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Cerebrospinal fluid aquaporin-4-immunoglobulin G disrupts blood brain barrier.

Asgari N, Berg CT, Mørch MT, Khorooshi R, Owens T - Ann Clin Transl Neurol (2015)

Bottom Line: A distinct distribution pattern of aquaporin-4-immunoglobulin G deposition was observed in the subarachnoid and subpial spaces where vessels penetrate the brain parenchyma, via a paravascular route with intraparenchymal perivascular deposition.Perivascular astrocyte-destructive lesions were associated with blood-borne horseradish peroxidase leakage indicating blood-brain barrier breakdown.The cerebrospinal fluid aquaporin-4-immunoglobulin G therefore distributes widely in brain to initiate astrocytopathy and blood-brain barrier breakdown.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology, Institute of Molecular Medicine, University of Southern Denmark Odense C, Denmark.

ABSTRACT
To clarify the significance of immunoglobulin G autoantibody specific for the astrocyte water channel aquaporin-4 in cerebrospinal fluid, aquaporin-4-immunoglobulin G from a neuromyelitis optica patient was administered intrathecally to naïve mice, and the distribution and pathogenic impact was evaluated. A distinct distribution pattern of aquaporin-4-immunoglobulin G deposition was observed in the subarachnoid and subpial spaces where vessels penetrate the brain parenchyma, via a paravascular route with intraparenchymal perivascular deposition. Perivascular astrocyte-destructive lesions were associated with blood-borne horseradish peroxidase leakage indicating blood-brain barrier breakdown. The cerebrospinal fluid aquaporin-4-immunoglobulin G therefore distributes widely in brain to initiate astrocytopathy and blood-brain barrier breakdown.

No MeSH data available.


Related in: MedlinePlus

BBB breakdown associates with CSF-derived AQP4-IgG + complement and perivascular astrocyte pathology. Micrographs show sagittal sections of the brain of animals injected with AQP4-IgG + complement. BBB breakdown was visualized by leakage of intravenously injected HRP as tracer (brown). (A–F) Micrographs show HRP leakage into the brain parenchyma in cerebellum and midbrain, (D) shows a magnified view of an area in (C) in midbrain. (B and E) show magnified views of perivascular HRP leakage shown in (A and C) respectively, as wide halos around blood vessels. Such pathology was not seen in controls mice (H and I). (G) Quantitation of HRP leakage into the brain parenchyma in animals injected with AQP4-IgG + complement (n = 14), AQP4-IgG alone (n = 12), control HuIgG (n = 10), control HuIgG + complement (n = 13), expressed on a scale of 0–3. Data are presented as mean ± SD. Data indicate BBB breakdown in AQP4-IgG + complement-treated mice. Bar 50 μm (B and D), 20 μm (E), 100 μm (A and F), 200 μm (C, F, and H). BBB, blood-brain barrier; CSF, cerebrospinal fluid; HRP, horseradish peroxidase.
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fig03: BBB breakdown associates with CSF-derived AQP4-IgG + complement and perivascular astrocyte pathology. Micrographs show sagittal sections of the brain of animals injected with AQP4-IgG + complement. BBB breakdown was visualized by leakage of intravenously injected HRP as tracer (brown). (A–F) Micrographs show HRP leakage into the brain parenchyma in cerebellum and midbrain, (D) shows a magnified view of an area in (C) in midbrain. (B and E) show magnified views of perivascular HRP leakage shown in (A and C) respectively, as wide halos around blood vessels. Such pathology was not seen in controls mice (H and I). (G) Quantitation of HRP leakage into the brain parenchyma in animals injected with AQP4-IgG + complement (n = 14), AQP4-IgG alone (n = 12), control HuIgG (n = 10), control HuIgG + complement (n = 13), expressed on a scale of 0–3. Data are presented as mean ± SD. Data indicate BBB breakdown in AQP4-IgG + complement-treated mice. Bar 50 μm (B and D), 20 μm (E), 100 μm (A and F), 200 μm (C, F, and H). BBB, blood-brain barrier; CSF, cerebrospinal fluid; HRP, horseradish peroxidase.

Mentions: Perivascular astrocyte-destructive lesions were associated with disruption of the BBB. HRP from peripheral blood leaked into the brain parenchyma in cerebellum and brainstem and to a lesser degree in cortex in the same five AQP4-IgG + complement-treated mice that exhibited perivascular astrocyte pathology (5/14) (Fig.3A–G). Staining for mouse IgG confirmed the HRP results, and verified that parenchymal diffusion of CSF-derived control HuIgG was not accompanied by endogenous mouse IgG (data not shown). BBB breakdown without AQP4-IgG-mediated immunopathology was not observed.


