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

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord. It is considered a severe variant of multiple sclerosis (MS), and frequently is misdiagnosed as MS, but prognosis and optimal treatments differ. A serum immunoglobulin G autoantibody (NMO-IgG) serves as a specific marker for NMO. Here we show that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier. NMO may represent the first example of a novel class of autoimmune channelopathy.

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Devic’s neuromyelitis optica: a critical review

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2008000100034 ◽

2008 ◽

Vol 66 (1) ◽

pp. 120-138 ◽

Cited By ~ 36

Author(s):

Marco Aurélio Lana-Peixoto

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Neuromyelitis Optica ◽

Brain Mri ◽

Water Channel ◽

Demyelinating Diseases ◽

Aquaporin 4 ◽

Igg Antibody ◽

Vascular Walls ◽

Devic’S Neuromyelitis Optica

Devic's neuromyelitis optica (NMO) is an idiopathic inflammatory demyelinating and necrotizing disease characterized by predominant involvement of the optic nerves and spinal cord. In Asian countries relapsing NMO has been known as opticospinal multiple sclerosis. It has long been debated if NMO is a variant of multiple sclerosis (MS) or a distinct disease. Recent studies have shown that NMO has more frequently a relapsing course, and results from attack to aquaporin-4 which is the dominant water channel in the central nervous system, located in foot processes of the astrocytes. Distinctive pathological features of NMO include perivascular deposition of IgG and complement in the perivascular space, granulocyte and eosinophil infiltrates and hyalinization of the vascular walls. These features distinguish NMO from other demyelinating diseases such as MS and acute demyelinating encephalomyelopathy. An IgG-antibody that binds to aquaporin-4, named NMO-IgG has high sensitivity and specificity. Magnetic resonance imaging (MRI) studies have revealed that more frequently there is a long spinal cord lesion that extends through three or more vertebral segments in length. Brain MRI lesions atypical for MS are found in the majority of cases. Treatment in the acute phase includes intravenous steroids and plasma exchange therapy. Immunosupressive agents are recommended for prophylaxis of relapses.

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Anti-aquaporin 4 antibody in selected Japanese multiple sclerosis patients with long spinal cord lesions

Multiple Sclerosis Journal ◽

10.1177/1352458507076976 ◽

2007 ◽

Vol 13 (7) ◽

pp. 850-855 ◽

Cited By ~ 80

Author(s):

K. Tanaka ◽

T. Tani ◽

M. Tanaka ◽

T. Saida ◽

J. Idezuka ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Demyelinating Disease ◽

Detection System ◽

Aquaporin 4 ◽

Specific Marker ◽

Spinal Cord Lesions ◽

Hek 293 ◽

Asian Populations ◽

Multiple Sclerosis Patients

Multiple sclerosis (MS) in Asian populations is often characterized by the selective involvement of the optic nerve (ON) and spinal cord (SP) (OSMS) in contrast to classic MS (CMS), where frequent lesions are observed in the cerebrum, cerebellum or brainstem. In Western countries, inflammatory demyelinating disease preferentially involving the ON and SP is called neuromyelitis optica (NMO). Recently, Lennon et al. discovered that NMO-IgG, shown to bind to aquaporin 4 (AQP4), could be a specific marker of NMO and also of Japanese OSMS whose clinical features were identical to NMO having long spinal cord lesions extending over three vertebral segments (LCL). To examine this antibody in larger populations of Japanese OSMS patients in order to know its epidemiological and clinical spectra, we established an immunohistochemical detection system for the anti-AQP4 antibody (AQP4-Ab) using the AQP4-transfected human embryonic kidney cell line (HEK-293) and confirmed AQP4-Ab positivity together with the immunohistochemical staining pattern of NMO-IgG in approximately 60% of Japanese OSMS patients with LCL. Patients with OSMS without LCL and those with CMS were negative for this antibody. Our results accorded with those of Lennon et al. suggest that Japanese OSMS with LCL may have an underlying pathogenesis in common with NMO. Multiple Sclerosis 2007; 13: 850—855. http://msj.sagepub.com

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Neuromyelitis Optica

10.1093/med/9780199937837.003.0088 ◽

2017 ◽

Cited By ~ 1

Author(s):

Teri L. Schreiner ◽

Jeffrey L. Bennett

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Optic Neuritis ◽

Neuromyelitis Optica ◽

Water Channel ◽

Transverse Myelitis ◽

Inflammatory Disorder ◽

The Central Nervous System

Neuromyelitis optica (NMO), or Devic’s disease is an inflammatory disorder of the central nervous system that preferentially affects the optic nerves and spinal cord. Initially considered a variant of multiple sclerosis (MS), NMO is now clearly recognized to have distinct clinical, radiographic, and pathologic characteristics. Historically, the diagnosis of NMO required bilateral optic neuritis and transverse myelitis; however, the identification of a specific biomarker, NMO-IgG, an autoantibody against the aquaporin-4 (AQP4) water channel, has broadened NMO spectrum disease to include patients with diverse clinical and radiographic presentations. This chapter addresses the diagnosis, pathophysiology, and management of the disease.

