Passively transferred human NMO-IgG exacerbates demyelination in mouse experimental autoimmune encephalomyelitis

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.

Neuromyelitis optica presenting with psychiatric symptoms and catatonia: a case report

“…The clinical presentation plus the presence of NMO-immunoglobulin G -targeting central nervous system aquaporin-4 receptors -is diagnostic of NMO [3,4].…”

Pathogenic aquaporin-4 reactive T cells are sufficient to induce mouse model of neuromyelitis optica

“…In human NMO pathology, death of astrocytes and loss of aquaporin-4 is a more downstream event initiated with binding of anti-AQP4 antibody, which leads to either complement-mediated destruction of the M23 isoform or internalization of the M1 isoform of AQP4 [ 17 , 18 ]. We and others have previously demonstrated a pathogenic function of the anti-AQP4 antibody in exacerbating neuroinflammation in rodents, but not in instigating the disease [ 5 – 7 ]. The specificity of the immune target to the nervous system is not mediated by the anti-AQP4 antibody as it will bind AQP4 in any organ [ 19 ].…”

“…After washing, slides were Fast Green counterstained, dehydrated and mounted. Quantification and analysis of myelin and CD3 staining was as described [ 7 ]. Glial fibrillary acidic protein (GFAP), myelin basic protein for myelin, and aquaporin-4 were examined by immunofluorescence (without antigen retrieval) applying mouse anti-GFAP (1:1000; Sigma), rabbit monoclonal anti-MBP (1:250; Epitomics/ Abcam), and rabbit anti-AQP4 (H-19) (1:250; Santa Cruz Biotechnology) overnight at 4 °C, followed by goat Alexa Fluor® 555-conjugated anti-rabbit IgG and Alexa Fluor® 488-conjugated anti-mouse IgG (1:250; Life Technologies / Molecular Probes) for 30 min at RT.…”

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

“…The acknowledged weakness of these studies is that preexisting EAE confounds interpretation of the effects of AQP4‐IgG, as NMO is not a disease of myelin‐targeted T cells. More recently, a longer term EAE model of NMO in mice was created by active immunization with myelin oligodendrocyte glycoprotein peptide (MOG 35‐55 ) for 60 days followed by AQP4‐IgG administration . AQP4‐IgG penetration into spinal cord was seen in this model, with clinical disability over 2 months, and unlike the early models there was significant demyelination and axonal injury.…”