Genetic basis and molecular mechanism of anti-NMDAR encephalitis in early infant.

• Project/Area Number: 18K15716
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Hiroshima University
• Principal Investigator: Kobayashi Yoshiyuki 広島大学, 病院(医), 助教 (20723290)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 抗NMDAR脳炎 / 若年発症 / IRAK4欠損症 / NMDA受容体脳炎 / 自己免疫 / 免疫不全 / IRAK4

Outline of Final Research Achievements

IRAK4 deficiency is an immunodeficiency syndrome caused by impairment of innate immunity, and early diagnosis is extremely important to prevent severe and fetal outcomes. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, on the other hand, is an autoimmune encephalitis characterized by central hypoventilation and involuntary movements. Since infantile-onset anti-NMDAR encephalitis is very rare, we performed whole exome analysis and identified novel heterozygous mutations in IRAK4 (Y10Cfs*9, R12P). We performed functional analysis of both mutations and established a novel evaluation system to properly assess IRAK4 mutations. In this study, we also suggest the possible link between inborn errors of immunity and early onset anti-NMDAR encephalitis.

Academic Significance and Societal Importance of the Research Achievements

抗NMDAR脳炎を発症したIRAK4欠損症の症例を世界で初めて同定し、稀少疾患に着目したという点で、独自性が高い。また、IRAK4欠損HEK293T細胞を用いることでIRAK4遺伝子変異の病的意義を簡便かつ正確に評価できる新規のNF-kBレポーターアッセイを確立した部分で学術的意義や社会的意義は高い。同時に乳児期発症の抗NMDAR脳炎が先天的な免疫異常に基づいて発症する可能性を示唆した部分でも学術的意義は高いと考える。

Research Products

• [Journal Article] IRAK4 Deficiency Presenting with Anti-NMDAR Encephalitis and HHV6 Reactivation (2020)
  • Author(s): Nishimura Shiho、Kobayashi Yoshiyuki、Ohnishi Hidenori、Moriya Kunihiko、Tsumura Miyuki、Sakata Sonoko、Mizoguchi Yoko、Takada Hidetoshi、Kato Zenichiro、Sancho-Shimizu Vanessa、Picard Capucine、Irani Sarosh R.、Ohara Osamu、Casanova Jean-Laurent、Puel Anne、Ishikawa Nobutsune、Okada Satoshi、Kobayashi Masao
  • Journal Title: Journal of Clinical Immunology Volume: 41 Issue: 1 Pages: 125-135
  • DOI: 10.1007/s10875-020-00885-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] IRAK4遺伝子異常が認められた抗NMDAR脳炎の乳児例 (2018)
  • Author(s): 小林良行
  • Organizer: 第60回日本小児神経学会総会