Identification and establishment of novel autoantibody in myelitis

• Project/Area Number: 17K09779
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Osaka University
• Principal Investigator: Okuno Tatsusada 大阪大学, 医学系研究科, 助教 (00464248)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 慢性脊髄炎 / 視神経脊髄炎 / アクアポリン４抗体 / 自己抗体 / モノクローナル抗体 / 標的抗原 / 脊髄炎

Outline of Final Research Achievements

We established anti-AQP4 recombinant autoantibodies (Ab) from plasmablasts in NMOSD patient’s CSF. Human astrocytes treated with anti-AQP4 Ab produced a significant amount of CCL2 and contributed to the efficient recruitment of monocytes. Moreover, mitochondrial DNA (mtDNA)was released from astrocytes treated with anti-AQP4 Ab. MtDNA further enhanced CCL2 production by monocytes, and it was demonstrated that mtDNA concentration correlated with the efficiency of monocyte recruitment in the CSF of NMOSD patients. These observations highlight that mtDNA which was released from astrocytes damaged by anti-AQP4 Ab has a central role in establishing the inflammatory loop of monocyte recruitment and activation via an innate immunity pathway.
Regarding myelitis　with unknown etiology, we tried to search for antigens We are currently selecting candidate antigens by establishing a cell base and assay.

Academic Significance and Societal Importance of the Research Achievements

アクアポリン４抗体はこれまで免疫吸着カラムから精製して使用していたが、量が限られていた。本研究では国内で初めてリコンビナントアクアポリン４抗体作成に成功しており今後安定的な動物モデル作成が可能になる。またNMOの疼痛は非常に強く、就業や家庭生活の妨げとなり、大きな社会的損失を来しているが、その治療法に結び付くと考えられる。

Research Products

• [Journal Article] Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese (2019)
  • Author(s): Ogawa, Kotaro; Okuno, Tatsusada; Hosomichi, Kazuyoshi; Hosokawa, Akiko; Hirata, Jun; Suzuki, Ken; Sakaue, Saori; Kinoshita, Makoto; Asano, Yoshihiro; Miyamoto, Katsuichi
  • Journal Title: Journal of neuroinflammation Volume: 16 Issue: 1 Pages: 162-162
  • DOI: 10.1186/s12974-019-1551-z
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of RGMa alleviates symptoms in a rat model of neuromyelitis optica. (2018)
  • Author(s): Harada K, Fujita Y, Okuno T, Tanabe S, Koyama Y, Mochizuki H, Yamashita T
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 34-34
  • DOI: 10.1038/s41598-017-18362-2
  • Peer Reviewed / Open Access
• [Journal Article] Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2-dependent manner. (2017)
  • Author(s): Honorat JA, Nakatsuji Y, Shimizu M, Kinoshita M, Sumi-Akamaru H, Sasaki T, Takata K, Koda T, Namba A, Yamashita K, Sanda E, Sakaguchi M, Kumanogoh A, Shirakura T, Tamura M, Sakoda S, Mochizuki H, Okuno T
  • Journal Title: PLoS One Volume: 12
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Identification of innate immunity activation in the pathogenesis of NMO (2019)
  • Author(s): M Shimizu, Makoto Kinoshita, Y Nakatsuji, T Koda, H Mochizuki
  • Organizer: Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
  • Int'l Joint Research
• [Presentation] 患者由来レコンビナントAQP4モノクローナル抗体を用いたNMOの病態解析 (2018)
  • Author(s): 清水幹人、奥野龍禎 木下允、甲田亨、南波明子、山下和哉、石倉照之、中辻祐司、、望月秀樹
  • Organizer: 第30回日本神経免疫学会学術大会
• [Presentation] Cerebrospinal fluid mitochondrial DNA elicits innate immune response in NMOSD (2018)
  • Author(s): Yamashita K, Kinoshita M, Miyamoto K, Namba A, Shimizu M, Koda T, Nakatsuji Y, Kumanogoh A, Kusunoki S, Mochizuki H, Okuno T
  • Organizer: ECTRIMS
  • Int'l Joint Research