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Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders.

10.21203/rs.3.rs-27104/v1 ◽

2020 ◽

Author(s):

Leung-Wah Yick ◽

Chi-Ho Tang ◽

Oscar Ka-Fai Ma ◽

Jason Shing-Cheong Kwan ◽

Koon Ho CHAN

Keyword(s):

Spinal Cord ◽

Neuromyelitis Optica ◽

Neurotrophic Factor ◽

Water Channel ◽

Transverse Myelitis ◽

Aquaporin 4 ◽

Glutamate Excitotoxicity ◽

Neuromyelitis Optica Spectrum Disorders ◽

Motor Impairments ◽

Spectrum Disorders

Abstract Background: Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) autoimmune inflammatory demyelinating diseases characterized by recurrent episodes of acute optic neuritis and transverse myelitis. Aquaporin-4 immunoglobulin G (AQP4-IgG) autoantibodies, which target the water channel aquaporin-4 (AQP4) on astrocytic membrane, are pathogenic in NMOSD. Glutamate excitotoxicity, which is triggered by internalization of AQP4-glutamate transporter complex after AQP4-IgG binding to astrocytes, is involved in early NMOSD pathophysiologies. We studied the effects of memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on motor impairments and spinal cord pathologies in mice which received human AQP4-IgG. Methods: Purified IgG from AQP4-IgG-seropositive NMOSD patients were passively transferred to adult C57BL/6 mice with disrupted blood-brain barrier. Memantine was administered by oral gavage. Motor impairments of the mice were assessed by beam walking test. Spinal cords of the mice were assessed by immunofluorescence and ELISA. Results: Oral administration of memantine ameliorated the motor impairments induced by AQP4-IgG, no matter the treatment was initiated before (preventive) or after (therapeutic) disease flare. Memantine profoundly reduced AQP4 and astrocyte loss, and attenuated demyelination and axonal loss in the spinal cord of mice which had received AQP4-IgG. The protective effects of memantine were associated with inhibition of apoptosis and suppression of neuroinflammation, with decrease in microglia activation and neutrophil infiltration and reduction of increase in levels of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). In addition, memantine elevated growth factors including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) in the spinal cord. Conclusions: Our findings support that glutamate excitotoxicity and neuroinflammation plays important roles in complement-independent pathophysiology during early development of NMOSD lesions, and highlight the potential of oral memantine as a therapeutic agent in NMOSD acute attacks.

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Central vein sign and other radiographic features distinguishing myelin oligodendrocyte glycoprotein antibody disease from multiple sclerosis and aquaporin-4 antibody-positive neuromyelitis optica

Multiple Sclerosis Journal ◽

10.1177/13524585211007086 ◽

2021 ◽

pp. 135245852110070

Author(s):

John R Ciotti ◽

Noah S Eby ◽

Matthew R Brier ◽

Gregory F Wu ◽

Salim Chahin ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Optic Nerve ◽

Neuromyelitis Optica ◽

Myelin Oligodendrocyte Glycoprotein ◽

Aquaporin 4 ◽

Central Vein ◽

Nerve Involvement ◽

Fluid Attenuated Inversion Recovery ◽

Optic Nerve Involvement

Background: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) can radiographically mimic multiple sclerosis (MS) and aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD). Central vein sign (CVS) prevalence has not yet been well-established in MOGAD. Objective: Characterize the magnetic resonance imaging (MRI) appearance and CVS prevalence of MOGAD patients in comparison to matched cohorts of MS and AQP4+ NMOSD. Methods: Clinical MRIs from 26 MOGAD patients were compared to matched cohorts of MS and AQP4+ NMOSD. Brain MRIs were assessed for involvement within predefined regions of interest. CVS was assessed by overlaying fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted sequences. Topographic analyses were performed on spinal cord and orbital MRIs when available. Results: MOGAD patients had fewer brain lesions and average CVS+ rate of 12.1%, compared to 44.4% in MS patients ( p = 0.0008). MOGAD spinal cord and optic nerve involvement was lengthier than MS (5.8 vs 1.0 vertebral segments, p = 0.020; 3.0 vs 0.5 cm, p < 0.0001). MOGAD patients tended to have bilateral/anterior optic nerve pathology with perineural contrast enhancement, contrasting with posterior optic nerve involvement in NMOSD. Conclusion: CVS+ rate and longer segments of involvement in the spinal cord and optic nerve can differentiate MOGAD from MS, but do not discriminate as well between MOGAD and AQP4+ NMOSD.

