Background Dimethyl fumarate (DMF) is an orally administered disease-modifying drug used for the treatment of multiple sclerosis (MS) in numerous countries worldwide.Aim An ongoing post-marketing surveillance (PMS) is assessing the real-world safety and effectiveness of DMF in Japanese patients with MS. Here, we report 2-year data from this PMS.Methods This interim analysis used data from all patients with MS who were treated with DMF in Japan between February 2017 and March 2024. Safety endpoints included adverse events (AEs) and important identified risks (i.e., progressive multifocal leukoencephalopathy (PML), anaphylaxis, acute kidney injury, hepatic dysfunction, changes in lymphocyte or white blood cell counts, infections other than PML, flushing-related AEs, and gastrointestinal events). Effectiveness endpoints included annualized relapse rate (ARR) and changes in Expanded Disability Status Scale (EDSS) score.Results Of 2092 patients in the safety analysis (median age 42 years; 70.9% female), AEs occurred in 1482 (70.8%); the most common events were lymphocyte count decreased, MS relapse, flushing, and gastrointestinal events. No cases of PML or anaphylaxis were reported; one patient developed acute kidney injury. In the effectiveness analysis (N = 2060), least squares mean ARR decreased by 61.25% and 78.30% after 12 and 24 months' DMF treatment, respectively, versus the 12 months prior to DMF initiation (both p < 0.0001). EDSS scores remained stable over 24 months.Conclusion The safety and effectiveness of DMF in Japanese patients with MS are consistent with previous reports, with significant reductions in ARR and no new safety concerns.

BACKGROUND:Natalizumab (TYSABRIⓇ) is known to be an efficacious treatment at a standard-interval dosing (SID; 300 mg administered intravenously every 4 weeks) for patients with relapsing-remitting sclerosis (RRMS). However, the SID of natalizumab is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Lengthening the time between doses of natalizumab beyond 4 weeks, also known as extended-interval dosing (EID), is associated with lower risk of PML in patients with RRMS, and patients have been switched from SID to EID without meaningful loss of efficacy. In this multicenter, retrospective, observational study, REFIND, we examined real-world natalizumab dosing patterns and MS disease activity in patients with RRMS in Japan. METHODS:REFIND retrospectively collected data from medical records of patients at 20 study centers in Japan. Patients with MS aged 20 years and older who received at least one dose of natalizumab after January 1, 2018, and had at least one clinical assessment were included. The primary endpoints were dosing patterns used in clinical practice and MS disease activity by dosing patterns. SID was defined as a mean natalizumab dosing interval ≤35 days, and EID was defined as a mean natalizumab dosing interval ≥36 to ≤84 days. Dosing pattern groups included SID-only, EID-only, or SID followed by EID (SID/EID). For each dosing pattern group, the annualized relapse rate (ARR) before and after administration of natalizumab was compared using a negative binomial regression model. RESULTS:Of the 203 patients with MS eligible for inclusion in the REFIND study, 120 patients with RRMS were treated with natalizumab for ≥1 year, with a mean ± standard deviation (SD) age of 36.0 ± 9.4 years and a mean ± SD administration period of 32.8 ± 18.8 months. Among these patients, 13 had an SID-only natalizumab dosing pattern, 49 had EID-only, and 58 had SID/EID, with mean ± SD dosing intervals of 30.8 ± 1.6 days, 45.9 ± 3.4 days, and 38.7 ± 3.4 days, respectively. Overall ARR 1 year before vs 1 year after initiation of natalizumab was 1.03 vs 0.12 (P < 0.0001). ARR before vs after natalizumab in the SID-only group was 1.08 vs 0.62 (P = 0.378), in the EID-only group was 0.95 vs 0.02 (97.9% reduction, P = 0.0005), and in the SID/EID group was 1.08 vs 0.09 (91.7% reduction, P < 0.0001). Proportions of patients with new or enlarging T2 lesions in the SID-only, and the EID-only, and SID/EID groups were reduced by 89.1%, 83.5%, and 95.7%, respectively, after natalizumab initiation compared with the year before natalizumab. CONCLUSIONS:The significant reduction in ARR observed with EID or SID/EID suggests that there is little difference between these dosing regimens in this retrospective dataset in Japan. The effectiveness of natalizumab in reducing the number of new or enlarging T2 lesions was similar across all dosing groups and consistent with known high efficacy of natalizumab in controlling disease activity. These real-world data on natalizumab EID in Japan may help inform treatment choices for Asian populations.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystemic disorder mostly triggered by viral infections, with core symptoms including post-exertional malaise (PEM), fatigue, pain, and cognitive dysfunction. Its prevalence has increased significantly in the context of the coronavirus disease 2019 (COVID-19) pandemic. Despite its severity and impact on patients' quality of life, ME/CFS remains poorly understood. On May 12 and 13, 2025, the 3rd International Conference hosted by the Charité Fatigue Center brought together nearly 200 researchers from various disciplines on-site, and around 3,700 participants online to discuss recent advances in ME/CFS research, diagnostics, clinical care, and therapeutic trials. The program featured 33 lectures by international experts on key topics such as post-COVID syndrome (PCS), care structures, and pathophysiological mechanisms including cardiovascular dysregulation, immune dysregulation, autoimmune mechanisms, and metabolic dysfunction. In addition, results from clinical trials addressing disease mechanisms, including those specifically targeting autoantibodies, were presented. While public awareness and funding opportunities have increased in the wake of the pandemic and the emergence of PCS, ME/CFS remains severely underresearched. Sustained and adequately funded research efforts are urgently required to advance understanding, identify diagnostic markers, and develop targeted therapeutic interventions.

