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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

Staining for the types of immune cells in acute lesions (24 hours after last human IgG injection) identified heavy infiltration by granulocytes (anti-Ly6G, BD Pharmingen, green) in parenchymal spinal cord lesions of mice that received NMO-IgG (A) especially around blood vessels as indicated by the arrow, compared to occasional scattered granulocytes in control IgG (B) and saline vehicle controls (C). T-cell infiltration was similar among all groups. The arrows identify T-cells (anti-CD5, BD Pharmingen, red) in lesions of the NMO-IgG mice (D) and isotype control IgG (E). Scale bars represent 100 μm.
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Figure 6: Staining for the types of immune cells in acute lesions (24 hours after last human IgG injection) identified heavy infiltration by granulocytes (anti-Ly6G, BD Pharmingen, green) in parenchymal spinal cord lesions of mice that received NMO-IgG (A) especially around blood vessels as indicated by the arrow, compared to occasional scattered granulocytes in control IgG (B) and saline vehicle controls (C). T-cell infiltration was similar among all groups. The arrows identify T-cells (anti-CD5, BD Pharmingen, red) in lesions of the NMO-IgG mice (D) and isotype control IgG (E). Scale bars represent 100 μm.

Mentions: In most models of rodent EAE, the majority of white blood cells in CNS lesions are T-cells, while human NMO pathology is characterized by the presence of granulocytes, including neutrophils and eosinophils in demyelinating lesions, along with T cells, a few B-cells, and macrophages. We found that several early (20 days post-immunization) lesions in the NMO-IgG-treated group developed lesions that were infiltrated by granulocytes in addition to typical EAE lesions identified by T cells (Figure 6). The spinal cords of control-IgG treated mice showed sporadic granulocytes, although not in high numbers or in a perivascular distribution. While further study is needed to quantify the granulocyte infiltration, it appears that granulocytes within EAE lesions may have contributed to the worsening of both the NMO and control-IgG groups. At 62 days after immunization, rare inflammatory EAE lesions in all three groups were still evident with typical infiltration by T-cells, but granulocytes were no longer present.


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)

Staining for the types of immune cells in acute lesions (24 hours after last human IgG injection) identified heavy infiltration by granulocytes (anti-Ly6G, BD Pharmingen, green) in parenchymal spinal cord lesions of mice that received NMO-IgG (A) especially around blood vessels as indicated by the arrow, compared to occasional scattered granulocytes in control IgG (B) and saline vehicle controls (C). T-cell infiltration was similar among all groups. The arrows identify T-cells (anti-CD5, BD Pharmingen, red) in lesions of the NMO-IgG mice (D) and isotype control IgG (E). Scale bars represent 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Staining for the types of immune cells in acute lesions (24 hours after last human IgG injection) identified heavy infiltration by granulocytes (anti-Ly6G, BD Pharmingen, green) in parenchymal spinal cord lesions of mice that received NMO-IgG (A) especially around blood vessels as indicated by the arrow, compared to occasional scattered granulocytes in control IgG (B) and saline vehicle controls (C). T-cell infiltration was similar among all groups. The arrows identify T-cells (anti-CD5, BD Pharmingen, red) in lesions of the NMO-IgG mice (D) and isotype control IgG (E). Scale bars represent 100 μm.
Mentions: In most models of rodent EAE, the majority of white blood cells in CNS lesions are T-cells, while human NMO pathology is characterized by the presence of granulocytes, including neutrophils and eosinophils in demyelinating lesions, along with T cells, a few B-cells, and macrophages. We found that several early (20 days post-immunization) lesions in the NMO-IgG-treated group developed lesions that were infiltrated by granulocytes in addition to typical EAE lesions identified by T cells (Figure 6). The spinal cords of control-IgG treated mice showed sporadic granulocytes, although not in high numbers or in a perivascular distribution. While further study is needed to quantify the granulocyte infiltration, it appears that granulocytes within EAE lesions may have contributed to the worsening of both the NMO and control-IgG groups. At 62 days after immunization, rare inflammatory EAE lesions in all three groups were still evident with typical infiltration by T-cells, but granulocytes were no longer present.

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