title: Disturbed function of the blood-cerebrospinal fluid barrier aggravates neuro-inflammation.
abstract: 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.
authors.affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands, g.kooij@vumc.nl.
authors.forename: Gijs
authors.initials: G
authors.lastname: Kooij
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kopplin
authors.forename: Rosel
authors.initials: R
authors.lastname: Blasig
authors.forename: Marchel
authors.initials: M
authors.lastname: Stuiver
authors.forename: Nathalie
authors.initials: N
authors.lastname: Koning
authors.forename: Gera
authors.initials: G
authors.lastname: Goverse
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: van der Pol
authors.forename: Bert
authors.initials: B
authors.lastname: van Het Hof
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
authors.forename: Joost A R
authors.initials: JA
authors.lastname: Drexhage
authors.forename: Arie
authors.initials: A
authors.lastname: Reijerkerk
authors.forename: Iwan C
authors.initials: IC
authors.lastname: Meij
authors.forename: Reina
authors.initials: R
authors.lastname: Mebius
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Willnow
authors.forename: Dominik
authors.initials: D
authors.lastname: Müller
authors.forename: Ingolf E
authors.initials: IE
authors.lastname: Blasig
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D002831:Choroid Plexus / Q000473:pathology / Q000503:physiopathology*; D062465:Claudin-3 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology / Q000503:physiopathology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D012720:Severity of Illness Index
chemical_list: C568122:CLDN3 protein, human; D062465:Claudin-3; C568123:Cldn3 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55)