Multiple sclerosis (MS) therapies primarily rely on lymphocyte depletion or trafficking blockade, carrying risks of systemic immunosuppression; however, such treatments have limited efficacy in secondary progressive multiple sclerosis (SPMS). Thus, drugs that target stage-specific inflammation without broad immunosuppression are an unmet clinical need. In this double-blind, placebo-controlled phase II trial, 30 patients with relapsing MS received weekly oral OCH or placebo for 24 weeks. In the pre-specified SPMS subgroup (n=12), OCH achieved complete relapse prevention (p=0.0003), prolonged relapse-free survival (p=0.0079), no new lesions (0/6), with no evidence of disease activity (NEDA-3) in 5/6 patients. In comparison, for the placebo-treated group, 5/6 patients suffered relapses, 2/6 patients developed new lesions, and no placebo-treated SPMS achieved NEDA-3. Invariant natural killer T (iNKT) cells, a regulatory lymphocyte population that is numerically and functionally impaired in MS, are a potential target for MS therapy. Glycolipid OCH is a selective iNKT cell stimulator, skewing the cytokine environment towards Th2. OCH treatment resulted in increased IL-4-producing Th cells in patient peripheral blood while decreasing pathogenic GM-CSF-producing Th cells. Parallel studies in mouse models of MS (EAE) corroborated this mechanism and further revealed that OCH activated gut iNKT cells. Disease amelioration by OCH depended on IL-4 and its efficacy was further enhanced by depletion of B cells. These data revealed the gut-brain axis mediation of progressive-stage pathology distinct from relapsing-remitting MS. Findings from this bidirectional translational study uncover mechanistic differences between SPMS and other types of MS and highlight divergent roles for B cells and Th cells. Furthermore, OCH exerts its therapeutic benefit via targeting mechanisms that are distinct from currently available drugs; exploiting iNKT cell regulatory potential to reprogram pathogenic T helper responses without lymphocyte depletion. The unique yet effective nature of OCH treatment positions it as an attractive future oral therapy for SPMS. ### Competing Interest Statement BJER, TO, WS, and T Yamamura disclose that royalties related to OCH were received based on a license agreement. All other authors have no relevant conflicts of interest to declare. ### Clinical Trial NCT04211740 (www.clinicaltrials.gov) ### Clinical Protocols ### Funding Statement This Study was funded by by Japan Agency for Medical Research and Development (AMED) grant number JP18ek0109342h0001 and JSPS KAKENHI grants JP24K10278 and JP25K10802. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committees of National Center Hospital, NCNP, Tokyo Medical and Dental University Hospital, and Tokyo Women's Medical University Hospital gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

