title: Abundant extracellular myelin in the meninges of patients with multiple sclerosis.
abstract: BACKGROUND
  In multiple sclerosis (MS) myelin debris has been observed within MS lesions, in cerebrospinal fluid and cervical lymph nodes, but the route of myelin transport out of the brain is unknown. Drainage of interstitial fluid from the brain parenchyma involves the perivascular spaces and leptomeninges, but the presence of myelin debris in these compartments has not been described.
  
  
  OBJECTIVE
  To determine whether myelin products are present in the meninges and perivascular spaces of MS patients.
  
  
  METHODS
  Formalin-fixed brain tissue containing meninges from 29 MS patients, 9 non-neurological controls, 6 Alzheimer's disease, 5 stroke, 5 meningitis and 7 leucodystrophy patients was investigated, and immunohistochemically stained for several myelin proteins [proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)]. On brain material from MS patients and (non)neurological controls, PLP immunostaining was used to systematically investigate the presence of myelin debris in the meninges, using a semiquantitative scale.
  
  
  RESULTS
  Extensive extracellular presence of myelin particles, positive for PLP, MBP, MOG and CNPase in the leptomeninges of MS patients, was observed. Myelin particles were also observed in perivascular spaces of MS patients. Immunohistochemical double-labelling for macrophage and dendritic cell markers and PLP confirmed that the vast majority of myelin particles were located extracellularly. Extracellular myelin particles were virtually absent in meningeal tissue of non-neurological controls, Alzheimer's disease, stroke, meningitis and leucodystrophy cases.
  
  
  CONCLUSIONS
  In MS leptomeninges and perivascular spaces, abundant extracellular myelin can be found, whereas this is not the case for controls and other neurological disease. This may be relevant for understanding sustained immunogenicity or, alternatively, tolerogenicity in MS.
authors.affiliation: Department of Pathology, VU University Medical Centre, Amsterdam, the Netherlands. e.kooi@vumc.nl
authors.forename: E-J
authors.initials: EJ
authors.lastname: Kooi
authors.forename: J
authors.initials: J
authors.lastname: van Horssen
authors.forename: M E
authors.initials: ME
authors.lastname: Witte
authors.forename: S
authors.initials: S
authors.lastname: Amor
authors.forename: L
authors.initials: L
authors.lastname: Bø
authors.forename: C D
authors.initials: CD
authors.lastname: Dijkstra
authors.forename: P
authors.initials: P
authors.lastname: van der Valk
authors.forename: J J G
authors.initials: JJ
authors.lastname: Geurts
mesh_terms: D000293:Adolescent; D000326:Adrenoleukodystrophy / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000378:metabolism; D005110:Extracellular Space / Q000737:chemistry*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008578:Meninges / Q000737:chemistry* / Q000473:pathology*; D008581:Meningitis / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology*; D009185:Myelin Proteins / Q000032:analysis*; D009186:Myelin Sheath / Q000737:chemistry / Q000473:pathology*; D020521:Stroke / Q000378:metabolism / Q000473:pathology
chemical_list: D009185:Myelin Proteins