Cerebrospinal fluid aquaporin-4-immunoglobulin G disrupts blood brain barrier.

Asgari N, Berg CT, Mørch MT, Khorooshi R, Owens T - Ann Clin Transl Neurol (2015)

BBB breakdown associates with CSF-derived AQP4-IgG + complement and perivascular astrocyte pathology. Micrographs show sagittal sections of the brain of animals injected with AQP4-IgG + complement. BBB breakdown was visualized by leakage of intravenously injected HRP as tracer (brown). (A–F) Micrographs show HRP leakage into the brain parenchyma in cerebellum and midbrain, (D) shows a magnified view of an area in (C) in midbrain. (B and E) show magnified views of perivascular HRP leakage shown in (A and C) respectively, as wide halos around blood vessels. Such pathology was not seen in controls mice (H and I). (G) Quantitation of HRP leakage into the brain parenchyma in animals injected with AQP4-IgG + complement (n = 14), AQP4-IgG alone (n = 12), control HuIgG (n = 10), control HuIgG + complement (n = 13), expressed on a scale of 0–3. Data are presented as mean ± SD. Data indicate BBB breakdown in AQP4-IgG + complement-treated mice. Bar 50 μm (B and D), 20 μm (E), 100 μm (A and F), 200 μm (C, F, and H). BBB, blood-brain barrier; CSF, cerebrospinal fluid; HRP, horseradish peroxidase.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig03: BBB breakdown associates with CSF-derived AQP4-IgG + complement and perivascular astrocyte pathology. Micrographs show sagittal sections of the brain of animals injected with AQP4-IgG + complement. BBB breakdown was visualized by leakage of intravenously injected HRP as tracer (brown). (A–F) Micrographs show HRP leakage into the brain parenchyma in cerebellum and midbrain, (D) shows a magnified view of an area in (C) in midbrain. (B and E) show magnified views of perivascular HRP leakage shown in (A and C) respectively, as wide halos around blood vessels. Such pathology was not seen in controls mice (H and I). (G) Quantitation of HRP leakage into the brain parenchyma in animals injected with AQP4-IgG + complement (n = 14), AQP4-IgG alone (n = 12), control HuIgG (n = 10), control HuIgG + complement (n = 13), expressed on a scale of 0–3. Data are presented as mean ± SD. Data indicate BBB breakdown in AQP4-IgG + complement-treated mice. Bar 50 μm (B and D), 20 μm (E), 100 μm (A and F), 200 μm (C, F, and H). BBB, blood-brain barrier; CSF, cerebrospinal fluid; HRP, horseradish peroxidase.
Mentions: Perivascular astrocyte-destructive lesions were associated with disruption of the BBB. HRP from peripheral blood leaked into the brain parenchyma in cerebellum and brainstem and to a lesser degree in cortex in the same five AQP4-IgG + complement-treated mice that exhibited perivascular astrocyte pathology (5/14) (Fig.3A–G). Staining for mouse IgG confirmed the HRP results, and verified that parenchymal diffusion of CSF-derived control HuIgG was not accompanied by endogenous mouse IgG (data not shown). BBB breakdown without AQP4-IgG-mediated immunopathology was not observed.

Bottom Line: A distinct distribution pattern of aquaporin-4-immunoglobulin G deposition was observed in the subarachnoid and subpial spaces where vessels penetrate the brain parenchyma, via a paravascular route with intraparenchymal perivascular deposition.Perivascular astrocyte-destructive lesions were associated with blood-borne horseradish peroxidase leakage indicating blood-brain barrier breakdown.The cerebrospinal fluid aquaporin-4-immunoglobulin G therefore distributes widely in brain to initiate astrocytopathy and blood-brain barrier breakdown.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology, Institute of Molecular Medicine, University of Southern Denmark Odense C, Denmark.

ABSTRACT
To clarify the significance of immunoglobulin G autoantibody specific for the astrocyte water channel aquaporin-4 in cerebrospinal fluid, aquaporin-4-immunoglobulin G from a neuromyelitis optica patient was administered intrathecally to naïve mice, and the distribution and pathogenic impact was evaluated. A distinct distribution pattern of aquaporin-4-immunoglobulin G deposition was observed in the subarachnoid and subpial spaces where vessels penetrate the brain parenchyma, via a paravascular route with intraparenchymal perivascular deposition. Perivascular astrocyte-destructive lesions were associated with blood-borne horseradish peroxidase leakage indicating blood-brain barrier breakdown. The cerebrospinal fluid aquaporin-4-immunoglobulin G therefore distributes widely in brain to initiate astrocytopathy and blood-brain barrier breakdown.

No MeSH data available.


Related in: MedlinePlus