A central unresolved question in multiple sclerosis (MS) is why therapies that effectively suppress relapsing-remitting MS (RRMS) fail in secondary progressive MS (SPMS), leading to the prevailing view that progressive disease becomes largely refractory to peripheral immune modulation. Using integrated human and animal studies, we identify a gut-immune axis that challenges this framework, demonstrating that chronic CNS autoimmunity remains responsive to modulation of peripheral immunity. These studies reveal a previously unrecognized principle: transient activation of invariant natural killer T (iNKT) cells in the gut can durably reprogram pathogenic adaptive immune responses in chronic autoimmune disease. Oral administration of the glycolipid OCH induced IL-4-producing gut-resident iNKT cells that suppressed GM-CSF-producing and Eomes⁺ T helper cell programs enriched in active and progressive disease. Despite inducing comparable immunological responses in both RRMS and SPMS, OCH produced markedly divergent clinical outcomes in a placebo-controlled phase II trial, with robust suppression of inflammatory disease activity in SPMS, including elimination of relapses and no evidence of disease activity (NEDA-3) in most treated patients, but limited efficacy in RRMS. Mechanistically, these divergent outcomes were associated with opposing downstream effects of IL-4 on B cell immunity. In RRMS, concomitant B cell activation may offset the therapeutic effects of suppressing pathogenic T cell programs, whereas the immune environment of SPMS permits T cell suppression to predominate. Therefore, this gut-immune-brain axis link, where gut iNKT cells can modulate CNS autoimmunity in SPMS, indicates that inflammatory activity in SPMS is governed by a peripheral immune logic distinct from RRMS. This study highlights gut iNKT cells as a physiological bridge between mucosal immunity and CNS autoimmunity and provides a new conceptual framework for SPMS: relapses in SPMS are mechanistically distinct from those in RRMS, and SPMS is not intrinsically inaccessible to immune modulation. Instead, therapeutic responsiveness depends on disease-specific immune context with direct implications for how progressive disease is diagnosed, stratified, and treated.

Neurodegeneration involves the entangled processes of cell-autonomous and non-cell-autonomous neuronal cell death, which leads to a collapse in the integrity of the neural network and causes behavioral symptoms. Here, we demonstrate that aberrant cell cycle re-entry (CCR) is prominent in mature neurons and that the replication fork acts as a target site for long interspersed nuclear element-1 (L1) retrotransposition during neurodegeneration. The fatal susceptibility of S-phase neurons in 5xFAD mice is attributed to a DNA repair deficiency in response to L1-mediated replication stress. Impaired sirtuin 6 expression seems to allow stochastic L1 activation and enhanced retrotransposition. Reduced estrogen/prolactin signaling correlates well with reduced Brca1 expression that is thought to protect neurons from replication stress. Importantly, L1-mediated pathogenesis correlates well with conventional Alzheimer’s disease pathology. In summary, the combination of enhanced L1 retrotransposition and DNA repair deficiency elicited synthetic lethality in S-phase neurons, highlighting a previously unknown pathogenic mechanism of neurodegeneration.

