Neuromyelitis optica IgG in the cerebrospinal fluid induces astrocytopathy in optic nerve
Author(s): ,
K.K. Soelberg
Affiliations:
Department of Neurology, Vejle Hospital, Vejle; Department of Ophthalmology, Odense University Hospital; Deparment of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark
,
S. Lillevang
Affiliations:
Department of Clinical Immunology, Odense University Hospital, Odense, Denmark
,
M.T. Mørch
Affiliations:
Deparment of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark
,
R. Khorooshi
Affiliations:
Deparment of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark
,
C.T. Berg
Affiliations:
Deparment of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark
,
B.P. Morgan
Affiliations:
Systems Immunity University Research Institute, Cardiff University, Cardiff, United Kingdom
,
N. Asgari
Affiliations:
Department of Neurology, Vejle Hospital, Vejle; Deparment of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark
T. Owens
Affiliations:
Deparment of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark; TO and NA Share Last Authorship, ., Denmark
(Abstract release date: 09/23/15) ECTRIMS Online Library. Soelberg K. 10/09/15; 116097; 1699
Kerstin Kathrine Soelberg
Kerstin Kathrine Soelberg
Contributions
Abstract
Abstract: P861

Type: Poster

Abstract Category: Experimental models

Background: Serum immunoglobulin G targeting the astrocyte water channel aquaporin-4 (AQP4) in the central nervous system (CNS) is a biomarker for neuromyelitis optica spectrum disease (NMOSD). Optic neuritis (ON) is believed to be immune-mediated and is associated with AQP4-IgG in NMOSD-ON. The predilection of the optic nerve in NMOSD may partly be explained by the dense expression of AQP4 in the optic nerve. We previously reported that AQP4-IgG in cerebrospinal fluid (CSF) becomes widely distributed in the brain and causes complement-dependent astrocyte injury in periventricular areas and brain parenchyma.

Objective: To examine the pathogenicity of CSF AQP4-IgG on the optic nerve.

Materials and methods: Purified AQP4-IgG from an NMOSD patient was given to naïve mice as a single intrathecal injection into CSF at the cisterna magna with human complement (C) +/- anti- regulatory protein CD59a antibody (anti-CD59a). A total of five mice received AQP4-IgG + C + anti-CD59a, four mice received normal-IgG + C + anti-CD59a, four mice received AQP4-IgG+ C and one normal-IgG + C. Mice were killed four days later. The optic nerves were isolated and fixed in paraformaldehyde. Paraffin embedded optic nerves were cut into sections of 6µm, and immunostaining was performed1. Histological changes were scored semiquantitatively 0-31.

Results: Intrathecal injection of AQP4-IgG + C induced focal astrocyte pathology with loss of AQP4 and glial fibrillary acidic protein (GFAP) in optic nerves from all mice, which was coincident with deposition of complement. Histopathological lesions were markedly enhanced with extensive/long-segment astrocytopathy of optic nerve and optic chiasm involvement in AQP4-IgG+ C + anti-CD59a treated mice. Such pathology was not seen in mice receiving normal human IgG, C and anti-CD59a.

Conclusion: We describe the induction of ON in an animal model for NMOSD, utilizing the intrathecal route for antibody administration, which mimics a physiological approach for the presence of antibody in the CSF.

Reference:

1- Asgari N, Khorooshi R, Lillevang ST, Owens T. Complement-dependent pathogenicity of brain-specific antibodies in cerebrospinal fluid. Journal of neuroimmunology 2013;254:76-82.

Disclosure:

KK. Soelberg: nothing to disclose

ST. Lillevang: nothing to disclose

M. Mørch: nothing to disclose

R Khorooshi: nothing to disclose

CT. Berg: nothing to disclose

BP. Morgan: nothing to disclose

N. Asgari: nothing to disclose

T. Owens: nothing to disclose

Abstract: P861

Type: Poster

Abstract Category: Experimental models

Background: Serum immunoglobulin G targeting the astrocyte water channel aquaporin-4 (AQP4) in the central nervous system (CNS) is a biomarker for neuromyelitis optica spectrum disease (NMOSD). Optic neuritis (ON) is believed to be immune-mediated and is associated with AQP4-IgG in NMOSD-ON. The predilection of the optic nerve in NMOSD may partly be explained by the dense expression of AQP4 in the optic nerve. We previously reported that AQP4-IgG in cerebrospinal fluid (CSF) becomes widely distributed in the brain and causes complement-dependent astrocyte injury in periventricular areas and brain parenchyma.

Objective: To examine the pathogenicity of CSF AQP4-IgG on the optic nerve.

Materials and methods: Purified AQP4-IgG from an NMOSD patient was given to naïve mice as a single intrathecal injection into CSF at the cisterna magna with human complement (C) +/- anti- regulatory protein CD59a antibody (anti-CD59a). A total of five mice received AQP4-IgG + C + anti-CD59a, four mice received normal-IgG + C + anti-CD59a, four mice received AQP4-IgG+ C and one normal-IgG + C. Mice were killed four days later. The optic nerves were isolated and fixed in paraformaldehyde. Paraffin embedded optic nerves were cut into sections of 6µm, and immunostaining was performed1. Histological changes were scored semiquantitatively 0-31.

Results: Intrathecal injection of AQP4-IgG + C induced focal astrocyte pathology with loss of AQP4 and glial fibrillary acidic protein (GFAP) in optic nerves from all mice, which was coincident with deposition of complement. Histopathological lesions were markedly enhanced with extensive/long-segment astrocytopathy of optic nerve and optic chiasm involvement in AQP4-IgG+ C + anti-CD59a treated mice. Such pathology was not seen in mice receiving normal human IgG, C and anti-CD59a.

Conclusion: We describe the induction of ON in an animal model for NMOSD, utilizing the intrathecal route for antibody administration, which mimics a physiological approach for the presence of antibody in the CSF.

Reference:

1- Asgari N, Khorooshi R, Lillevang ST, Owens T. Complement-dependent pathogenicity of brain-specific antibodies in cerebrospinal fluid. Journal of neuroimmunology 2013;254:76-82.

Disclosure:

KK. Soelberg: nothing to disclose

ST. Lillevang: nothing to disclose

M. Mørch: nothing to disclose

R Khorooshi: nothing to disclose

CT. Berg: nothing to disclose

BP. Morgan: nothing to disclose

N. Asgari: nothing to disclose

T. Owens: nothing to disclose

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