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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

Spinal cord sections from mouse 24 hours after 4 injections of NMO-IgG on days 13, 14, 18, and 19 (A) versus control IgG (B) showing NMO-IgG penetration into the parenchyma of the spinal cord as shown by anti-human IgG staining (green). Sections were costained with anti-human IgG (green, C), anti-AQP4 antibody (red, D) showing co-localization in areas of AQP4 expression especially around blood vessels (arrow in merged image, E).
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Figure 2: Spinal cord sections from mouse 24 hours after 4 injections of NMO-IgG on days 13, 14, 18, and 19 (A) versus control IgG (B) showing NMO-IgG penetration into the parenchyma of the spinal cord as shown by anti-human IgG staining (green). Sections were costained with anti-human IgG (green, C), anti-AQP4 antibody (red, D) showing co-localization in areas of AQP4 expression especially around blood vessels (arrow in merged image, E).

Mentions: To determine the target(s) of human IgG injected into EAE mice, we sacrificed a cohort of mice 24 hours after the final of four intraperitoneal injections and stained tissue sections for anti-human antibody. In addition to positive staining in non-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). The control-IgG was also found in the CNS, but largely in the meninges and not within the parenchyma of the spinal cord (Figure 2B). Co-staining with anti-AQP4 revealed colocalization with anti-human antibody, especially around blood vessels and in the pia-glia limitans of the spinal cord (Figures 2C-E). This suggests that human NMO-IgG antibodies injected intraperitoneally can reach their target in the spinal cord of inflamed mouse spinal cord in EAE. Forty-three days following the last intraperitoneal injection of NMO or control-IgG, staining for human IgG in the spinal cords was indistinguishable from vehicle control mice (injected with PBS), confirming that the human antibodies were removed from circulation.


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)

Spinal cord sections from mouse 24 hours after 4 injections of NMO-IgG on days 13, 14, 18, and 19 (A) versus control IgG (B) showing NMO-IgG penetration into the parenchyma of the spinal cord as shown by anti-human IgG staining (green). Sections were costained with anti-human IgG (green, C), anti-AQP4 antibody (red, D) showing co-localization in areas of AQP4 expression especially around blood vessels (arrow in merged image, E).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750922&req=5

Figure 2: Spinal cord sections from mouse 24 hours after 4 injections of NMO-IgG on days 13, 14, 18, and 19 (A) versus control IgG (B) showing NMO-IgG penetration into the parenchyma of the spinal cord as shown by anti-human IgG staining (green). Sections were costained with anti-human IgG (green, C), anti-AQP4 antibody (red, D) showing co-localization in areas of AQP4 expression especially around blood vessels (arrow in merged image, E).
Mentions: To determine the target(s) of human IgG injected into EAE mice, we sacrificed a cohort of mice 24 hours after the final of four intraperitoneal injections and stained tissue sections for anti-human antibody. In addition to positive staining in non-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). The control-IgG was also found in the CNS, but largely in the meninges and not within the parenchyma of the spinal cord (Figure 2B). Co-staining with anti-AQP4 revealed colocalization with anti-human antibody, especially around blood vessels and in the pia-glia limitans of the spinal cord (Figures 2C-E). This suggests that human NMO-IgG antibodies injected intraperitoneally can reach their target in the spinal cord of inflamed mouse spinal cord in EAE. Forty-three days following the last intraperitoneal injection of NMO or control-IgG, staining for human IgG in the spinal cords was indistinguishable from vehicle control mice (injected with PBS), confirming that the human antibodies were removed from circulation.

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