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

Saini H, Rifkin R, Gorelik M, Huang H, Ferguson Z, Jones MV, Levy M - BMC Neurol (2013)

Bottom Line: NMO is associated with the highly specific NMO-IgG biomarker, an antibody that binds the aquaporin-4 water channel.In humans, the NMO-IgG portends more frequent exacerbations and a worse long-term clinical outcome.Clinical worsening is associated with an increased concentration of large demyelinating lesions primarily to subpial AQP4-rich regions of the spinal cord.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.

ABSTRACT

Background: Neuromyelitis 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.

Methods: We 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.

Results: Passively 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.

Conclusions: NMO-IgG is pathogenic in the context of EAE in mice.

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Related in: MedlinePlus

Quantification and characterization of demyelinated lesions in the spinal cord were based on manual outlines of the total myelinated area (blue) and the demyelinated area (red/yellow) as shown in A. The number of pial lesions greater than 10,000 μm2 made up nearly 40% of all the demyelinated lesions in the NMO-IgG group (B). In addition, the total number of pial lesions in each NMO-IgG mouse on average was higher (C). Accounting for pial lesions of all sizes, the NMO-IgG group had almost double the number compared to the control-IgG and vehicle groups (D).
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Figure 4: Quantification and characterization of demyelinated lesions in the spinal cord were based on manual outlines of the total myelinated area (blue) and the demyelinated area (red/yellow) as shown in A. The number of pial lesions greater than 10,000 μm2 made up nearly 40% of all the demyelinated lesions in the NMO-IgG group (B). In addition, the total number of pial lesions in each NMO-IgG mouse on average was higher (C). Accounting for pial lesions of all sizes, the NMO-IgG group had almost double the number compared to the control-IgG and vehicle groups (D).

Mentions: The overall proportion of demyelinated area was not significantly different between the 3 groups (NMO-IgG vs. CTL-IgG p=0.43, vs. Vehicle p=0.70). However, there were a significantly greater number of large lesions (defined as ≥10,000 μm2) that were primarily subpial in the NMO group (5.4± 1.2) compared to the control-IgG (2.0± 0.0) or the vehicle control group (2.0± 1.2) (p=0.048 and 0.049 respectively; Figure 4C). When expressed as a percentage of the total demyelinated area, large subpial lesions comprised a greater proportion of the lesioned area in the NMO-IgG group (39.0 ± 3.5%) than in the control-IgG (18.9 ± 5.1%) or the vehicle-treated group (11.8 ± 7.0%) (p<0.008 and p<0.005 respectively) (Figure 4). Considering pial lesions of all sizes, 72.9 ± 3.8% of all demyelinated area in the NMO-IgG group was subpial compared to 39.9 ±16.7% in the control-IgG group (p=0.02 vs. NMO-IgG) and 40.6 ± 11.5% in the vehicle control group (p=0.02 vs. NMO-IgG). Simply injecting non-specific IgG into mice did not alter lesion localization, since the pattern of demyelination in the control-IgG and vehicle control groups were not significantly different from each other (p=0.97).


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

Saini H, Rifkin R, Gorelik M, Huang H, Ferguson Z, Jones MV, Levy M - BMC Neurol (2013)

Quantification and characterization of demyelinated lesions in the spinal cord were based on manual outlines of the total myelinated area (blue) and the demyelinated area (red/yellow) as shown in A. The number of pial lesions greater than 10,000 μm2 made up nearly 40% of all the demyelinated lesions in the NMO-IgG group (B). In addition, the total number of pial lesions in each NMO-IgG mouse on average was higher (C). Accounting for pial lesions of all sizes, the NMO-IgG group had almost double the number compared to the control-IgG and vehicle groups (D).
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Figure 4: Quantification and characterization of demyelinated lesions in the spinal cord were based on manual outlines of the total myelinated area (blue) and the demyelinated area (red/yellow) as shown in A. The number of pial lesions greater than 10,000 μm2 made up nearly 40% of all the demyelinated lesions in the NMO-IgG group (B). In addition, the total number of pial lesions in each NMO-IgG mouse on average was higher (C). Accounting for pial lesions of all sizes, the NMO-IgG group had almost double the number compared to the control-IgG and vehicle groups (D).
Mentions: The overall proportion of demyelinated area was not significantly different between the 3 groups (NMO-IgG vs. CTL-IgG p=0.43, vs. Vehicle p=0.70). However, there were a significantly greater number of large lesions (defined as ≥10,000 μm2) that were primarily subpial in the NMO group (5.4± 1.2) compared to the control-IgG (2.0± 0.0) or the vehicle control group (2.0± 1.2) (p=0.048 and 0.049 respectively; Figure 4C). When expressed as a percentage of the total demyelinated area, large subpial lesions comprised a greater proportion of the lesioned area in the NMO-IgG group (39.0 ± 3.5%) than in the control-IgG (18.9 ± 5.1%) or the vehicle-treated group (11.8 ± 7.0%) (p<0.008 and p<0.005 respectively) (Figure 4). Considering pial lesions of all sizes, 72.9 ± 3.8% of all demyelinated area in the NMO-IgG group was subpial compared to 39.9 ±16.7% in the control-IgG group (p=0.02 vs. NMO-IgG) and 40.6 ± 11.5% in the vehicle control group (p=0.02 vs. NMO-IgG). Simply injecting non-specific IgG into mice did not alter lesion localization, since the pattern of demyelination in the control-IgG and vehicle control groups were not significantly different from each other (p=0.97).

Bottom Line: NMO is associated with the highly specific NMO-IgG biomarker, an antibody that binds the aquaporin-4 water channel.In humans, the NMO-IgG portends more frequent exacerbations and a worse long-term clinical outcome.Clinical worsening is associated with an increased concentration of large demyelinating lesions primarily to subpial AQP4-rich regions of the spinal cord.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.

ABSTRACT

Background: Neuromyelitis 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.

Methods: We 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.

Results: Passively 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.

Conclusions: NMO-IgG is pathogenic in the context of EAE in mice.

Show MeSH
Related in: MedlinePlus