Comprehensive Analysis of N6-Methyladenosine (m6A) Methylation in Neuromyelitis Optica Spectrum Disorders

Background: N6-Methyladenosine (m6A) methylation is the most prevalent internal posttranscriptional modification on mammalian mRNA. But its role in neuromyelitis optica spectrum disorders (NMOSD) is not known.Aims: To explore the mechanism of m6A in NMOSD patients.Methods: This study assessed the m6A methylation levels in blood from two groups: NMOSD patients and healthy controls. Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) and RNA-seq were performed to assess differences in m6A methylation between NMOSD patients and healthy controls. Ultra-high performance liquid chromatography coupled with triple quadruple mass spectrometry (UPLC-QQQ-MS) method was performed to check m6A level. Differential m6A methylation genes were validated by MeRIP-qPCR.Results: Compared with that in the control group, the total m6A level was decreased in the NMOSD group. Genes with upregulated methylation were primarily enriched in processes associated with RNA splicing, mRNA processing, and innate immune response, while genes with downregulated methylation were enriched in processes associated with the regulation of transcription, DNA-templating, and the positive regulation of I-kappa B kinase/NF-kappa B signalling.Conclusion: These findings demonstrate that differential m6A methylation may act on functional genes to regulate immune homeostasis in NMOSD.

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Analysis of Peripapillary Retinal Nerve Fiber Layer and Macular Volume in Patients with Multiple Sclerosis, Neuromyelitis Optica Spectrum Disorders, and Healthy Controls Using Spectral Domain Optical Coherence Tomography in a Turkish Cohort

Turkish Journal Of Neurology ◽

10.4274/tnd.2018.33230 ◽

2019 ◽

Vol 25 (1) ◽

pp. 26-31

Author(s):

Ayşe İlksen Çolpak ◽

Duygu Gülmez Sevim ◽

Aslı Tuncer ◽

Sevda Diker ◽

Rana Karabudak ◽

...

Keyword(s):

Multiple Sclerosis ◽

Optical Coherence Tomography ◽

Nerve Fiber ◽

Neuromyelitis Optica ◽

Retinal Nerve Fiber Layer ◽

Healthy Controls ◽

Neuromyelitis Optica Spectrum Disorders ◽

Fiber Layer ◽

Nerve Fiber Layer ◽

Spectrum Disorders

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Mapping white matter damage distribution in neuromyelitis optica spectrum disorders with a multimodal MRI approach

Multiple Sclerosis Journal ◽

10.1177/1352458520941493 ◽

2020 ◽

pp. 135245852094149

Author(s):

Laura Cacciaguerra ◽

Maria A Rocca ◽

Loredana Storelli ◽

Marta Radaelli ◽

Massimo Filippi

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Fractional Anisotropy ◽

Neuromyelitis Optica ◽

Mean Diffusivity ◽

Healthy Controls ◽

Neuromyelitis Optica Spectrum Disorders ◽

White Matter Damage ◽

Axial Diffusivity ◽

Spectrum Disorders

Background: The pathogenetic mechanisms sustaining neuroinflammatory disorders may originate from the cerebrospinal fluid. Objective: To evaluate white matter damage with diffusion tensor imaging and T1/T2-weighted ratio at progressive distances from the ventricular system in neuromyelitis optica spectrum disorders and multiple sclerosis. Methods: Fractional anisotropy, mean, axial, and radial diffusivity and T1/T2-weighted ratio maps were obtained from patients with seropositive neuromyelitis optica spectrum disorders, multiple sclerosis, and healthy controls ( n = 20 each group). White matter damage was assessed as function of ventricular distance within progressive concentric bands. Results: Compared to healthy controls, neuromyelitis optica spectrum disorders patients had similar fractional anisotropy, radial and axial diffusivity, increased mean diffusivity ( p = 0.009–0.013) and reduced T1/T2-weighted ratio ( p = 0.024–0.037) in all bands. In multiple sclerosis, gradient of percentage lesion volume and intra-lesional mean and axial diffusivity were higher in periventricular bands. Compared to healthy controls, multiple sclerosis patients had reduced fractional anisotropy ( p = 0.001–0.043) in periventricular bands, increased mean ( p < 0.001), radial ( p < 0.001–0.004), and axial diffusivity ( p = 0.002–0.008) and preserved T1/T2-weighted ratio in all bands. Conclusion: White matter damage is higher at periventricular level in multiple sclerosis and diffuse in neuromyelitis optica spectrum disorders. Fractional anisotropy preservation, associated with increased mean diffusivity and reduced T1/T2-weighted ratio may reflect astrocyte damage.

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Monoclonal Antibody Therapy in Neuromyelitis Optica Spectrum Disorders: a Meta-analysis of Randomized Control Trials

Frontiers in Pharmacology ◽

10.3389/fphar.2021.652759 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fanxin Kong ◽

Jianjun Wang ◽

Haotao Zheng ◽

Haobin Cai ◽

Jun Hua ◽

...

