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Toll-like receptors (TLRs) are a class of proteins that play essential roles in innate and adaptive immune responses. Recently, accumulating evidence has demonstrated that impairments in the TLR signalling pathway contribute to the development and progression of neuroimmune diseases, such as neuromyelitis optica spectrum disorder (NMOSD). However, the cellular and molecular mechanisms are still largely unknown. In this study, we report a novel variant, C52Y, of canopy FGF signalling regulator 3 (CNPY3) from patients with familial NMOSD and demonstrate that this variant shows a stronger interaction with GP96 and TLRs than with wild-type CNPY3. We find that C52Y has dominant negative effects on TLR4 surface expression. Importantly, the TLR4 surface expression level is decreased in RAW264.7 cells infected with the C52Y virus upon LPS stimulation. We further demonstrate that bone marrow-derived macrophages (BMDMs) from CNPY3 C52Y/+ transgenic mice secrete less tumour necrosis factor (TNF) and interleukin (IL)-6 than BMDMs from wild-type mice upon stimulation with LPS. These data suggest that impairment of TLR trafficking may contribute to the development of neuroimmune disorders., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Objective: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease. Although genetic factors are involved in its pathogenesis, limited evidence is available in this area. The aim of the present study was to identify the major genetic factors contributing to NMOSD in Chinese patients with aquaporin 4 (AQP4)-IgG seropositivity., Methods: Whole-exome sequencing (WES) was performed on 228 Chinese NMOSD patients seropositive for AQP4-IgG and 1400 healthy controls in Guangzhou, South China. Human leukocyte antigen (HLA) sequencing was also utilized. Genotype model and haplotype, gene burden, and enrichment analyses were conducted., Results: A significant region of the HLA composition is on chromosome 6, and great variation was observed in DQB1, DQA2 and DQA1. HLA sequencing confirmed that the most significant allele was HLA-DQB1*05:02 (p < 0.01, odds ratio [OR] 3.73). The genotype model analysis revealed that HLA-DQB1*05:02 was significantly associated with NMOSD in the additive effect model and dominant effect model (p < 0.05). The proportion of haplotype "HLA-DQB1*05:02-DRB1*15:01" was significantly greater in the NMOSD patients than the controls, at 8.42% and 1.23%, respectively (p < 0.001, OR 7.39). The gene burden analysis demonstrated that loss-of-function mutations in NOP16 were more common in the NMOSD patients (11.84%) than the controls (5.71%; p < 0.001, OR 2.22). The IgG1-G390R variant was significantly more common in NMOSD, and the rate of the T allele was 0.605 in patients and 0.345 in the controls (p < 0.01, OR 2.92). The enrichment analysis indicated that most of the genetic factors were mainly correlated with nervous and immune processes., Conclusions: Human leukocyte antigen is highly correlated with NMOSD. NOP16 and IgG1-G390R play important roles in disease susceptibility., (© 2021 European Academy of Neurology.)

Background: Few data exists on paediatric neuromyelitis optica spectrum disorder (NMOSD). Here, we investigated the clinical presentation, treatment responses and long-term prognoses in a large cohort of patients with NMOSD and compared between children and adults with aquaporin-4 antibody (AQP4-IgG)., Methods: A retrospective chart review of patients followed in multiple centres identified 127 patients with NMOSD (31 children; 96 adults). Data were collected through medical records and structured questionnaire., Results: In the paediatric cohort, median age at onset was 14 (range 7-17) years; 87% were female. AQP4 and myelin oligodendrocyte glycoprotein antibodies were detected in 82% and 16%, respectively. During a median disease duration of 48 months, 23% developed visual acuity of <6/60 Snellen, 3% were wheelchair-dependent. The frequency of brain/brainstem phenotype (18% vs 9%, p = 0.018) was more common in AQP4-IgG-positive children, while AQP4-IgG-positive adults were more likely to present transverse myelitis (TM) (44% vs 29%, p = 0.005) of all 452 episodes. Multivariable analyses showed that sustained disability was independently associated with the presence of TM (p = 0.030), brain/brainstem symptoms (p = 0.010), annualized relapse rate (p < 0.001) and possibly age of onset (p = 0.069). The reduction of ARR after azathioprine was more prominent in adults (79%) than in children (48%). Mycophenolate mofetil and rituximab decreased the relapse frequency of children, with a reduction of 94% and 100%, respectively., Conclusions: paediatric NMOSD is a severely disabling disorder characterized by repeated brain attacks and early disability accrual. Prompt therapy including mycophenolate mofetil and rituximab should be considered to improve paediatric care., (Copyright © 2019. Published by Elsevier B.V.)