ABSTRACT Objectives To evaluate the safety and effectiveness of dimethyl fumarate (DMF) in Japanese patients with multiple sclerosis (MS) in subgroups defined by baseline age and prior therapy. Methods This analysis used 2‐year post‐marketing surveillance data from all MS patients receiving DMF in Japan between February 2017 and March 2024. Safety (adverse events, lymphocyte counts) and effectiveness (annualized relapse rate [ARR]) were assessed in patients aged < 50, ≥ 50, < 15, ≥ 15–< 65, or ≥ 65 years at baseline, and in patients with no prior disease‐modifying drug (DMD) therapy or switching from fingolimod or natalizumab. Results Of 2092 patients, baseline age was < 50 and ≥ 50 years in 1601 (76.5%) and 491 (23.5%) and < 15, ≥ 15 to < 65, and ≥ 65 years in 3 (0.1%), 2014 (96.3%), and 75 (3.6%), respectively; 576 (27.5%) had no prior DMD therapy, while 549 (26.2%), 71 (3.4%), and 896 (42.8%) had switched from fingolimod, natalizumab, and other DMDs, respectively. Lymphocyte count decreased occurred with higher incidence in the ≥ 65‐year (34.7%) and prior fingolimod (40.6%) subgroups than the overall population (23.1%). Among relapsing–remitting MS patients ( n = 1714), ARR significantly decreased at Years 1 and 2 after DMF initiation (−63.6% and −78.4% vs. the 1 year before DMF), with similar reductions in most age subgroups and in the no prior DMD subgroup. ARR non‐significantly increased at Year 1 and decreased at Year 2 in the prior fingolimod or natalizumab subgroups. Conclusion DMF had consistent safety and effectiveness in Japanese MS patients, including older patients and those switching from fingolimod or natalizumab.

Age-associated B cells (ABCs), initially identified in aged mice, are a distinct B cell subset that plays crucial roles in autoimmune diseases through the production of autoantibodies, proinflammatory cytokines, and antigen presentation. Although a definitive set of markers for identifying ABCs has not yet been established, they are commonly characterized by the expression of CD11c, CD11b, and the transcription factor T-bet, along with reduced levels of CD21, either alone or in combination. ABC differentiation is driven by Toll-like receptor 7 (TLR7) signaling in conjunction with cytokines such as interleukin-21 (IL-21) and interferon-gamma (IFNγ). Importantly, ABCs expand in the blood or inflamed tissues and exhibit pathogenic functions in various autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, Crohn's disease, axial spondyloarthritis, Grave's disease, and multiple sclerosis. Recently, ABCs have been implicated in neuromyelitis optica spectrum disorder (NMOSD), a chronic inflammatory astrocytopathy mediated by anti-AQP4 antibody-producing B cells characterized by relapses and remissions. In the acute phase, CD21 lo B cells can differentiate into anti-AQP4 antibody-producing cells and expand in both cerebrospinal fluid and blood. In the chronic phase, an increased frequency of CD11c hi B cells in the blood correlates with chronic neurological damage or brain injury. T peripheral helper type 1 cells, which produce IFNγ and IL-21, may support ABC differentiation in both phases. This review explores the role of ABCs in NMOSD, highlighting key studies that link ABC subsets to disease pathology. Understanding ABC-mediated mechanisms in NMOSD may open avenues for novel therapeutic strategies.

