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Background: Immune system dysfunction and blood-brain barrier (BBB) impairment are implicated in multiple sclerosis (MS) risk and severity. However, the causal relationships and potential therapeutic targets remain unclear., Methods: Leveraging the MRC IEU OpenGWAS data infrastructure, we extracted 1254 peripheral immune systems and 792 BBB biomarkers as genetic instruments for exposure. MS risk data from the International Multiple Sclerosis Genetics Consortium (IMSGC) (47,429 MS cases, 68,374 controls) served as one outcome, replicated in FinnGen (1048 cases, 217,141 controls) and the UK Biobank (1679 cases, 461,254 controls). Genetic associations with MS severity derived from IMSGC and MultipleMS Consortium GWAS data (12,584 cases). Two-sample, bidirectional, and protein drug-target MR analyses were conducted, along with interaction analysis of identified proteins and druggability assessment., Results: Causal relationships between 45 immunological markers, 15 BBB markers, and MS risk were strongly supported. In peripheral immunity, the causal associations with MS are predominantly concentrated in CD4+ T cells and CD8+ T cells. Notably, anti-Epstein-Barr virus nuclear antigen (EBNA) IgG levels exhibited the most significant causal effect on MS risk (OR = 225.62, P = 5.63E-208), replicated in the MS severity (OR = 1.11, P = 0.04). Weak causal evidence was found between 62 immunological markers, 35 BBB markers, and MS severity. Reverse MR analysis suggested potential causal effects of MS risk on 8 markers. Drug-targeted MR analysis indicated potential therapeutic benefits in reducing MS risk for CD40 (OR = 0.71, P = 7.24E-13, PPH4 = 97.6 %), AHSG (OR = 0.88, P = 2.91E-05, PPH4 = 94.4 %), and FCRL3 (Sun BB et al.: OR = 0.83, P = 8.93E-09, PPH4 = 94.2 %, Suhre K et al.: OR = 0.88, P = 5.20E-08, PPH4 = 99.2 %)., Conclusions: This study provides evidence supporting the causal effects of immune system and BBB dysfunction on MS risk and severity. It emphasizes the significant role of anti-EBNA IgG levels, CD4+ T cells, and CD8+ T cells in MS, and delineates the potential therapeutic benefits of targeting three proteins associated with MS risk: CD40, AHSG, and FCRL3., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Gut microbiota alterations in multiple sclerosis (MS) patients have been reported in observational studies, but whether these associations are causal is unclear., Objective: We performed a Mendelian randomization study (MR) to assess the causal effects of gut microbiota on MS., Methods: Independent genetic variants associated with 211 gut microbiota phenotypes were selected as instrumental variables from the largest genome-wide association studies (GWAS) previously published by the MiBioGen study. GWAS data for MS were obtained from the International Multiple Sclerosis Genetics Consortium (IMSGC) for primary analysis and the FinnGen consortium for replication and collaborative analysis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy., Results: After inverse-variance-weighted and sensitivity analysis filtering, seven gut microbiota with potential causal effects on MS were identified from the IMSGC. Only five metabolites remained significant associations with MS when combined with the FinnGen consortium, including genus Anaerofilum id.2053 (odds ratio [OR] = 1.141, 95% confidence interval [CI]: 1.021-1.276, p = .021), Ruminococcus2 id.11374 (OR = 1.190, 95% CI: 1.007-1.406, p = .042), Ruminococcaceae UCG003 id.11361 (OR = 0.822, 95% CI: 0.688-0.982, p = .031), Ruminiclostridium5 id.11355 (OR = 0.724, 95% CI: 0.585-0.895, p = .003), Anaerotruncus id.2054 (OR = 0.772, 95% CI: 0.634-0.940, p = .010)., Conclusion: Our MR analysis reveals a potential causal relationship between gut microbiota and MS, offering promising avenues for advancing mechanistic understanding and clinical investigation of microbiota-mediated MS., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Background: Observational studies have suggested an association between multiple sclerosis (MS) and cortical structure, but the results have been inconsistent., Objective: We used two-sample Mendelian randomization (MR) to assess the causal relationship between MS and cortical structure., Methods: MS data as the exposure trait, including 14,498 cases and 24,091 controls, were obtained from the International Multiple Sclerosis Genetics Consortium. Genome-wide association study (GWAS) data for cortical surface area (SAw/nw) and thickness (THw/nw) in 51,665 individuals of European ancestry were obtained from the ENIGMA Consortium. The inverse-variance weighted (IVW) method was used as the primary analysis for MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Enrichment analysis was performed on MR analyses filtered by sensitivity analysis., Results: After IVW and sensitivity analysis filtering, only six surviving MR results provided suggestive evidence supporting a causal relationship between MS and cortical structure, including lingual SAw (p = .0342, beta (se) = 5.7127 (2.6969)), parahippocampal SAw (p = .0224, beta (se) = 1.5577 (0.6822)), rostral middle frontal SAw (p = .0154, beta (se) = - 9.0301 (3.7281)), cuneus THw (p = .0418, beta (se) =  - 0.0020 (0.0010)), lateral orbitofrontal THw (p = .0281, beta (se) = 0.0025 (0.0010)), and lateral orbitofrontal THnw (p = .0417, beta (se) = 0.0029 (0.0014)). Enrichment analysis suggested that leukocyte cell-related pathways, JAK-STAT signaling pathway, NF-kappa B signaling pathway, cytokine-cytokine receptor interaction, and prolactin signaling pathway may be involved in the effect of MS on cortical morphology., Conclusion: Our results provide evidence supporting a causal relationship between MS and cortical structure. Enrichment analysis suggests that the pathways mediating brain morphology abnormalities in MS patients are mainly related to immune and inflammation-driven pathways., (© 2024. The Author(s).)

