title: Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica.
abstract: Pathogenic autoantibodies associated with neuromyelitis optica (NMO) induce disease by targeting aquaporin-4 (AQP4) water channels enriched on astrocytic endfeet at blood-brain interfaces. AQP4 is also expressed at cerebrospinal fluid (CSF)-brain interfaces, such as the pial glia limitans and the ependyma and at the choroid plexus blood-CSF barrier. However, little is known regarding pathology at these sites in NMO. Therefore, we evaluated AQP4 expression, microglial reactivity, and complement deposition at pial and ependymal surfaces and in the fourth ventricle choroid plexus in 23 autopsy cases with clinically and/or pathologically confirmed NMO or NMO spectrum disorder. These findings were compared to five cases with multiple sclerosis, five cases of choroid plexus papilloma, and five control cases without central nervous system disease. In the NMO cases, AQP4 immunoreactivity was reduced relative to control levels in the pia (91%; 21/23), ependyma (56%; 9/16), and choroid plexus epithelium (100%; 12/12). AQP4 immunoreactivity was normal in MS cases in these regions. Compared to MS, NMO cases also showed a focal pattern of pial and ependymal complement deposition and more pronounced microglial reactivity. In addition, AQP4 loss, microglial reactivity, and complement deposition colocalized along the pia and ependyma only in NMO cases. Within the choroid plexus, AQP4 loss was coincident with C9neo immunoreactivity on epithelial cell membranes only in NMO cases. These observations demonstrate that NMO immunopathology extends beyond perivascular astrocytic foot processes to include the pia, ependyma, and choroid plexus, suggesting that NMO IgG-induced pathological alterations at CSF-brain and blood-CSF interfaces may contribute to the occurrence of ventriculitis, leptomeningitis, and hydrocephalus observed among NMO patients. Moreover, disruption of the blood-CSF barrier induced by binding of NMO IgG to AQP4 on the basolateral surface of choroid plexus epithelial cells may provide a unique portal for entry of the pathogenic antibody into the central nervous system.
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weigand
authors.affiliation: Department of Anatomy and Cell Biology, Cameco MS Neuroscience Research Center, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: Bogdan F
authors.initials: BF
authors.lastname: Popescu
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.|Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.|Department of Immunology, Mayo Clinic, Rochester, MN, USA.|Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Vanda A
authors.initials: VA
authors.lastname: Lennon
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.|Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.|Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Pittock
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Parks
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Clardy
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. howe@mayo.edu.|Department of Immunology, Mayo Clinic, Rochester, MN, USA. howe@mayo.edu.|Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA. howe@mayo.edu.|Department of Neuroscience, Mayo Clinic, Rochester, MN, USA. howe@mayo.edu.
authors.forename: Charles L
authors.identifier: 0000-0002-3889-8739
authors.initials: CL
authors.lastname: Howe
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. clucchinetti@mayo.edu.|Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA. clucchinetti@mayo.edu.
authors.forename: Claudia F
authors.initials: CF
authors.lastname: Lucchinetti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051401:Aquaporin 4 / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002555:Cerebrospinal Fluid; D002831:Choroid Plexus / Q000378:metabolism / Q000473:pathology*; D015331:Cohort Studies; D004805:Ependyma / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009471:Neuromyelitis Optica / Q000378:metabolism / Q000473:pathology*; D010841:Pia Mater / Q000378:metabolism / Q000473:pathology*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4
keywords: Astrocyte; Choroid plexus; Complement; Hydrocephalus; Immunopathology; Leptomeninges