BACKGROUND AND OBJECTIVES:Satralizumab (SAT), an interleukin-6 receptor inhibitor, reduced the risk of protocol-defined relapse (PDR) vs placebo (PBO) with a favorable safety profile in patients with neuromyelitis optica spectrum disorder (NMOSD) in 2 pivotal phase 3 trials, SAkuraSky and SAkuraStar. We evaluated the long-term safety and efficacy of SAT in patients with NMOSD in the single-arm, open-label, rollover study SAkuraMoon. METHODS:Patients who completed the double-blind periods (DBPs) and open-label extensions (OLEs) of SAkuraSky and SAkuraStar were enrolled in SAkuraMoon, where they continued receiving subcutaneous SAT 120 mg 4 times a week (Q4W) ± immunosuppressive therapy. Safety analyses included all patients who received ≥1 dose of SAT in the overall SAT treatment (OST) period. The rates of adverse events (AEs) and infections per 100 patient-years (PYs) in the OST vs the DBPs were compared. Efficacy analyses were performed in the aquaporin-4 immunoglobulin-G-seropositive (AQP4-IgG+) population. Annualized investigator-assessed PDR rate (i.e., annualized relapse rate, ARR), time to first investigator-reported PDR (iPDR), severe iPDR (increase of ≥2 points in the Expanded Disability Status Scale [EDSS] score), and sustained EDSS score worsening were reported. The data cutoff date of these analyses was May 28, 2024. RESULTS:Overall, 166 patients with NMOSD were included in the analysis. The median (range) SAT exposure in the OST period was 6.9 years (0-10). Rates of AEs and serious AEs (95% CI) in the OST period (AEs: 299.4 (288.8-310.2)/100 PYs; serious AEs: 8.1 (6.4-10.0)/100 PYs) were lower compared with the DBP. Rates of infections (87.5 [81.9-93.5]/100 PYs) and serious infections (2.4 [1.5-3.5]/100 PYs) in the OST period were comparable with those of the DBP and did not increase over time. No fatalities occurred. In the AQP4-IgG+ population (n = 111), the overall adjusted ARR (95% CI) was 0.07 (0.05-0.10). At Week 456 (8.8 years), 67% (56%-76%), 89% (80%-94%), and 82% (72%-89%) of SAT-treated patients were free from iPDR, severe iPDR, and sustained EDSS score worsening, respectively. DISCUSSION:The safety and efficacy of SAT (±IST) is sustained with long-term treatment, supporting SAT as an effective maintenance therapy option for patients with AQP4-IgG+ NMOSD. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov registration numbers: NCT02028884 (SAkuraSky), NCT02073279 (SAkuraStar), and NCT04660539 (SAkuraMoon); EudraCT: 2020-003413-35 (SAkuraMoon). CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that SAT is safe and effective in patients with NMOSD.

The role of the thyroid hormone receptor beta (TR-β) in the immune system remains poorly understood; although its effect on TGF-β signaling has been reported in nonimmune systems. Here, we report that Thrb is highly expressed in pathogenic CD4+ T cells that infiltrate the central nervous system during experimental autoimmune encephalomyelitis (EAE), and Thrb is exclusively expressed in IL-17-producing CD4+ T cells (Th17 cells) that develop both in vitro or in vivo. Sobetirome, a selective TR-β agonist, promoted pathogenic Th17 differentiation and IL-17 production in the presence of exogenous IL-1β. Conversely, small interfering RNA (siRNA)-mediated silencing of TR-β reduced IL-17 production, further supporting a T cell-intrinsic role of TR-β. Because C75, an inhibitor of de novo lipogenesis, blocked Th17 cell differentiation by sobetirome, the influence of TR-β signaling on Th17 cell induction is likely to act via a de novo lipogenesis-dependent mechanism. Furthermore, blocking TR-βexpression by siRNA changed the balance of IL-10/IL-17 production in cultured splenocytes, favoring an IL-10 phenotype. In contrast, IL-10 production by T cells was attenuated by activating TR-β signaling with sobetirome. Finally, the manipulation of TR-β signaling altered the severity of autoimmune disease: blocking TR-β reduced passive EAE and enhancing TR-β increased active EAE. These effects were accompanied by corresponding changes in the IL-10/IL-17 balance in encephalitogenic CD4+ T cells. In summary, our results demonstrate that TR-β signaling controls pathogenic Th cell function and autoimmunity.

