Neuromyelitis optica: Passive transfer to rats by human immunoglobulin

doi:10.1016/j.bbrc.2009.06.085

Biochemical and Biophysical Research Communications

Volume 386, Issue 4, 4 September 2009, Pages 623-627

https://doi.org/10.1016/j.bbrc.2009.06.085 Get rights and content

Abstract

Recurrent attacks of optic neuritis and myelitis are the hallmarks of both neuromyelitis optica (NMO) and multiple sclerosis (MS). NMO immunoglobulin G (NMO-IgG), which recognizes astrocytic aquaporin-4 (AQP4) water channels, is a specific serum autoantibody that distinguishes NMO from MS. The pathogenic role of the anti-AQP4 antibody (AQP4-Ab, NMO-IgG) in NMO has been speculated based on several studies in vitro. The aim of this study was to demonstrate the pathogenicity of AQP4-Ab in vivo. We obtained IgG from patients who underwent therapeutic plasmapheresis, and developed an animal model by passive transfer of IgG to rats. The active lesions of the rats exhibited pathological characteristics strikingly similar to those of NMO, marked by astrocytic loss and perivascular deposition of immunoglobulin and complements. These findings provide the first evidence of the pathogenicity of AQP4-Ab in vivo and support the therapeutic efficacy of eliminating the antibodies by plasmapheresis.

Section snippets

Materials and methods

Patients and immunoglobulin preparations. Human samples were collected from three patients with NMO [13] who tested positive for AQP4-Ab, and two patients with clinically definite MS [14] who tested negative for the autoantibody [15]. Plasma proteins of three NMO patients and one MS patient who received therapeutic immunoadsorption plasmapheresis (IAPP) were eluted from the immunoadsorption columns (TR-350, Asahi Medical) with 1 M NaCl buffer. The other MS patient underwent therapeutic plasma

Passive transfer of IgG from patients with NMO exacerbates EAE

To investigate a possible pathogenic role of AQP4-Ab in vivo, IgG purified from AQP4-Ab-harboring NMO patients, or control IgG from MS patients and a pooled human polyclonal immunoglobulin preparation were administered to EAE rats actively immunized to compromise the integrity of the blood–brain barrier (BBB). Compared with the rapid spontaneous recovery, which is consistent with an ordinary clinical course of EAE, in the control group, rats of the NMO group exhibited more severe disease

Discussion

The present study clearly shows that IgG from NMO patients can reproduce pathological characteristics strikingly similar to those of NMO when passively transferred to rats. The active lesions of our animal model were marked by extensive loss of astrocytes and perivascular deposition of immunoglobulin and complements. Among various autoantibodies targeted against antigens in the CNS, only a few of them, such as antibodies against oligodendrocyte glycoprotein and neurofascin in MS and

Acknowledgments

We thank Dr. Tomoyuki Sugimoto for expert statistical assistance and Dr. Keiko Tanaka for the serum AQP4-Ab test. This study was supported in part by the Program of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) and by Health and Labour Sciences Research Grants for research on intractable diseases from Ministry of Health, Labour and Welfare of Japan.

References (23)

V.A. Lennon et al.
A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis
Lancet
(2004)
T. Fujimoto et al.
Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats
J. Neuroimmunol.
(1999)
C. Sommer et al.
Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin
Lancet
(2005)
T. Tani et al.
Identification of binding sites for anti-aquaporin 4 antibodies in patients with neuromyelitis optica
J. Neuroimmunol.
(2009)
D.V. Krysko et al.
Apoptosis and necrosis: detection, discrimination and phagocytosis
Methods
(2008)
T. Matsuoka et al.
Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese
Brain
(2007)
T. Misu et al.
Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis
Brain
(2007)
S.F. Roemer et al.
Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis
Brain
(2007)
V.A. Lennon et al.
IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel
J. Exp. Med.
(2005)
S. Jarius et al.
Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica
Nat. Clin. Pract. Neurol.
(2008)

S.R. Hinson et al.

Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica

Neurology

(2007)

Cited by (218)

