Naive B cells in neuromyelitis optica spectrum disorders: impact of steroid use and relapses
Malou JanssenArlette L. BruijstensJamie van LangelaarYuYi WongAnnet F. Wierenga‐WolfMarie‐José MeliefLiza RijversE Daniëlle van PeltJoost SmoldersBeatrijs WokkeMarvin M. van Luijn
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Abstract:
Neuromyelitis optica spectrum disorders are a group of rare, but severe autoimmune diseases characterized by inflammation of the optic nerve(s) and/or spinal cord. Although naive B cells are considered key players by escaping central tolerance checkpoints, it remains unclear how their composition and outgrowth differ in patients with neuromyelitis optica spectrum disorders. Under complete treatment-naive circumstances, we found that naive mature/transitional B-cell ratios were reduced in the blood of 10 patients with aquaporin-4 immunoglobulin G-positive disease (neuromyelitis optica spectrum disorders) as compared to 11 both age- and gender-matched healthy controls, eight patients with myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders and 10 patients with multiple sclerosis. This was the result of increased proportions of transitional B cells, which were the highest in patients with neuromyelitis optica spectrum disorders with relapses and strongly diminished in a separate group of nine patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders who received corticosteroid treatment. These findings need to be confirmed in longitudinal studies. For purified naive mature B cells of seven patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders with relapses, Toll-like receptor 9 ligand synergized with interferon-γ to enhance plasmablast formation during germinal centre-like cultures. This was not seen for 11 patients without relapses and nine healthy controls. In the neuromyelitis optica spectrum disorders group, in vitro plasmablast formation corresponded to total and anti-aquaporin-4 immunoglobulin G secretion, of which the latter was found only for relapsing cases. These data indicate that naive B-cell homoeostasis is different and selectively targeted by corticosteroids in patients with neuromyelitis optica spectrum disorders. This also supports further exploration of naive B cells for their use in Toll-like receptor 9-dependent in vitro platforms in order to predict the activity of neuromyelitis optica spectrum disorders.Keywords:
Neuromyelitis Optica
Myelin oligodendrocyte glycoprotein
Demyelinating Disorder
Neuromyelitis Optica
Myelin oligodendrocyte glycoprotein
Spectrum disorder
Optic neuritis
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While neuromyelitis optica (NMO) immunoglobulin (Ig) G is considered the hallmark serologic marker of NMO, its association is not absolute, as NMO IgG is not detected in approximately one-fourth of the patients diagnosed with NMO spectrum disorder (NMOSD). Thus, the recent discovery that antibodies to myelin oligodendrocyte glycoprotein (MOG) are detected in some NMO IgG-seronegative patients manifesting clinical and neuroimaging signs of NMO or NMOSD has created tremendous excitement. However, it may be premature to classify this subgroup as NMOSD. NMO is considered an autoimmune astrocytopathy, and aquaporin-4 (AQP4), expressed on astrocytes, is recognized as the target autoantigen of NMO IgG. As its name denotes, MOG is produced by oligodendrocytes, CNS myelin-producing cells, and MOG is well-recognized as one of the candidate autoantigens in multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). Thus, is it possible that the clinical NMOSD-like phenotype associated with MOG-specific antibodies represents a variant of opticospinal MS or ADEM but not AQP4 autoimmunity or NMOSD? Whether this MOG-Ig positive AQP4-seronegative phenotype should be classified as NMOSD, opticospinal MS, or a unique entity is not simply a theoretical question but rather has practical implications for patients, their physicians, insurance carriers, and clinical investigators conducting NMO treatment trials.
Neuromyelitis Optica
Myelin oligodendrocyte glycoprotein
Acute disseminated encephalomyelitis
Spectrum disorder
Demyelinating disease
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Abstract: Neuromyelitis optica (NMO) refers to an antibody mediated, inflammatory disorder of the central nervous system (CNS) characterized by recurrent or monophasic attacks of optic neuritis and myelitis. Most patients with NMO possess a specific serum immunoglobin, NMO-IgG, which can serve as a biomarker for NMO. The autoantibodies target aquaporin-4 (AQP4), the main water channel protein found in the CNS including the brain, spinal cord, and optic nerve. The remaining 10–25% of patients are seronegative for NMO-IgG despite meeting the diagnostic criteria for NMO. Recent studies have shown that a subset of these patients is seropositive for antibodies against myelin oligodendrocyte glycoprotein (MOG). This paper will provide an overview of the current English scientific literature published regarding the history, epidemiology, AQP4 biomarker, MOG biomarker, diagnosis, clinical features, related diseases in NMO spectrum disorder (NMOSD), and treatments of NMO.
