Neuromyelitis optica pathology in rats following intraperitoneal injection of NMO-IgG and intracerebral needle injury.

Nithi Asavapanumas,As Verkman

doi:10.1186/2051-5960-2-48

Nithi Asavapanumas, As Verkman

Open Access

https://doi.org/10.1186/2051-5960-2-48

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Abstract

IntroductionAnimal models of neuromyelitis optica (NMO) are needed for drug testing and evaluation of NMO disease pathogenesis mechanisms.ResultsWe describe a novel passive-transfer model of NMO in which rats made seropositive for human anti-aquaporin-4 (AQP4) immunoglobulin G antibody (NMO-IgG) by intraperitoneal (IP) injections were subject to intracerebral needle injury. Following a single IP injection, NMO-IgG distributed rapidly to peripheral AQP4-expressing cells (kidney collecting duct, gastric glands, airways, skeletal muscle) and area postrema in brain, but not elsewhere in the central nervous system; however, no pathology was seen in brain, spinal cord, optic nerve or peripheral tissues. After testing various maneuvers to produce NMO-IgG-dependent pathology in brain, we found that transient puncture of brain parenchyma with a 28-gauge needle in NMO-IgG seropositive rats produced robust NMO pathology around the needle track, with loss of AQP4 and glial fibrillary acidic protein, granulocyte and macrophage infiltration, centrovascular deposition of activated complement, and blood–brain barrier disruption, with demyelination by 5 days. Pathology was not seen in rats receiving control (non-NMO) human IgG or in NMO-IgG-seropositive rats made complement-deficient by cobra venom factor. Interestingly, at 1 day a reversible, multifocal astrocytopathy was seen with loss of AQP4 and GFAP (but not myelin) in areas away from the needle track.ConclusionsNMO-IgG-seropositivity alone is not sufficient to cause NMO pathology in rats, but a single intracerebral needle insertion, without pre-existing inflammation or infusion of pro-inflammatory factors, was sufficient to produce robust NMO pathology in seropositive rats.

Highlights

Animal models of neuromyelitis optica (NMO) are needed for drug testing and evaluation of NMO disease pathogenesis mechanisms
Most NMO patients are seropositive for immunoglobulin G autoantibodies (NMO-IgG) directed against aquaporin-4 (AQP4) [4,5], a water channel expressed in the plasma membrane of astrocytes in brain, spinal cord and optic nerve [6,7]
There is a substantial body of evidence supporting a pathogenesis mechanism in which NMO-IgG binding to astrocytic AQP4 produces complement-dependent cytotoxicity (CDC), which leads to inflammation and blood–brain barrier disruption with secondary oligodendrocyte injury, demyelination and neuronal injury [13,14,15]

Summary

Introduction

Animal models of neuromyelitis optica (NMO) are needed for drug testing and evaluation of NMO disease pathogenesis mechanisms. Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that can produce motor and visual impairment [1,2,3]. NMO lesions in the human central nervous system show astrocyte damage with loss of AQP4 and glial fibrillary acidic protein (GFAP), inflammation with granulocyte and macrophage infiltration, vasculocentric deposition of activated complement, blood–brain barrier disruption and demyelination [4,5,10,11,12]. There is a substantial body of evidence supporting a pathogenesis mechanism in which NMO-IgG binding to astrocytic AQP4 produces complement-dependent cytotoxicity (CDC), which leads to inflammation and blood–brain barrier disruption with secondary oligodendrocyte injury, demyelination and neuronal injury [13,14,15]. Antibodydependent cellular cytotoxicity (ADCC) plays a role [16], as does, perhaps, AQP4-sensitized T cells or other factors promoting blood–brain barrier breakdown [17,18,19]

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