Background: Cerebrospinal fluid oligoclonal band (CSF-OCB) is an established biomarker in diagnosing multiple sclerosis (MS), however, there are no nationwide data on CSF-OCB prevalence and its diagnostic performance in Chinese MS patients, especially in the virtue of common standard operation procedure (SOP)., Methods: With a consensus SOP and the same isoelectric focusing system, we conducted a nationwide multi-center study on OCB status in consecutively, and recruited 483 MS patients and 880 non-MS patients, including neuro-inflammatory diseases (NID, n = 595) and non-inflammatory neurological diseases (NIND, n=285). Using a standardized case report form (CRF) to collect the clinical, radiological, immunological, and CSF data, we explored the association of CSF-OCB positivity with patient characters and the diagnostic performance of CSF-OCB in Chinese MS patients. Prospective source data collection, and retrospective data acquisition and statistical data analysis were used., Findings: 369 (76.4%) MS patients were OCB-positive, while 109 NID patients (18.3%) and 6 NIND patients (2.1%) were OCB-positive, respectively. Time from symptom onset to diagnosis was significantly shorter in OCB-positive than that in OCB-negative MS patients (13.2 vs 23.7 months, P=0.020). The prevalence of CSF-OCB in Chinese MS patients was significantly higher in high-latitude regions (41°-50°N)(P=0.016), and at high altitudes (>1000m)(P=0.025). The diagnostic performance of CSF-OCB differentiating MS from non-MS patients yielded a sensitivity of 76%, a specificity of 87%., Interpretation: The nationwide prevalence of CSF-OCB was 76.4% in Chinese MS patients, and demonstrated a good diagnostic performance in differentiating MS from other CNS diseases. The CSF-OCB prevalence showed a correlation with high latitude and altitude in Chinese MS patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Hao, Jin, Qiu, Yang, Xue, Yin, Shi, Yu, Ji, Sun, Zeng, Liu, Wang, Li, He, Yang, Li, Liu, Lau, Gao, Hu, Chu, Ding, Zhou, Li and Chen.)

Background: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS., Methods: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively., Results: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + T EMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy., Conclusions: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + T EMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS., (© 2023. The Author(s).)

Background: The COVID-19 pandemic outbreak raises the question of whether immunization is recommended for patients with CNS demyelinating diseases. On the one hand, existing studies suggested that SARS-CoV-2 vaccinations are not associated with increased risk of relapse activity. On the other hand, case reports with acute CNS demyelinating disease post vaccination were emerging and raising clinicians' attention., Methods: In this longitudinal observational study, we included 556 patients with neuromyelitis optica spectrum disorder (NMOSD) and 280 patients with relapsing-remitting multiple sclerosis (RRMS). Each vaccinated patient was matched to two unvaccinated patients according to age, gender, ARR and immunotherapy status, based on propensity score matching model (PSM). The primary outcome is the short- and medium-term risk of relapse, which were evaluated by Kaplan-Meier analysis between groups., Results: In our cohort, 649 patients (77.6%) have not yet been vaccinated, mainly due to their concerns about relapse. After PSM, 109 vaccinated patients with NMOSD, 218 PS-matched unvaccinated patients with NMOSD, 78 vaccinated patients with RRMS, and 156 PS-matched unvaccinated patients with RRMS were included in the survival analysis to explore the safety of vaccines, with a median of 9-month follow-up. Following the first vaccination dose, 10 patients with NMOSD (9.2%) and four with RRMS (5.1%) experienced an acute relapse. Meanwhile, in the PS-matched unvaccinated group, 15 patients with NMOSD (6.9%) and 12 patients with RRMS (7.7%) presented with an acute relapse. There was no significant difference between the two curves in both NMOSD and RRMS groups over the course of the observation period. There were no significant differences in demographic characteristics, clinical characteristics, and symptoms of relapses between the vaccinated and PS-matched unvaccinated groups. Post vaccination adverse events (ADE) were reported in 39 individuals (20.9%)., Conclusion: Our results indicate that inactivated SARS-CoV-2 vaccines appear safe for patients with CNS demyelinating diseases., Competing Interests: Declaration of Competing Interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Background Sex-specific differences in multiple sclerosis (MS) have been recognized, but few were known about how sex influences the characteristics of MS in Asian and the social burden of MS. This study aimed to investigate the symptoms, mental health, and social functions of Chinese MS patients and find differences between sexes. Methods MS patients were enrolled from January 2004 to