Experimental animal models of aquaporin‐4‐IgG‐seropositive neuromyelitis optica spectrum disorders: progress and shortcomings

Abstract

Neuromyelitis optica spectrum disorders (NMOSD) is a heterogeneous group of neuroinflammatory conditions associated with demyelination primarily in spinal cord and optic nerve, and to a lesser extent in brain. Most NMOSD patients are seropositive for IgG autoantibodies against aquaporin-4 (AQP4-IgG), the principal water channel in astrocytes. There has been interest in establishing experimental animal models of seropositive NMOSD (herein referred to as NMO) in order to elucidate NMO pathogenesis mechanisms and to evaluate drug candidates. An important outcome of early NMO animal models was evidence for a pathogenic role of AQP4-IgG. However, available animal models of NMO, based largely on passive transfer to rodents of AQP4-IgG or transfer of AQP4-sensitized T cells, often together with pro-inflammatory maneuvers, only partially recapitulate the clinical and pathological features of human NMO, and are inherently biased toward humoral or cellular immune mechanisms. This review summarizes current progress and shortcomings in experimental animal models of seropositive NMOSD, and opines on the import of advancing animal models.

Burns Impair Blood-Brain Barrier and Mesenchymal Stem Cells Can Reverse the Process in Mice

“…Its normal biological function is to facilitate the removal of waste from the brain (78). Moreover, AQP-4, an intrinsic pro-inflammatory factor, is only activated by the inflammatory factors in the brain tissue and promotes swelling in astrocytes, secretion of inflammatory cytokines (47,79), as well as the occurrence of cerebral edema (28,80). In the present study, we detect increased level of AQP-4 in mouse brain after burns, which further confirmed that burns could induce neuroinflammation, mainly via the infiltration of peripheral cytokines.…”

Autoantibodies in neurological disease

“…In NMO, AQP4-IgG was initially administered into experimental autoimmune encephalomyelitis animals, leading to spinal cord inflammation and complement deposition, but little demyelination 87 . Passive immunization of AQP4 autoantibodies in rodents was also combined with complement injection or was targeted into the spinal cord, optic nerve or retina, resulting in better recapitulation of disease 117 . Passive intrathecal transfer of CSF or monoclonal antibodies from patients with NMDAR encephalitis resulted in decreased NMDAR density in the hippocampus, hypofunction in NMDAR-mediated synaptic transmission, behavioural changes compatible with human disease and a low threshold for seizures 118 – 120 .…”

Protective roles for myeloid cells in neuroinflammation

“…1,46 These cells are not well-represented in the current generation of animal models for NMOSD. 46 NMOSD patients either show no benefit or indeed worsening after treatment with IFNβ, in contrast to relapsing-remitting MS. 47 Dependence on type I IFN signalling has been shown in mouse models for NMOSD and anti-MOG-associated encephalitis, mirroring the clinical situation. 48,49 One study suggests that microglia may play a detrimental role in NMOSD, 50 although this and signals that can activate suppressor function for granulocytes remain to be more fully defined.…”