Investigation into the mechanism of the blood-nerve barrier disruption in chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy

• Project/Area Number: 24790886
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Yamaguchi University
• Principal Investigator: SHIMIZU Fumitaka 山口大学, 医学(系)研究科(研究院), 助教 (90535254)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 自己免疫性ニューロパチー / 血液神経関門 / 慢性炎症性脱髄性根ニューロパチー / 多巣性運動ニューロパチー / 自己免疫性末梢神経疾患 / 末梢神経障害 / 国際情報交換 / 多国籍

Outline of Final Research Achievements

<Purpose> The aim of this project was to elucidate the severity and mechanism of breakdown of the blood-nerve barrier (BNB) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). <Methods> We evaluated the effects of sera obtained from patients with typical CIDP/atypical CIDP/MMN and control subjects on the expression of claudin-5 and transendothelial electrical resistance (TEER) value in human peripheral nerve microvascular endothelial cells (PnMECs). <Result> Sera obtained from the patients with typical CIDP/atypical CIDP/MMN decreased the amount of claudin-5 protein levels and TEER values in PnMECs. The autocrine secretion of VEGF in PnMECs induced by MMN sera and immunoglobulin G purified from MMN sera decreased the expression of claudin-5. <Conclusion> Sera from CIDP/MMN patients disrupt the BNB function. In MMN, the autocrine secretion of VEGF in PnMECs and autoantibodies against PnMECs may be responsible for the BNB disruption.