Neuromyelitis optica spectrum disorders (NMOSD) are a group of autoimmune astrocytopathies in the central nervous system, which are mainly caused by immunoglobulin G (IgG) against astrocyte water channel aquaporin-4 (AQP4). In this study, we aimed to establish a model of NMOSD-related optic neuritis (NMOSD-ON) and to evaluate the progressive changes of the optic nerve and visual function. AQP4 IgG-positive serum from NMOSD patients was injected into the subarachnoid space of the rat optic nerve to induce the NMOSD-ON model (AQP4 + group), and healthy serum was injected as the control. The visual evoked potential, pupillary light reflex and optical coherence tomography were monitored every week for 3 weeks after induction. Compared with the control group, the amplitude of the N1-P1 peak and pupillary light reflex in the AQP4+ group were reduced within the first week and then remained low thereafter. Consistent with the functional deficits, the thickness of the peripapillary retinal nerve fiber layer in the AQP4 + group was also greatly reduced. At the end of 3 weeks, there was a loss of retinal ganglion cells and the optic nerves showed characteristic NMOSD-like pathologic changes, including deposition of AQP4 IgG, local astrocyte damage, demyelination, microglia activation, macrophage infiltration and axonal injury. Thus, we have established an NMOSD-ON rat model with deficits in the optic nerve and visual function that may be a valuable tool for exploring the mechanism of NMOSD-ON and evaluating its potential therapeutic treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Previous studies have shown that circulating AQP4-IgG may lead to negative consequences during pregnancy in patients with neuromyelitis optica spectrum disorder (NMOSD). The objective of this study was to explore whether AQP4-IgG influences pregnancy by affecting AQP4 expression and inducing placental inflammation in patients with NMOSD. We prospectively collected clinical data from six pregnant AQP4-IgG-seropositive NMOSD patients and their infants, and investigated AQP4 expression and placental inflammatory infiltration by comparing hematoxylin and eosin and immunohistochemical (AQP1, AQP4, C5b-9, IgG, CD3, CD8, CD20, and CD68) staining results with three normal controls. Four patients were term pregnant and their infants were normal for development, serum AQP4-IgG was positive at the time of birth, and three infants were negative for AQP4-IgG after 3 months. Two patients underwent induced abortion; one because of NMOSD relapse and another because of fetal malformation. Histological investigation showed normal structure of the chorionic villi, and no significant difference in the intensity of the immunohistochemical staining for AQP1, AQP4, and inflammatory markers in placentae of patients and the controls. Our results showed that there was no significant decrease in placental AQP4 expression, and no obvious placental inflammation or signs of damage in term placentae of NMOSD patients seropositive for AQP4-IgG., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory astrocytopathy that has both genetic and environmental causes. A growing body of evidence suggests that the presence of several infectious agents correlates with the development of NMOSD. In this review, we summarize studies that either support or present evidence against the hypothesized association between infection and NMOSD. We will also present an overview of potential mechanisms underlying the pathogenesis of NMOSD. Finally, we provide some beneficial properties that infectious elements may have based on "hygiene hypothesis". It is of great clinical significance to further investigate the complex mechanisms by which infections may affect autoimmune diseases to develop better strategies to prevent and treat them, although so far no causal link between infectious agents and NMOSD has been established., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To screen cytokines and chemokines and determine their dynamic changes in the serum and cerebrospinal fluid (CSF) of patients with neuromyelitis optica spectrum disorder (NMOSD)., Methods: Eight NMOSD with seropositive aquaporin-4 antibody (AQP4-IgG) were enrolled, as well as 8 matched patients with multiple sclerosis (MS) and 8 with noninflammatory neurological diseases, who were included as controls. In total, 102 