Satralizumab showed a comparable safety profile versus placebo in 2 pivotal neuromyelitis optica spectrum disorder (NMOSD) studies. We analyzed infection rates with long-term satralizumab treatment in the open-label study, SAkuraMoon, and in a post-marketing setting (PMS), comparing frequencies with US-based health claims real-world data (US-RWD). Incidence rates of infection per 100 patient-years (IR/100 PY) were analyzed in the SAkura studies (clinical cut-off date: 31 January 2023). Reported rates of infection ( %) in a PMS using Periodic Benefit-Risk Evaluation Reports (2020-2023), and cumulative incidence of infections ( %) from the US PharMetrics claims data in NMOSD patients (2017-2022) were analyzed. 166 patients (SAkura studies), 2951 patients (PMS) and 2872 patients (US-RWD) were included. In the SAkura studies, the incidence rates of infection, serious infection, and sepsis were lower versus the double-blind period (IR/100 PY [95 % confidence intervals (Tur, C. et al.)] infection 91.7 [85.5-98.3] vs 113.0 [98.6-129.0]; serious infection 2.6 [1.7-3.9] vs 4.1 [1.8-8.1]; sepsis 0.6 [0.2-1.3] vs 1.0 [0.1-3.7], respectively). In a PMS, reported rates of infection, serious infection, and sepsis were 7.3 %, 3.8 %, and 0.6 %, respectively. In the US-RWD, cumulative incidence of infection, serious infection, and sepsis in NMOSD were 67.3 %, 8.4 %, and 4.9 %, respectively. Concomitant IST use, comorbidities, Expanded Disability Status Scale score ≥4.0, and age >65 years were potential confounders of sepsis. US-RWD indicated infection is a major comorbidity in NMOSD, independent of satralizumab treatment. Infection rates were consistently lower in satralizumab-treated patients compared with US-RWD. Trial Registration: NCT04660539(SAkuraMoon), NCT02028884(SAkuraSky), NCT02073279(SAkuraStar).

Multiple sclerosis is a chronic inflammatory disease affecting the central nervous system. While treatment made huge advances, progression remains a challenge. Eomesodermin+ Th cells are associated with cytotoxicity, neuroinflammation and disease progression in secondary progressive multiple sclerosis. We performed a prospective longitudinal study over one year to investigate the role of Eomesodermin+ T cells in multiple sclerosis progression and neurodegeneration. Patients underwent detailed clinical assessment and immunophenotyping. In a subcohort of patients, cross-sectional magnetic resonance imaging using voxel-based morphometry was performed. Frequencies of Eomesodermin+ Th cells could differentiate between patients with secondary and primary progressive multiple sclerosis and correlated with B-cells in secondary progressive multiple sclerosis. Secondary progressive patients experiencing a subjective worsening of disease activity showed higher baseline frequencies of Eomesodermin+ Th cells. Higher baseline frequencies of Eomesodermin+ Th cells predicted prospective one-year disability progression in a small group of secondary progressive patients. Conclusively, voxel-based morphometry analysis revealed pronounced infratentorial brain atrophy in a sub-cohort of patients with higher Eomesodermin+ Th frequencies. In summary, Eomesodermin+ Th cells may shape a dysregulated and proinflammatory immune milieu, driving disease progression and neurodegeneration in secondary progressive multiple sclerosis with potential as both biomarker and therapeutic target.

A large-scale post-marketing surveillance (PMS) study is ongoing to evaluate the safety and effectiveness of satralizumab over 6 years in Japanese patients with neuromyelitis optica spectrum disorder (NMOSD) in real-world settings. We present the results of a 30-month interim analysis of the study. This PMS is being conducted across 234 sites in Japan. In this 30-month interim analysis, the end of the observation period was defined as either the date of data lock for the 30-month case report form for all patients or the last observation date for patients with satralizumab discontinuation. Primary outcomes include proportion of patients experiencing adverse drug reactions (ADRs), event rate, and oral glucocorticoid use. Secondary outcomes include time to relapse and relapse rate. Of 571 patients included (mean age: 52.4 years), 91.76

While post-infectious (PI-ME/CFS) and gradual onset (GO-ME/CFS) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) manifest similar symptoms, it has long been suspected that different disease processes underlie them. However, the lack of biological evidence has left this question unanswered. In this study, how white matter microstructural changes in PI-ME/CFS and GO-ME/CFS patients were investigated. PI-ME/CFS and GO-ME/CFS patients were recruited based on consensus diagnoses made by two experienced clinicians and compared their diffusion MRI features with those of rigorously matched healthy controls (HCs) with sedentary lifestyles. PI-ME/CFS participants showed significantly higher axial diffusivity (AD) in several association and projection fibres compared to HCs. Higher AD in PI-ME/CFS was significantly related to worse physical health. In contrast, GO-ME/CFS participants exhibited significantly decreased AD in the corpus callosum. Lower AD in GO-ME/CFS was significantly associated with worse mental health in commissural and projection fibres. No significant group differences were found for fractional anisotropy, mean diffusivity, or radial diffusivity. Distinct patterns of AD alterations in PI-ME/CFS and GO-ME/CFS provide neurophysiological evidence of different disease processes and highlight the heterogeneities of ME/CFS.

