Dataset Information

Markedly increased IP-10 production by blood-brain barrier in neuromyelitis optica.

ABSTRACT:

Objective

Severe damage to the blood-brain barrier (BBB) allows anti-aquaporin 4 (AQP4) antibodies to access the astrocytic endfeet in neuromyelitis optica (NMO). In the current study, we identified the pathogenic cytokines/chemokines that are responsible for the BBB malfunction induced by NMO sera.

Methods

We measured the levels of 27 cytokines/chemokines in human brain microvascular endothelial cells (BMECs) after exposure to sera obtained from patients with the acute and stable phases of anti-AQP4 antibody-positive NMO spectrum disorder (NMOSD), multiple sclerosis (MS) patients and healthy controls (HC) using a multiplexed fluorescent bead-based immunoassay system.

Results

The induced protein (IP)-10 level in the cells was markedly increased following exposure to acute phase NMOSD sera. Other cytokines/chemokines including interleukin (IL)-6 and monocyte chemotactic protein (MCP)-1 were also significantly increased in the acute NMOSD group compared to both the MS and HC groups. The up-regulation of the IP-10 levels in the cells after exposure to the acute-phase NMOSD sera was also observed using another specified ELISA, and this effect was significantly decreased during the remission phase in the individual NMOSD patients. Furthermore, the increase in the level of IP-10 after exposure to the sera was significantly correlated with the cerebrospinal fluid/serum albumin ratio.

Conclusions

Sera from the acute phase of NMO markedly increased the autocrine secretion of IP-10 by BMECs. The over-production of IP-10 in BMECs may play an important role in the pathogenesis of NMO and may therefore help to mediate the trafficking of T cells expressing its receptor across the BBB.

SUBMITTER: Shimizu F

PROVIDER: S-EPMC4374747 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Markedly increased IP-10 production by blood-brain barrier in neuromyelitis optica.

Shimizu Fumitaka F Nishihara Hideaki H Sano Yasuteru Y Takeshita Yukio Y Takahashi Shiori S Maeda Toshihiko T Takahashi Toshiyuki T Abe Masaaki M Koga Michiaki M Kanda Takashi T

PloS one 20150326 3

<h4>Objective</h4>Severe damage to the blood-brain barrier (BBB) allows anti-aquaporin 4 (AQP4) antibodies to access the astrocytic endfeet in neuromyelitis optica (NMO). In the current study, we identified the pathogenic cytokines/chemokines that are responsible for the BBB malfunction induced by NMO sera.<h4>Methods</h4>We measured the levels of 27 cytokines/chemokines in human brain microvascular endothelial cells (BMECs) after exposure to sera obtained from patients with the acute and stable ...[more]

PMID: 25811465

Similar Datasets

Project description:BackgroundNeuromyelitis optica spectrum disorders (NMOSD) is a primary astrocytopathy driven by antibodies directed against the aquaporin-4 water channel located at the end-feet of the astrocyte. Although blood-brain barrier (BBB) breakdown is considered one of the key steps for the development and lesion formation, little is known about the molecular mechanisms involved. The aim of the study was to evaluate the effect of human immunoglobulins from NMOSD patients (NMO-IgG) on BBB properties.MethodsFreshly isolated brain microvessels (IBMs) from rat brains were used as a study model. At first, analysis of the secretome profile from IBMs exposed to purified NMO-IgG, to healthy donor IgG (Control-IgG), or non-treated, was performed. Second, tight junction (TJ) proteins expression in fresh IBMs and primary cultures of brain microvascular endothelial cells (BMEC) was analysed by Western blotting (Wb) after exposition to NMO-IgG and Control-IgG. Finally, functional BBB properties were investigated evaluating the presence of rat-IgG in tissue lysate from brain using Wb in the rat-model, and the passage of NMO-IgG and sucrose in a bicameral model.ResultsWe found that NMO-IgG induces functional and morphological BBB changes, including: 1) increase of pro-inflammatory cytokines production (CXCL-10 [IP-10], IL-6, IL-1RA, IL-1β and CXCL-3) in IBMs when exposed to NMO-IgG; 2) decrease of Claudin-5 levels by 25.6% after treatment of fresh IBMs by NMO-IgG compared to Control-IgG (p = 0.002), and similarly, decrease of Claudin-5 by at least 20% when BMEC were cultured with NMO-IgG from five different patients; 3) a higher level of rat-IgG accumulated in periventricular regions of NMO-rats compared to Control-rats and an increase in the permeability of BBB after NMO-IgG treatment in the bicameral model.ConclusionHuman NMO-IgG induces both structural and functional alterations of BBB properties, suggesting a direct role of NMO-IgG on modulation of BBB permeability in NMOSD.

Project description: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.

Dataset Information

Markedly increased IP-10 production by blood-brain barrier in neuromyelitis optica.

Objective

Methods

Results

Conclusions

Publications

Markedly increased IP-10 production by blood-brain barrier in neuromyelitis optica.

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