mediator against RASFs. Both RIG-I and its cooperative binding protein may play important role in the exosome-induced signal pathway in RASFs.

Academic Significance and Societal Importance of the Research Achievements

HTLV-1陽性関節リウマチは炎症反応が高く，TNF阻害療法など既存の抗リウマチ治療に治療抵抗性を示すことが報告されている．その詳細な炎症病態は不明な点が多い．本研究では，HTLV-1感染細胞由来エクソソームが炎症性メディエータとして関節リウマチ滑膜細胞を刺激し，炎症性サイトカインの産生を促進することが明らかとなった．更に，そのメカニズムにおいてRASF細胞質に存在するパターン認識受容体RIG-1とその補助分子が重要であることが示された．HTLV-1陽性関節リウマチの炎症病態の制御に，これら分子を標的とした新規治療について今後の研究が期待される．

Research Products

• [Presentation] HTLV-1 infection and rheumatic diseases. (2019)
  • Author(s): 梅北邦彦
  • Organizer: HTLV PERU 2019
  • Int'l Joint Research / Invited
• [Presentation] HTLV-1 感染とリウマチ性疾患. (2019)
  • Author(s): 梅北邦彦
  • Organizer: 第6回日本HTLV-1学会学術集会
  • Invited
• [Presentation] HTLV-1感染とリウマチ性疾患. (2019)
  • Author(s): 梅北邦彦
  • Organizer: 第64回日本臨床検査医学会九州地方会 第30回日本臨床化学会九州支部総会.
  • Invited
• [Presentation] HUMAN T CELL LEUKEMIA VIRUS TYPE 1 (HTLV-1) EXACERBATES RHEUMATOID ARTHRITIS; EXOSOMES AND IFN-GAMMA DERIVED FROM HTLV-1 INFECTED CELLS ENHANCE THE INFLAMMATORY RESPONSE OF RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS VIA PATTERN RECOGNITION RECEPTOR, RIG-I. (2017)
  • Author(s): 1.Umekita K, Miyauchi S, Kubo K, Kawano A, Iwao K, Komura M, Matsuda M, Takajo I, Nomura H, Nagatomo Y, Okayama A.
  • Organizer: EULAR 2017.
  • Int'l Joint Research
• [Presentation] Exosomes Derived from T Lymphocytes Enhance Expression of CXCL10 Induced by IFN-γ in Rheumatoid Arthritis Synovial Fibroblasts Via Pattern Recognition Receptor, RIG-I. (2017)
  • Author(s): Umekita K, Miyauchi S, Iwao K, Rikitake M, Rikitake Y, Kawada C, Aizawa A, Kariya Y, Matsuda M, Kawaguchi T, Nomura H, Takajo I, Okayama A.
  • Organizer: 2017 ACR/ARHP ANNUAL MEETING.
  • Int'l Joint Research