Abstract
BackgroundNeuromyelitis optica (NMO) is a devastating inflammatory disorder of the optic nerves and spinal cord characterized by frequently recurring exacerbations of humoral inflammation. NMO is associated with the highly specific NMO-IgG biomarker, an antibody that binds the aquaporin-4 water channel. Aquaporin-4 is present on glial endfeet in the central nervous system (CNS). In humans, the NMO-IgG portends more frequent exacerbations and a worse long-term clinical outcome.MethodsWe tested the longer-term outcome of mice with EAE injected with NMO-IgG and followed them for 60 days. Clinical exams and pathology of the spinal cord and optic nerves were compared to mice that received control human IgG.ResultsPassively transferred human NMO-IgG leads to more severe neurology disability over two months after onset of disease. Clinical worsening is associated with an increased concentration of large demyelinating lesions primarily to subpial AQP4-rich regions of the spinal cord.ConclusionsNMO-IgG is pathogenic in the context of EAE in mice.
Highlights
Neuromyelitis optica (NMO) is a devastating inflammatory disorder of the optic nerves and spinal cord characterized by frequently recurring exacerbations of humoral inflammation
While EAE induced by myelin basic protein in complete Freund’s adjuvant (CFA) in Lewis rats generally leads to a complete neurologic recovery [7], EAE induced by myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35-55) in C57Bl6 mice causes demyelination and axon loss in the spinal cord with limited behavioral recovery, the latter of which may better represent a more suitable animal model system for severe human neuromyelitis optica disease
In addition to positive staining in non-central nervous system (CNS) tissue such as the lung and kidney, we found significant levels of anti-human antibody staining in the spinal cord and optic nerve, which are the predominant sites of NMO disease in humans (Figure 2A)
Summary
Neuromyelitis optica (NMO) is a devastating inflammatory disorder of the optic nerves and spinal cord characterized by frequently recurring exacerbations of humoral inflammation. The NMO-IgG is hypothesized to be pathogenic; binding of the antibody to its glial target triggers a humoral inflammatory cascade involving IgG, IgM, complement deposition and recruitment of neutrophils and eosinophils [4]. This model of disease is supported by two reports of passively transferred NMO-IgG in which the NMO-IgG exacerbates behavioral signs of rat experimental autoimmune encephalomyelitis (EAE) and induces a pathology similar to human NMO: areas of acute inflammation with granulocytes, a dramatic loss of aquaporin-4 staining and complement deposition [5,6]. While EAE induced by myelin basic protein in complete Freund’s adjuvant (CFA) in Lewis rats generally leads to a complete neurologic recovery [7], EAE induced by myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35-55) in C57Bl6 mice causes demyelination and axon loss in the spinal cord with limited behavioral recovery, the latter of which may better represent a more suitable animal model system for severe human neuromyelitis optica disease
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