Associated factors with cerebrospinal fluid cytokine levels in patients with neuropsychiatric systemic lupus erythematosus

• Project/Area Number: 16K09901
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Wakayama Medical University
• Principal Investigator: Takao Fujii 和歌山県立医科大学, 医学部, 教授 (70255462)
• Research Collaborator: Ishigooka Nozomi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); 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); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 全身性エリテマトーデス / 抗核抗体 / サイトカイン / 中枢神経症状 / 自己抗体 / 脳脊髄液 / IL-6 / ケモカイン / 血液脳関門 / 中枢神経障害

Outline of Final Research Achievements

Autoantibodies (autoAbs) and inflammatory mediators (IMs) in cerebrospinal fluid (CSF) may be involved in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). We examined combined effects of CSF anti-N-methyl D-aspartate receptor NR2 subunit (NR2) Ab and anti-U1RNP Ab on IMs in patients with NPSLE. CSF samples were collected from 69 patients with acute-phase NPSLE and 13 non-NPSLE controls. Levels of IL-6, IL-8, and monokine induced by IFN-γ (MIG) in CSF were measured by quantitative multiplex cytokine analysis. Elevated CSF IL-6 and IL-8 levels were mainly associated with anti-NR2 and U1RNP Ab positivity, respectively. CSF IL-6, IL-8 and MIG levels were higher in CSF anti-NR2 and anti-U1RNP Ab double positive group than in anti-NR2 Ab-positive alone group. Therefore, CSF anti-NR2 and anti-U1RNP Abs have combined effects on the elevation of CSF IL-6 and MIG levels in patients with NPSLE.

Academic Significance and Societal Importance of the Research Achievements

膠原病の代表的疾患である全身性エリテマトーデスではしばしば脳の炎症を引き起こし、生命予後に影響を与える。この病態（NPSLE）は極めて重症と考えられ、そりよい治療法の開発が望まれるが、世界的にもガイドラインが整備されているとは言いがたい。本研究で、NPSLE患者の症状と深く関連するとされる脳脊髄液（CSF）中の液性因子がいかなる自己抗体と関連するかを明確にした。専門施設においてCSFは比較的容易に採取できるため、その自己抗体の検査を行うことでいかなる液性因子をターゲットとして治療すればよいかについて示唆に富む結果が得られたため、近日中に論文発表する予定である。

Research Products

• [Journal Article] Anti-nuclear antibody development is associated with poor treatment response to biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis. (2019)
  • Author(s): Ishikawa Y, Hashimoto M, Ito H, Tanaka M, Yukawa N, Fujii T, Yamamoto W, Mimori T, Terao C.
  • Journal Title: Seminars in Arthritis and Rheumatism Volume: （印刷中） Issue: 2 Pages: 204-210
  • DOI: 10.1016/j.semarthrit.2019.02.003
  • Peer Reviewed
• [Journal Article] 膠原病における自己抗体の臨床的意義と病原性 (2019)
  • Author(s): 藤井 隆夫
  • Journal Title: 日本内科学会雑誌 Volume: 108 Pages: 493-497
• [Journal Article] Anti-centromere antibody exhibits specific distribution levels among anti-nuclear antibodies and may characterize a distinct subset in rheumatoid arthritis. (2017)
  • Author(s): Kuramoto N, Ohmura K, Ikari K, Yano K, Furu M, Yamakawa N, Hashimoto M, Ito H, Fujii T, Murakami K, Nakashima R, Imura Y, Yukawa N, Yoshifuji H, Taniguchi A, Momohara S, Yamanaka H, Matsuda F, Mimori T, Terao C
  • Journal Title: Sc Rep Volume: 7 Issue: 1 Pages: 6911-6911
  • DOI: 10.1038/s41598-017-07137-4
  • NAID: 120006368159
  • Peer Reviewed / Open Access
• [Journal Article] Anti-carbamylated Protein Antibodies Are Detectable in Various Connective Tissue Diseases. (2017)
  • Author(s): Nakabo S, Yoshifuji H, Hashimoto M, Imura Y, Nakashima R, Murakami K, Kuramoto N, Ito S, Satoh J, Tanaka M, Fujii T, Mimori T, Ohmura K
  • Journal Title: J Rheumatol Volume: 44 Pages: 1384-1388
  • Peer Reviewed
• [Journal Article] Carbamylated albumin is one of the target antigens of anti-carbamylated protein antibodies. (2017)
  • Author(s): Nakabo S, Hashimoto M, Ito S, Furu M, Ito H, Fujii T, Yoshifuji H, Imura Y, Nakashima R, Murakami K, Kuramoto N, Tanaka M, Satoh J, Ishigami A, Morita S, Mimori T, Ohmura K.
  • Journal Title: Rheumatology (Oxford) Volume: in press Issue: 7 Pages: 1217-1226
  • DOI: 10.1093/rheumatology/kex088
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cell-contact-dependent activation of CD4+ T cells by adhesion molecules on synovial fibroblasts (2017)
  • Author(s): Mori M, Hashimoto M, Matsuo T, Fujii T, Furu M, Ito H, Yoshitomi H, Hirose J, Ito Y, Akizuki S, Nakashima R, Imura Y, Yukawa N, Yoshifuji H, Ohmura K, Mimori T
  • Journal Title: Mod Rheumatol Volume: 27 Issue: 3 Pages: 448-456
  • DOI: 10.1080/14397595.2016.1220353
  • Peer Reviewed
• [Journal Article] Immunogenicity and lupus-like autoantibody production can be linked to each other along with type I interferon production in patients with rheumatoid arthritis treated with infliximab: A retrospective study of a single center cohort (2016)
  • Author(s): Yuki Ishikawa, Takao Fujii, Seiko Kondo Ishikawa, Naoichiro Yukawa, Motomu Hashimoto, Moritoshi Furu, Hiromu Ito, Koichiro Ohmura, and Tsuneyo Mimori
  • Journal Title: PLoS One Volume: 11 Issue: 9 Pages: e0162896-e0162896
  • DOI: 10.1371/journal.pone.0162896
  • NAID: 120005860037
  • Peer Reviewed / Open Access
• [Presentation] Indirect pathogenic roles of cerebrospinal fluid anti-U1RNP antibodies in the presence of anti-NR2 antibodies in patients with neuropsychiatric systemic lupus erythematosus. (2018)
  • Author(s): Fujii T, Kondo-Ishikawa S, Ishigooka N, Yoshifuji H, Ohmura K, Mimori T.
  • Organizer: The Annual European Congress of Rheumatology EULAR 2018
  • Int'l Joint Research
• [Presentation] 全身性エリテマトーデスの中枢神経症状と関連する自己抗体とその臨床的・病因的意義 (2017)
  • Author(s): 藤井 隆夫
  • Organizer: 第61回日本リウマチ学会総会
  • Invited
• [Presentation] 膠原病診療における自己抗体測定の臨床的意義と活用法 (2016)
  • Author(s): 藤井隆夫
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-04-21
  • Invited
• [Presentation] 精神神経ループスにおける脳脊髄液中の自己抗体とサイトカインとの相関 (2016)
  • Author(s): 近藤聖子、藤井隆夫、石郷岡望、橋本求、井村嘉孝、湯川尚一郎、吉藤元、大村浩一郎、三森経世
  • Organizer: 第113回日本内科学会総会・講演会
  • Place of Presentation: 東京
  • Year and Date: 2016-04-15
• [Book] 内科外来診断navi (2017)
  • Author(s): 藤井隆夫
  • Total Pages: 358
  • Publisher: 中外医学社