cytokines and 34 chemokines were detected in the CSF and serum of NMOSD patients and controls., Results: CSF interleukin (IL)-17A levels were significantly higher in NMOSD patients in the relapsing phase (27.15 ± 11.33) than in those in the remitting phase (10.04 ± 3.11, p = 0.0017), and patients with MS (14.72 ± 3.20, p = 0.0283) and other controls (10.39 ± 11.38, p = 0.0021). CSF IL-6 levels were higher in the NMOSD patients in the relapsing phase (12.23 ± 3.47) than in those in the remitting phase (5.87 ± 2.78, p = 0.0001), and MS patients (7.38 ± 2.35, p = 0.0033) and other controls (7.50 ± 0.37, p = 0.0043). CSF CCL19 levels were also significantly higher in NMOSD patients in the relapsing phase (35.87 ± 27.07) than in those in the remitting phase (10.71 ± 3.62, p = 0.0215). Serum IL-19 levels were lower in NMOSD patients in the relapsing phase (6.23 ± 1.95) than in those in the remitting phase (10.72 ± 4.46, p = 0.0092). Further, there was a positive, significant correlation between serum IL-9 concentration and the Expanded Disability Status Scale score in the NMOSD patients in the relapsing phase (p = 0.04)., Conclusion: In addition to IL-6 and IL-17A, IL-16 and CCL19 act as proinflammatory cytokines/chemokines, while IL-19 plays a protective role in NMOSD pathogenesis., (© 2017 S. Karger AG, Basel.)

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) are inflammatory demyelinating diseases of the central nervous system. Exosomal microRNAs (miRNAs) are emerging biomarkers for demyelinating diseases. In this study, 52 aquaporin-4 antibody serum-positive NMOSD patients, 18 relapsing-remitting multiple sclerosis (RRMS) patients and 17 healthy controls (HCs) were included for the next-generation sequencing (NGS). To validate the NGS results, the valuable miRNAs were selected for validation by real-time quantitative polymerase chain reaction in another cohort of patients, comprising 31 NMOSD patients and 14 HCs. In addition, these miRNAs were also validated in a longitudinal study. NGS data revealed the exosomal miRNAs profile in NMOSD patients was different from HCs. Among those potential exosomal miRNAs which can distinguish NMOSD status, hsa-miR-122-3p and hsa-miR-200a-5p were the most abundant miRNAs. In addition, hsa-miR-122-3p and hsa-miR-200a-5p were significantly upregulated in the serum exosome of relapsing NMOSD compared with that in remitting NMOSD. Hsa-miR-122-3p and hsa-miR-200a-5p had positive correlations with disease severity in NMOSD patients. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the MAPK, Wnt and Ras signaling pathways were enriched. Further biological function analysis demonstrated that these two miRNAs might be involved in the immunoregulation of NMOSD pathogenesis. Our results indicated that miRNAs delivered by exosomes could be applied as potential biomarkers for NMOSD. [ABSTRACT FROM AUTHOR]

Background: Recurrent optic neuritis (ON) was previously thought to be associated with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Meningoencephalitis has recently been suggested to be a clinical finding typical of myelin oligodendrocyte glycoprotein (MOG) encephalomyelitis. We report a Chinese patient with recurrent ON at disease initiation, who had a delayed diagnosis of MOG-IgG syndrome, until recurrent meningoencephalitis appeared and serum MOG-IgG was detected.Case Presentation: From the age of 7 years, an AQP4-IgG negative female patient had 10 disease recurrences, including 4 episodes of recurrent ON, 4 episodes of fever and meningoencephalitis, and 2 episodes of ON as well as meningoencephalitis. She was initially diagnosed as recurrent ON and treated with glucocorticoids followed by gradual tapering when ON reoccurred. Later, she was diagnosed as central nervous system infection when fever and meningoencephalitis appeared, and antiviral drugs and glucocorticoids were used. However, when she returned to our department for follow-up on July 2017, the results of serum demyelinating autoimmune antibody revealed positive MOG-IgG (titer 1:320 by an in-house, cell-based assay using live cells transfected with full-length human MOG). A diagnosis of MOG-IgG syndrome was established.Conclusions: Testing for MOG-IgG in atypical MS and NMOSD patients, and patients with meningoencephalitis with a history of relapsing demyelinating symptoms is warranted. [ABSTRACT FROM AUTHOR]