Research Products

• [Journal Article] Markedly Increased IP-10 Production by Blood-Brain Barrier in Neuromyelitis Optica. (2015)
  • Author(s): Shimizu F, Nishihara H, Sano Y, Takeshita Y, Takahashi S, Maeda T, Takahashi T, Abe M, Koga M, Kanda T.
  • Journal Title: PLoS One Volume: 10 Issue: 3 Pages: e0122000-e0122000
  • DOI: 10.1371/journal.pone.0122000
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis. (2015)
  • Author(s): Nishihara H, Shimizu F, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Kanda T.
  • Journal Title: PLoS One Volume: 10 Issue: 3 Pages: e0121488-e0121488
  • DOI: 10.1371/journal.pone.0121488
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Severity and patterns of blood-nerve barrier breakdown in patients with chronic inflammatory demyelinating polyradiculoneuropathy: correlations with clinical subtypes. (2014)
  • Author(s): Shimizu F, Sawai S, Sano Y, Beppu M, Misawa S, Nishihara H, Koga M, Kuwabara S, Kanda T.
  • Journal Title: PLOS One Volume: 9 Issue: 8 Pages: e104205-e104205
  • DOI: 10.1371/journal.pone.0104205
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier. (2014)
  • Author(s): Shimizu F, Tasaki A, Sano Y, Ju M, Nishihara H, Oishi M, Koga M, Kawai M, Kanda T.
  • Journal Title: PLOS One Volume: 9 Issue: 3 Pages: e92872-e92872
  • DOI: 10.1371/journal.pone.0092872
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Breakdown of the blood-brain barrier in neuromyelitis optica: Roles of matrix-metalloproteinases-2/9, vascular endothelial growth factor and autoantibodies against the blood-brain barrier. (2014)
  • Author(s): Shimizu F, Tasaki A, Kanda T.
  • Journal Title: Clinical and Experimental Neuroimmunology Volume: 5 Pages: 2-3
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Autocrine MMP-2/9 secretion increases the BBB permeability in neuromyelitis optica. (2014)
  • Author(s): Tasaki A, Shimizu F, Sano Y, Fujisawa M, Takahashi T, Haruki H, Abe M, Koga M, Kanda T.
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 85 Issue: 4 Pages: 419-430
  • DOI: 10.1136/jnnp-2013-305907
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 血液神経関門と自己免疫性ニューロパチー (2014)
  • Author(s): 清水文崇，神田 隆
  • Journal Title: Peripheral Nerve Volume: 24 Pages: 54-62
  • Peer Reviewed
• [Journal Article] Sera from patients with multifocal motor neuropathy disrupt the blood-nerve barrier. (2013)
  • Author(s): Shimizu F, Omoto M, Sano Y, Mastui N, Miyashiro A, Tasaki A, Maeda T, Koga M, Kaji R, Kanda T.
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 7 Issue: 5 Pages: 526-537
  • DOI: 10.1136/jnnp-2013-305405
  • Peer Reviewed
• [Journal Article] Advanced glycation end-products disrupt the blood-brain barrier by stimulating the release of transforming growth factor-β by pericytes and vascular endothelial growth factor and matrix metalloproteinase-2 by endothelial cells in vitro. (2013)
  • Author(s): Fumitaka Shimizu
  • Journal Title: Neurobiol Aging Volume: 34 Issue: 7 Pages: 1902-1912
  • DOI: 10.1016/j.neurobiolaging.2013.01.012
  • Peer Reviewed
• [Journal Article] Blood-brain barrier destruction determines Fischer/Bickerstaff clinical phenotypes: an in vitro study (2013)
  • Author(s): Kazuyuki Saito, Fumitaka Shimizu, Michiaki Koga, Yasuteru Sano, Ayako Tasaki, Masa-aki Abe, Hiroyo Haruki, Toshihiko Maeda, S. Suzuki, Susumu Kusunoki, Hidehiro Mizusawa, Takashi Kanda.
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 84 Issue: 7 Pages: 756-765
  • DOI: 10.1136/jnnp-2012-304306
  • Peer Reviewed
• [Journal Article] 血液脳関門と神経免疫疾患 (2013)
  • Author(s): 清水文崇，神田 隆
  • Journal Title: Brain and Nerve Volume: 65 Pages: 165-176
• [Journal Article] Sera from neuromyelitis optica patients disrupt the blood-brain barrier (2012)
  • Author(s): Shimizu F, Sano Y, Takahashi T, Haruki H, Saito K, Koga M, Kanda T
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 83 Issue: 3 Pages: 288-297
  • DOI: 10.1136/jnnp-2011-300434
  • Peer Reviewed
• [Journal Article] Pericyte-derived glial cell line-derived neurotrophic factor increase the expression of claudin-5 in the blood-brain barrier and the blood-nerve barrier (2012)
  • Author(s): Shimizu F, Sano Y, Saito K, Abe MA, Maeda T, Haruki H, Kanda T
  • Journal Title: Neurochem Res Volume: 37 Issue: 2 Pages: 401-409
  • DOI: 10.1007/s11064-011-0626-8
  • Peer Reviewed
• [Presentation] 傍腫瘍性小脳変性症を合併したLambert-Eaton筋無力症候群では血液脳関門が破綻する． (2014)
  • Author(s): 清水文崇, 本村政勝, 中田るか，白石 裕一，佐野泰照, 神田 隆．
  • Organizer: 第55回日本神経学会学術集会総会
  • Place of Presentation: 福岡国際会議場（福岡県・福岡市）
  • Year and Date: 2014-05-23 – 2014-05-24
• [Presentation] 多発性硬化症患者血清が血液脳関門に及ぼす影響の解析 (2013)
  • Author(s): 清水文崇，田崎彩子，佐野泰照，朱 美和，前田敏彦，大石真莉子，古賀道明，神田 隆.
  • Organizer: 第54回日本神経学会学術集会総会
  • Place of Presentation: 東京(東京国際フォーラム)
• [Presentation] 血液神経関門の破綻が慢性炎症性脱髄性多発根ニューロパチーの臨床病型を決定する. (2013)
  • Author(s): 清水文崇，澤井 摂，佐野泰照，別府美奈子，三澤園子，前田敏彦，古賀道明，桑原 聡，神田 隆.
  • Organizer: 第24回日本末梢神経学会学術集会．
  • Place of Presentation: 新潟（朱鷺メッセ）
• [Presentation] 血液神経関門の破綻が慢性炎症性脱髄性多発根ニューロパチーの臨床病型を決定する. (2013)
  • Author(s): 清水文崇，澤井 摂，佐野泰照，別府美奈子，三澤園子，前田敏彦，古賀道明，桑原 聡，神田 隆
  • Organizer: 第25回日本神経免疫学会学術集会．
  • Place of Presentation: 下関（海峡メッセ）
• [Presentation] 傍腫瘍性小脳変性症を合併したLambert-Eaton筋無力症候群では血液脳関門が破綻する. (2013)
  • Author(s): 清水文崇，本村政勝，中田るか，白石 裕一，佐野泰照，神田 隆
  • Organizer: 第25回日本神経免疫学会学術集会
  • Place of Presentation: 下関（海峡メッセ）
• [Presentation] The effect of sera from multifocal motor neuropathy on blood-nerve barrier. (2013)
  • Author(s): Fumitaka Shimizu, Yasuteru Sano, Naoko Mastui, Ai Miyashiro, Ryuji Kaji, Takashi Kanda.
  • Organizer: Neuroscience
  • Place of Presentation: San Diego, U.S.A
• [Presentation] Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier. (2013)
  • Author(s): Fumitaka Shimizu, Ayako Tasaki, Yasuteru Sano, Takashi Kanda.
  • Organizer: PACTRIMS
  • Place of Presentation: Kyot (ウェスティンホテル京都）,
• [Presentation] 多巣性運動ニューロパチー血清は血液神経関門を破綻させる． (2012)
  • Author(s): 清水文崇，佐野泰照，斎藤和幸，安部真彰，前田敏彦，春木明代，松井尚子，宮城 愛，梶 龍兒, 神田 隆.
  • Organizer: 第53回日本神経学会学術集会総会．
  • Place of Presentation: 東京国際フォーラム(東京)
• [Presentation] 多巣性運動ニューロパチー血清による血液神経関門破綻メカニズムの解析． (2012)
  • Author(s): 清水文崇，佐野泰照，古賀道明，田崎彩子，安部真彰，前田敏彦，春木明代，松井尚子，宮城 愛，梶 龍兒，神田 隆.
  • Organizer: 第23回日本末梢神経学会学術集会．
  • Place of Presentation: 九州大学医学部百年講堂（福岡）
• [Presentation] 多巣性運動ニューロパチー血清による血液神経関門破綻メカニズムの解析． (2012)
  • Author(s): 清水文崇，佐野泰照，古賀道明，田崎彩子，安部真彰，前田敏彦，春木明代，松井尚子，宮城 愛，梶 龍兒，神田 隆.
  • Organizer: 第24回日本神経免疫学会学術集会．
  • Place of Presentation: 軽井沢プリンスホテルウエスト（長野）
• [Presentation] The effect of advanced glycation end-products on blood-brain barrier. (2012)
  • Author(s): Fumitaka Shimizu, Yasuteru Sano, Hiroyo Haruki, and Takashi Kanda.
  • Organizer: Neuroscience 13 Oct 2012.
  • Place of Presentation: New Orleans (USA)
• [Book] 日本臨床 多発性硬化症と視神経脊髄炎- 血液神経関門とその障害モデル- (2014)
  • Author(s): 清水文崇，神田 隆．
  • Publisher: 日本臨床社
• [Book] The Blood-Brain Barrier in Neuroinflammation. In Suzumura A, Ikenaka K, editors. Neuron-Glia Interaction in Neuroinflammation. (2013)
  • Author(s): Shimizu F, Kanda T
  • Total Pages: 22
  • Publisher: New York, NY: Springer Science+Business Media New York.