Keyword(s):

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Adverse Events ◽

Neuromyelitis Optica ◽

Antibody Therapy ◽

Cochrane Library ◽

Control Group ◽

Monoclonal Antibody Therapy ◽

Neuromyelitis Optica Spectrum Disorders ◽

Spectrum Disorders

Background: To update the efficacy and safety data of monoclonal antibodies for the treatment of neuromyelitis optica spectrum disorders (NMOSD) and explore the differences in the effect of treatment between patients seropositive and seronegative for AQP4-IgG. Methods: PubMed, Embase, and the Cochrane Library published up to July 2020 were searched for randomized controlled trials (RCTs) of monoclonal antibodies treatment (mAb) in patients with NMOSD. The primary outcome was the hazard ratio (HR) for relapse. The secondary outcomes included Expanded Disability Status Scale (EDSS) changes from baseline, adverse events (AEs), and serious adverse events (SAEs). A random-effects model was applied for the effect of heterogeneity among trials. Results: We included 603 patients (monoclonal antibody group, n=382, and control group, n=221) from seven RCTs. There were fewer relapses in the mAb group (HR=0.32, 95% CI: 0.23-0.46, p<0.001), as well as in the AQP4-IgG-seropositive patients (HR=0.18, 95% CI: 0.10–0.32, p<0.001), but not in AQP4-IgG-seronegative NMOSD. Similar results were observed when considering satralizumab only. The mAb had no impact on the changes in EDSS scores from baseline (WMD=−0.21, 95% CI: −0.50-0.09, p=0.176). The mAb did not lead to a higher frequency of AEs (OR=1.18, 95% CI: 0.70–1.98, p=0.529) or SAEs (OR=0.99, 95% CI: 0.63–1.56, p=0.975) compared with the control group. Conclusions: Compared to the control arm, monoclonal antibody therapy showed a significantly better outcome in restraining the HR for relapse among patients with NMOSD but insignificant effects in NMOSD patients with seronegative APQ4-IgG. The safety profile in each arm had no significant difference.

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Association of Circulating T Follicular Helper Cells With Idiopathic Optic Neuritis and Neuromyelitis Optica Spectrum Disorders

Frontiers in Neurology ◽

10.3389/fneur.2021.638473 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qian Wu ◽

Binbin Yang ◽

Jiawei Wang

Keyword(s):

Optic Neuritis ◽

Neuromyelitis Optica ◽

Healthy Controls ◽

Neuromyelitis Optica Spectrum Disorders ◽

T Follicular Helper Cells ◽

Tfh Cells ◽

Helper Cells ◽

Follicular Helper ◽

Significant Difference ◽

Spectrum Disorders

Background: T follicular helper cells (Tfh cells) play an important role in activating B lymphocytes and may associate with idiopathic Optic Neuritis (ON) and Neuromyelitis Optica Spectrum Disorders (NMOSD).Objective: This study aimed to examine the potential role of Tfh cells in pathogenesis of idiopathic ON and NMOSD.Methods: Circulating CD4+CXCR5+ and CD4+CXCR5+PD-1+ cells in 46 idiopathic ON and 68 NMOSD patients as well as 28 healthy controls were examined by flow cytometry before treatment. Serum AQP4 antibody, Expended Disability Status Scale (EDSS) and Visual Outcome Scale (VOS) were detected before and after treatment.Results: The percentages of circulating CD4+CXCR5+ and CD4+CXCR5+PD-1+Tfh cells in CD4+ cells (%) were significantly increased in idiopathic ON and NMOSD compared with those of healthy controls (p < 0.01). No significant difference of Tfh cells in blood and cerebral spinal fluid (CSF) was found between ON and NMOSD patients. The percentages of CSF, CD4+, CXCR5+, and CD4+CXCR5+PD-1+ cells in CD4+ cells (%) were positively correlated with those of the blood (r = 0.5781, r = 0.6079, p = 0.0076, and p = 0.0045, respectively). EDSS scores of NMOSD group were higher than those of ON group and the time course of NMOSD patients was longer than that of ON patients (p < 0.01). After methylprednisolone treatment, both EDSS and VOS scores were significantly decreased at discharge compared with before treatment (p < 0.01). There was no significant correlation among Tfh cell percentages in CD4+ cells, CSF leukocytes, CSF protein, annual recurrence rate, EDSS and VOS scores between two groups (p > 0.05).Conclusion: The Circulating T follicular helper cells were increased in both idiopathic ON and NMOSD.

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Naive B cells in neuromyelitis optica spectrum disorders: impact of steroid use and relapses

Brain Communications ◽

10.1093/braincomms/fcaa197 ◽

2020 ◽

Vol 2 (2) ◽

Author(s):

Malou Janssen ◽

Arlette L Bruijstens ◽

Jamie van Langelaar ◽

YuYi Wong ◽

Annet F Wierenga-Wolf ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Neuromyelitis Optica ◽

Immunoglobulin G ◽

Myelin Oligodendrocyte Glycoprotein ◽

Healthy Controls ◽

Neuromyelitis Optica Spectrum Disorders ◽

Toll Like Receptor ◽

Spectrum Disorders

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.

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