Multiple sclerosis (MS) is an autoimmune-demyelinating disease with an inflammatory pathology formed by self-reactive lymphocytes with activated glial cells. Progressive MS, characterized by resistance to medications, significantly differs from the non-progressive form in gut microbiome profiles. After confirming an increased abundance of “Tyzzerella nexilis” in various cohorts of progressive MS, we identified a distinct cluster of T. nexilis strains enriched in progressive MS based on long-read metagenomics. The distinct T. nexilis cluster is characterized by a large number of mobile genetic elements (MGEs) and a lack of defense systems against MGEs. Microbial genes for sulfate reduction and flagella formation with pathogenic implications are specific to this cluster. Moreover, these flagellar genes are encoded on MGEs. Mono-colonization with MGE-enriched T. nexilis made germ-free mice more susceptible to experimental autoimmune encephalomyelitis. These results indicate that the progression of MS may be promoted by MGE-enriched T. nexilis with potentially pathogenic properties.

'No evidence of disease activity (NEDA)', judged by clinical and radiological findings, is a therapeutic goal in patients with multiple sclerosis (MS). It is, however, unclear if distinct biological mechanisms contribute to the maintenance of NEDA. To clarify the immunological background of long-term disease stability defined by NEDA, circulating immune cell subsets in patients with relapsing-remitting MS (RRMS) were analyzed using flow cytometry. Patients showing long-term NEDA (n = 31) had significantly higher frequencies of non-classical monocytes (NCMs) (6.1% vs 1.4%) and activated regulatory T cells (Tregs; 2.1% vs 1.6%) than those with evidence of disease activity (n = 8). The NCM frequency and NCMs to classical monocytes ratio (NCM/CM) positively correlated with activated Treg frequency and duration of NEDA. Co-culture assays demonstrated that NCMs could increase the frequency of activated Tregs and the expression of PD-L1, contributing to development of Tregs, was particularly high in NCMs from patients with NEDA. Collectively, NCMs contribute to stable remission in patients with RRMS, possibly by increasing activated Treg frequency. In addition, the NCM frequency and NCM/CM ratio had high predictive values for disease stability (AUC = 0.97 and 0.94, respectively), suggesting these markers are potential predictors of a long-term NEDA status in RRMS.

Background Previous studies have identified a diverse group of microbial taxa that differ between patients with multiple sclerosis (MS) and the healthy population. However, interpreting findings on MS-associated microbiota is challenging, as there is no true consensus. It is unclear whether there is gut microbiota commonly altered in MS across studies. Methods To answer this, we performed a meta-analysis based on the 16S rRNA gene sequencing data from seven geographically and technically diverse studies comprising a total of 524 adult subjects (257 MS and 267 healthy controls). Analysis was conducted for each individual study after reprocessing the data and also by combining all data together. The blocked Wilcoxon rank-sum test and linear mixed-effects regression were used to identify differences in microbial composition and diversity between MS and healthy controls. Network analysis was conducted to identify bacterial correlations. A leave-one-out sensitivity analysis was performed to ensure the robustness of the findings. Results The microbiome community structure was significantly different between studies. Re-analysis of data from individual studies revealed a lower relative abundance of Prevotella in MS across studies, compared to controls. Meta-analysis found that although alpha and beta diversity did not differ between MS and controls, a higher abundance of Actinomyces and a lower abundance of Faecalibacterium were reproducibly associated with MS. Additionally, network analysis revealed that the recognized negative Bacteroides-Prevotella correlation in controls was disrupted in patients with MS. Conclusions Our meta-analysis identified common gut microbiota associated with MS across geographically and technically diverse studies.