Neuromyelitis Optica
Myelin oligodendrocyte glycoprotein
Optic neuritis
Spectrum disorder
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Neuromyelitis Optica spectrum disorder (NMO-SD) is a rare demyelinating disease detected in pediatric patients affecting the primary optic nerve and spinal cord. Clinical findings might overlap with other demyelinating diseases and compare to particularly multiple sclerosis the treatment regimens significantly differ. Therefore, to establish an immediate and definite diagnosis of NMO-SD is crucial. In the majority of patients, the aquaporin-4 antibody is detected in the serum as one of the supporting diagnostic criteria. The antibody against myelin oligodendrocyte glycoprotein (MOG) is recently reported to be associated with serum aquaporin-4 antibody seronegative NMO-SD. Although not included in the diagnostic criteria, we believe that anti-MOG antibody may facilitate the diagnosis of NMO-SD. We herein report a pediatric case of NMO-SD with the anti-MOG antibody seropositivity.
Neuromyelitis Optica
Myelin oligodendrocyte glycoprotein
Optic neuritis
Demyelinating Disorder
Demyelinating disease
Aquaporin 4
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The myelin/oligodendrocyte glycoprotein (MOG) is identified by monoclonal antibody 8–18C5. MOG is localized on the surface of myelin and oligodendrocyte processes. Recently, several studies have shown that MOG plays an important role as a target for antibody-induced demyelination. In the present study, we investigated MOG expression in the brains of normal and myelin-deficient (mld)mutant mice during development. By gel electrophoresis and immunoblotting, we observed the developmental pattern of two closely migrating bands, with apparent molecular masses of 26 and 28 kilodaltons. Their concentrations increased coordinately during the most active phase of myelin and myelin basic protein (MBP) synthesis. Between 20 and 25 days of age, the MOG developmental pattern superimposed that of MBP as well as myelin yields. In mld mutant mice, which are affected by a severe deficit of MBP synthesis, MOG was present at reduced levels (40% of controls at 60 days of age). At 85 days of age, mld mice exhibited increased concentrations of MBP, and myelin was better compacted. At this age, MOG concentrations increased and reached 70% of controls. These results suggest that MOG could play a role in the maintenance or completion of the myelin sheath. Its expression level may be modulated by the presence of compact myelin and/or MBP in the myelin sheath.
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Myelin oligodendrocyte glycoprotein
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Neuromyelitis Optica
Myelin oligodendrocyte glycoprotein
Spectrum disorder
Demyelinating Disorder
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Several syndromes have been described with associated myelin oligodendrocyte glycoprotein (MOG) antibodies (Abs). The studies evaluating prognosis in
Neuromyelitis Optica
Myelin oligodendrocyte glycoprotein
Spectrum disorder
Demyelinating Disorder
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Abstract This review highlights the most common presentations of demyelination of the central nervous system (CNS, termed acquired demyelinating syndrome) in children, the difficulty in determining whether the first episode represents a monophasic/transient illness or relapsing disease, and the potential underlying etiologies that must be considered, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and disorders associated with antibodies to myelin oligodendrocyte glycoprotein (MOG) antibodies. The initial clinical and magnetic resonance imaging (MRI) features, as well as those observed over time, are highlighted, emphasizing the distinct and overlapping features of each of these disorders.
Neuromyelitis Optica
Myelin oligodendrocyte glycoprotein
Spectrum disorder
Demyelinating Disorder
Demyelinating disease
Etiology
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Neuromyelitis Optica Spectrum Disorder (NMOSD) is a central nervous system (CNS) inflammatory demyelinating disease characterized by recurrent inflammatory events that primarily involve optic nerves and the spinal cord, but also affect other regions of the CNS, including hypothalamus, area postrema and periaqueductal gray matter. The aquaporin-4 antibody (AQP4-IgG) is specific for NMOSD. Recently, myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) have been found in a group of AQP4-IgG negative patients. NMOSD is rare among children and adolescents, but early diagnosis is important to start adequate therapy. In this report, we present cases of seven pediatric patients with NMOSD and we review the clinical and neuroimaging characteristics, diagnosis, and treatment of NMOSD in children.
Neuromyelitis Optica
Myelin oligodendrocyte glycoprotein
Spectrum disorder
Demyelinating Disorder
Optic neuritis
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Neuromyelitis optica (NMO) is an autoimmune, demyelinating disease of the central nervous system manifesting with optic neuritis and longitudinally extensive transverse myelitis.Aquaporin-4 (AQP4)-IgG is currently regarded as a specific biomarker of NMO.Nevertheless, AQP4-IgG seronegativity in 10%-25% of NMO patients suggests that there are several other factors involved in NMO immunopathogenesis.In this article, we reviewed current knowledge about biomarkers of NMO from AQP4, myelin-oligodendrocyte glycoprotein, AQP1 and glial fibrillary acidic protein, providing a new insight in the diagnosis of NMO.
Key words:
Neuromyelitis optica; Aquaporin-4; Myelin-oligodendrocyte glycoprotein; Aquaporin-1; Glial fibrillary acidic protein
Neuromyelitis Optica
Myelin oligodendrocyte glycoprotein
Optic neuritis
Aquaporin 4
Citrullination
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