A comprehensive review of the advances in neuromyelitis optica spectrum disorder
2023, Autoimmunity Reviews
Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing neuroinflammatory autoimmune astrocytopathy, with a predilection for the optic nerves and spinal cord. Most cases are characterised by aquaporin-4-antibody positivity and have a relapsing disease course, which is associated with accrual of disability. Although the prognosis in NMOSD has improved markedly over the past few years owing to advances in diagnosis and therapeutics, it remains a severe disease. In this article, we review the evolution of our understanding of NMOSD, its pathogenesis, clinical features, disease course, treatment options and associated symptoms. We also address the gaps in knowledge and areas for future research focus.
Modelling MOG antibody-associated disorder and neuromyelitis optica spectrum disorder in animal models: Spinal cord manifestations
2023, Multiple Sclerosis and Related Disorders
Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) or aquaporin 4 (AQP4-IgG) are associated with CNS inflammatory disorders. We directly compared MOG_35–55-induced experimental autoimmune encephalomyelitis exacerbated by MOG- and AQP4-IgG (versus isotype IgG, Iso-IgG). Disease severity was highest after MOG-IgG application. MOG- and AQP4-IgG administration increased disease incidence compared to Iso-IgG. Inflammatory lesions appeared earlier and with distinct localizations after AQP4-IgG administration. AQP4 intensity was more reduced after AQP4- than MOG-IgG administration at acute disease phase. The described models are suitable for comparative analyses of pathological features associated with MOG- and AQP4-IgG and the investigation of therapeutic interventions.
Intradermal AQP4 peptide immunization induces clinical features of neuromyelitis optica spectrum disorder in mice
2023, Journal of Neuroimmunology
We challenged to create a mouse model of neuromyelitis optica spectrum disorder (NMOSD) induced by AQP4 peptide immunization. Intradermal immunization with AQP4 p201–220 peptide induced paralysis in C57BL/6J mice, but not in AQP4 KO mice. AQP4 peptide-immunized mice showed pathological features similar to NMOSD. Administration of anti-IL-6 receptor antibody (MR16–1) inhibited the induction of clinical signs and prevented the loss of GFAP/AQP4 and deposition of complement factors in AQP4 peptide-immunized mice. This novel experimental model may contribute to further understanding the pathogenesis of NMOSD, elucidating the mechanism of action of therapeutic agents, and developing new therapeutic approaches.
Food additive succinate exacerbates experimental autoimmune encephalomyelitis accompanied by increased IL-1β production
2023, Biochemical and Biophysical Research Communications
Identification of double-stranded DNA in the cerebrospinal fluid of patients with acute neuromyelitis optica spectrum disorder
2023, Journal of Clinical Neuroscience
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system (CNS) characterized by severe myelitis and optic neuritis. Double-stranded DNA (dsDNA) is involved in the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus. However, its role in NMOSD remains unclear. In this study, the concentration of dsDNA in the cerebrospinal fluid (CSF) was quantified in 23 patients with NMOSD and 16 patients with other neurological diseases (ONDs). CSF dsDNA levels in patients with NMOSD (median: 0.03 ng/µL) were significantly higher than those in patients with ONDs (median: 0.01 ng/μl). CSF dsDNA levels showed no significant difference before and after treatment. Elevation of CSF dsDNA levels may suggest its essential role in the augmentation of CNS inflammation in patients with NMOSD.
NMO-IgG Induce Interleukin-6 Release via Activation of the NF-κB Signaling Pathway in Astrocytes
2022, Neuroscience
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system (CNS) that frequently affects the optic nerve and spinal cord. Interleukin-6 (IL-6) is considered a key cytokine in the pathogenesis of NMOSD, and the level of IL-6 is significantly increased in the sera and cerebrospinal fluid (CSF) of patients with NMOSD. We have reported that the production of IL-6 depends on the JAK/STAT3 signaling pathway. However, it is not clear whether the NF-κB-dependent inflammatory response stimulated by neuromyelitis optica IgG (NMO-IgG) could also drive the production of IL-6 in astrocytes. In this study, we used an in vitro model of primary rat astrocytes stimulated by NMO-IgG to study the role of the NF-κB signaling pathway in mediating the release of IL-6. First, we confirmed that the level of IL-6 was significantly higher in the sera of NMOSD patients than that of healthy people by humoral fluid analysis and that NMO-IgG can significantly induce the release of IL-6 from astrocytes by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Then, Western blotting and immunocytochemistry showed that NMO-IgG can activate the intracellular NF-κB signaling pathway. Finally, it was found that S3633, an inhibitor of the NF-κB signaling pathway, can effectively inhibit the increase in IL-6 levels. These results prove that the production of IL-6 is partly mediated by the NF-κB signaling pathway, providing a potential effective strategy for targeted treatment of NMOSD.

View all citing articles on Scopus

View full text

Neuromyelitis optica: Passive transfer to rats by human immunoglobulin

Abstract

Section snippets

Materials and methods

Passive transfer of IgG from patients with NMO exacerbates EAE

Discussion

Acknowledgments

Lancet

J. Neuroimmunol.

Lancet

J. Neuroimmunol.

Methods

Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese

Brain

Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis

Brain

Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis

Brain

IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel

J. Exp. Med.

Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica

Nat. Clin. Pract. Neurol.

Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica

Neurology