September 2018. A questionnaire was distributed by 47 medical centers. Patients' physical symptoms, negative emotions, interpersonal communication, social intercourse, employment condition, and suicidal thoughts and behavior were collected. Patients were asked to fill in the questionnaire independently and undergo Expanded Disability Status Scale (EDSS) measurement. Unpaired t-tests between sexes were conducted for normally distributed continuous variables. Mann-Whitney u-tests were conducted for non-normally distributed data. Chi-square tests, Fisher exact tests and rank sum tests were performed for categorical variables. Results 931 patients were enrolled and 631 were female. Frequency of fatigue and pain were higher in female MS patients (P<0.05), while male patients complained more weakness, diplopia, sexual dysfunction, and micturition and defecation dysfunction (P<0.05). Females were more likely to experience sadness and helplessness than males (P<0.05) while males were more likely to experience nonacceptance than females (P<0.05). MS had a worse influence on male patients in relationships with family and friends (P<0.05). The employment rate of MS patients was 39.31%. The frequency of suicidal attempt was 2.36%, which was higher than general population. Conclusions The study provided evidence that characteristics of MS were different between males and females, and influence in mental and social function was a common problem among MS patients. More attention should be paid to the mental health and social function of MS patients., (Copyright © 2020. Published by Elsevier B.V.)

Background: Teriflunomide is a first-line oral immunomodulatory agent approved in China for the treatment of relapsing multiple sclerosis. Objective: To compare the treatment outcomes of teriflunomide and no disease-modifying therapy (DMT) treatment (in first year) in multi-center real-world Chinese multiple sclerosis patients. Design: Retrospective study. Methods: This study was conducted in five tertiary hospitals in different geographical regions of China. We collected clinical data of patients treated with teriflunomide and no DMT treatment (in first year) between 1 January 2017 and 31 August 2021. The effectiveness of teriflunomide was described. Potential factors influencing the effectiveness of teriflunomide were investigated. Results: A total of 372 patients treated with teriflunomide and 148 no DMT treatment patients were included. A total of 292 patients were treated with teriflunomide for at least 6 months, described as a stable teriflunomide cohort. The annualized relapse rate was significantly lower in the stable teriflunomide cohort than in the no DMT treatment cohort (0.23 ± 0.47 versus 0.87 ± 0.67, p < 0.001). The mean Expanded Disability Status Scale (EDSS) score of the stable teriflunomide cohort (1.77 ± 1.62) was slightly different from that of the no DMT treatment cohort (2.09 ± 2.00). A previous annualized relapse rate of ⩾1, a previous EDSS score of ⩾2, and a long disease duration of ⩾5 years were associated with better clinical effectiveness. Conclusion: Teriflunomide is associated with a lower relapse rate and less disability accumulation in Chinese patients with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Objective: Our study aimed to investigate circulating CD8+ T cell subpopulations and pro‐inflammatory cytokines in the neuromyelitis optica spectrum disorder (NMOSD). Methods: A total of 121 peripheral blood samples were obtained from 57 patients with NMOSD, 34 patients with multiple sclerosis (MS), and 30 sex‐ and age‐matched healthy controls (HCs) for detection of CD8+ T cell subpopulations, including phenotypes of naïve (TN, CD62LhiCD45RO‐), effector/memory (TE/M, CD62LloCD45RO+), memory precursor (TMP, CD127hiKLRG1lo), and short lived effector (TSLEC, CD127loKLRG1hi). In addition, 36 samples from 18 NMOSD, 12 MS, and 6 sex‐ and age‐matched HCs for detecting pro‐inflammatory cytokines (IFNγ and TNFα) using flow cytometry. Results: Compared with HCs, we found significantly reduced CD8+ TN and increased CD8+ TE/M in both NMOSD and MS，while decreased CD8+ TMP was only observed in NMOSD. Patients treated with immunotherapy were associated with increased CD8+ TN and decreased CD8+ TE/M in NMOSD. Moreover NMOSD cohort showed significant higher proportions of IFNγ+CD8+ T cells and proportions of TNFα+CD8+ T cells than HC and MS cohorts. On the contrary, obviously decreased IFNγ and TNFα were found in NMOSD patients treated with immunotherapy. Furthermore, Multivariate linear regression analyses revealed that age was negatively correlated with CD8+ TN and TMP, and positively associated with TSLEC; however, sex, EDSS scores and disease phase were not significantly associated with CD8+ T subpopulations. Interpretation: This current study provides an evidence that circulating CD8+ T cell with abnormal subpopulations and increased pro‐inflammatory were associated with pathogenesis of autoimmune demyelinating disease of CNS, especially in NMOSD. [ABSTRACT FROM AUTHOR]