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Neuromyelitis Optica Spectrum Disorders

10.1093/med/9780199341016.003.0023 ◽

2016 ◽

Cited By ~ 3

Author(s):

Dean M. Wingerchuk

Keyword(s):

Multiple Sclerosis ◽

Neuromyelitis Optica ◽

Water Channel ◽

Transverse Myelitis ◽

Central Nervous System Disease ◽

Aquaporin 4 ◽

Pathogenic Potential ◽

System Disease ◽

Secondary Demyelination ◽

Spectrum Disorders

Neuromyelitis optica (NMO) is an inflammatory demyelinating central nervous system disease. It has been classically defined as a monophasic, isolated co-occurrence of optic neuritis and transverse myelitis with uncertain relationship to multiple sclerosis. In the past decade, however, NMO has emerged as a distinct disorder associated with serum antibodies that target the astrocyte water channel aquaporin-4, distinguishing it from multiple sclerosis. The specificity of aquaporin-4 antibodies has led to appreciation of a wider spectrum of clinical and neuroimaging features, termed NMO spectrum disorders (NMOSD), than was encompassed by the classic NMO definition. Moreover, immunopathological studies have demonstrated that aquaporin-4 antibodies have pathogenic potential and that the disorder is a primary astrocytopathy with secondary demyelination. This chapter discusses the clinical definition and diagnosis of NMOSD and approaches to management, many informed by rapid advances in the understanding of NMO pathobiology.

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No association of AQP4 polymorphisms with neuromyelitis optica and multiple sclerosis

Translational Neuroscience ◽

10.1515/tnsci-2016-0012 ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 2

Author(s):

Ting-Ting Yang ◽

Yang He ◽

Ya-Juan Xiang ◽

Dong-Hui Ao ◽

Yang-Yang Wang ◽

...

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Environmental Factors ◽

Neuromyelitis Optica ◽

Water Channel ◽

Aquaporin 4 ◽

The Central Nervous System ◽

Genetic And Environmental Factors ◽

Demyelinating Disorders

AbstractMultiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory demyelinating disorders of the central nervous system (CNS). Various genetic and environmental factors have been identified to contribute to etiology of MS and NMO. Aquaporin 4 (AQP4), is the most abundant water channel in CNS.

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NMO-IgG: A Specific Biomarker for Neuromyelitis Optica

Disease Markers ◽

10.1155/2006/586306 ◽

2006 ◽

Vol 22 (4) ◽

pp. 197-206 ◽

Cited By ~ 55

Author(s):

Brian G. Weinshenker ◽

Dean M. Wingerchuk ◽

Sean J. Pittock ◽

Claudia F. Lucchinetti ◽

Vanda A. Lennon

Keyword(s):

Spinal Cord ◽

Optic Neuritis ◽

Neuromyelitis Optica ◽

Demyelinating Disease ◽

Water Channel ◽

Clinical Manifestations ◽

Transverse Myelitis ◽

Spinal Cord Tissue ◽

Igg Binding ◽

Complex Deposition

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that principally targets the optic nerves and spinal cord and often leads to severe disability and occasionally life threatening respiratory failure. Although its clinical manifestations overlap with those of multiple sclerosis (MS), in established cases these two conditions can be distinguished on the basis of clinical, radiological, and routine spinal fluid studies. The diagnosis in early cases or limited forms of NMO is difficult. We recently discovered a unique IgG autoantibody (NMO-IgG) that is highly specific to patients with NMO and thus a valuable diagnostic aid. Its antigen, aquaporin-4 (AQP4), is the central nervous system’s predominant water channel protein. This antibody has not yet been proven to be pathogenic, but several facts suggest that it might be, including the similarity of the immunohistochemical pattern of NMO-(AQP4) IgG binding to mouse CNS tissues to the pattern of immune complex deposition in autopsied patients’ spinal cord tissue. The spectrum of diseases identified by NMO-IgG is broader than has previously been recognized clinically and includes incomplete forms of NMO, such as recurrent transverse myelitis without optic neuritis and recurrent optic neuritis without myelitis.

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