All CNS regions exhibited AQP4 loss at the pia, most frequently in spinal cord (Fig
All CNS regions exhibited AQP4 loss at the pia, most frequently in spinal cord (Fig.?3b, Supplementary Determine?3). cases in these regions. Compared to MS, NMO cases also showed a focal pattern of pial and ependymal match deposition and more pronounced microglial reactivity. In addition, AQP4 loss, microglial reactivity, and match 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 CSFCbrain and bloodCCSF interfaces may contribute to the occurrence of ventriculitis, leptomeningitis, and hydrocephalus observed among NMO patients. Moreover, disruption of the bloodCCSF barrier induced by binding of NMO IgG to AQP4 around the basolateral surface of choroid plexus epithelial cells may provide a unique portal for access of the pathogenic antibody into the central nervous system. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1682-1) contains supplementary material, which is available to authorized users. Keywords: Choroid plexus, Leptomeninges, Astrocyte, Match, Immunopathology, Hydrocephalus Introduction Neuromyelitis optica (NMO) is usually a disabling inflammatory disorder of the central nervous system (CNS) that is marked by expression of a pathogenic IgG autoantibody directed against the ectodomain of aquaporin-4 (AQP4), the major water channel in the CNS [34, 35]. AQP4 functions to couple bidirectional fast water transport to active ion flux across the plasma membrane, thereby controlling astrocyte homeostasis and CNS osmotic stability [76]. The enrichment of AQP4 on astrocytic endfeet at the bloodCbrain barrier is consistent with a crucial role in maintaining physiological water balance and with responding to pathological perturbations of this balance associated with ischemia or trauma [75]. Early NMO pathology is usually characterized by the presence of reactive astrocytes, intramyelinic edema, loss of AQP4 expression, variable perivascular deposition of IgG and match components, and granulocytic leukocyte infiltration [40, 61]. Advanced lesions demonstrate more profound match deposition, loss of myelin, and astrocyte destruction. Astrocytic responses in NMO range from sublytic gliosis to overt lysis, and these responses are frequently observed in regions without myelin loss, suggesting that PF-06409577 NMO is PF-06409577 usually a primary astrocytopathy associated with secondary demyelination [39]. Such a model for NMO pathogenesis is usually consistent with observations of water dyshomeostasis [62], lesion reversibility [41, 42, 80], and behavioral sequelae in NMO patients [59]. AQP4 is also expressed at the pial glia limitans, the ependyma, and the choroid plexus [53, 61]. Notably, differential cellCcell junction expression at these barrier sites [78] may provide a unique route for NMO IgG to enter the cerebrospinal fluid (CSF) and access AQP4-expressing targets in the brain parenchyma. Recently, PF-06409577 loss of AQP4 expression was observed in cortical layer I in NMO tissue and was associated with cognitive impairment and a corresponding loss of neurons in cortical layer II [65]. This obtaining suggests that subpial AQP4 was targeted by NMO IgG and indicates that PF-06409577 astrocytopathy outside of the typical periventricular lesion may have profound pathogenic and neurologic effects. However, at present, little is known about the pathology of CSFCbrain and bloodCCSF barriers in NMO patients. Therefore, in this study, we analyzed astrocyte and microglia reactivity, AQP4 expression level, and match deposition at these interfaces. Materials and methods Study design and series This study was approved by the Institutional Review Table of Mayo Medical center, Rochester, MN (IRB 2067-99). Inclusion criteria were (i) H3F1K clinical and pathological diagnosis of NMO or NMOSD; (ii) sufficient archival tissue for pathological analysis; and (iii) no evidence of option diagnosis. Twenty-three autopsy cases met the inclusion criteria (315 total tissue blocks) (Supplemental Physique?1). Table?1 provides demographics for the patient cohort. As controls, we included five multiple sclerosis (MS) cases (79 blocks; 4 relapsing remitting MS, 1 secondary progressive MS) and five control cases without known CNS disease (45 blocks). As additional controls for choroid plexus disease, we included five hydrocephalus cases (five blocks) and five papilloma cases (five blocks). We analyzed supratentorial brain (including optic nerve), brain stem, cerebellum, and spinal cord for histopathological abnormalities in the pial surface, ependyma, and choroid plexus. To reduce anatomical variability in the choroid plexus analysis, we specifically assessed the choroid plexus in the fourth ventricle at the level of the medulla. Table?1 Demographic and clinical summaries (%)?NMO18 (78%)?NMO spectrum disorder5 (22%)AQP4-IgG serostatus, positive:negativea 9:0Number of clinical attacks3 (2C7)Disease duration, months36 (8C240)Age at death, years52 (16C80) Open in a separate window.