Disturbed function of the blood–cerebrospinal fluid barrier aggravates neuro-inflammation

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• 作者：Gijs Kooij (1)
  Kathrin Kopplin (2)
  Rosel Blasig (3)
  Marchel Stuiver (2)
  Nathalie Koning (1)
  Gera Goverse (1)
  Susanne M. A. van der Pol (1)
  Bert van het Hof (1)
  Maik Gollasch (4) (5)
  Joost A. R. Drexhage (1)
  Arie Reijerkerk (1)
  Iwan C. Meij (4)
  Reina Mebius (1)
  Thomas E. Willnow (4)
  Dominik Müller (2)
  Ingolf E. Blasig (3)
  Helga E. de Vries (1)
  
• 关键词：Multiple sclerosis ; Choroid plexus ; Claudin ; 3 ; Neuro ; inflammation ; Blood–cerebrospinal fluid barrier
• 刊名：Acta Neuropathologica
• 出版年：2014
• 出版时间：August 2014
• 年：2014
• 卷：128
• 期：2
• 页码：267-277
• 全文大小：4,226 KB
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• 作者单位：Gijs Kooij (1)
  Kathrin Kopplin (2)
  Rosel Blasig (3)
  Marchel Stuiver (2)
  Nathalie Koning (1)
  Gera Goverse (1)
  Susanne M. A. van der Pol (1)
  Bert van het Hof (1)
  Maik Gollasch (4) (5)
  Joost A. R. Drexhage (1)
  Arie Reijerkerk (1)
  Iwan C. Meij (4)
  Reina Mebius (1)
  Thomas E. Willnow (4)
  Dominik Müller (2)
  Ingolf E. Blasig (3)
  Helga E. de Vries (1)
  
  1. Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands
  2. Department of Pediatric Nephrology, Charité Universit?tsmedizin, Berlin, Germany
  3. Department of Molecular Cell Physiology, Leibniz-Institut für Molekulare Pharmakologie (FMP), Forschungsverbund Berlin, e.V, 13125, Berlin-Buch, Germany
  4. Max Delbrück Center for Molecular Medicine, Berlin, Germany
  5. Medical Clinic for Nephrology and Internal Intensive Care, Charité Universit?tsmedizin and Experimental and Clinical Research Center (ECRC), Berlin, Germany
  
• ISSN：1432-0533

文摘

Multiple sclerosis (MS) is a chronic neuro-inflammatory disorder, which is marked by the invasion of the central nervous system by monocyte-derived macrophages and autoreactive T cells across the brain vasculature. Data from experimental animal models recently implied that the passage of leukocytes across the brain vasculature is preceded by their traversal across the blood–cerebrospinal fluid barrier (BCSFB) of the choroid plexus. The correlation between the presence of leukocytes in the CSF of patients suffering from MS and the number of inflammatory lesions as detected by magnetic resonance imaging suggests that inflammation at the choroid plexus contributes to the disease, although in a yet unknown fashion. We here provide first insights into the involvement of the choroid plexus in the onset and severity of the disease and in particular address the role of the tight junction protein claudin-3 (CLDN3) in this process. Detailed analysis of human post-mortem brain tissue revealed a selective loss of CLDN3 at the choroid plexus in MS patients compared to control tissues. Importantly, mice that lack CLDN3 have an impaired BCSFB and experience a more rapid onset and exacerbated clinical signs of experimental autoimmune encephalomyelitis, which coincides with enhanced levels of infiltrated leukocytes in their CSF. Together, this study highlights a profound role for the choroid plexus in the pathogenesis of multiple sclerosis, and implies that CLDN3 may be regarded as a crucial and novel determinant of BCSFB integrity.