IntroductionB001 is a recombinant humanized anti-CD20 monoclonal antibody targeting CD20+ B cells, that has demonstrated superior B cell depletion and anti-proliferative and cytotoxic effects compared to rituximab in a pre-clinical study. The present phase 1b trial assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary efficacy of B001 in aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (NMOSD).MethodsThis phase 1b randomized, double-blind, placebo-controlled trial screened 25 NMOSD patients (April 2022–June 2024). Twenty-two patients received intravenous B001 (350, 700 or 1,000 mg) or placebo via a 3 + 3 dose escalation design, randomized 3:1 to active drug or placebo on days 1 and 15. The primary endpoints were the occurrence of dose-limiting toxicity (DLT) and to recommend the dosage for the phase 2 trial.ResultsAmong 22 randomized patients (350 mg: n = 3; 700 mg: n = 8; 1,000 mg: n = 6; placebo: n = 5), 20 (90.9%) completed the study. No DLT occurred in evaluable patients. Treatment-related adverse events (TRAEs) occurred in 7/21 (33.3%) patients, including urinary tract infection (14.3%), infusion-related reactions (9.5%), abnormal blood routine tests (9.5%) and hyperlipidemia (4.8%). No TRAEs led to discontinuation, dose reduction or death. Pharmacokinetic analysis revealed that supra-proportional exposure increased at 1,000 mg vs. 700 mg. Pharmacodynamics showed sustained B cell depletion (nearly 0/μL) for 24 weeks. No NMOSD relapses occurred during the 24-week study.ConclusionB001 demonstrated favorable safety and tolerability, with 700 mg selected as the recommended phase 2 dose.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT05145361, identifier NCT05145361.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of cells composed of myeloid progenitor cells, immature granulocytes, monocytes, and dendritic cells. These cells were initially discovered in cancer research and have been confirmed to show immunosuppressive functions. In recent years, their role in autoimmune diseases has attracted more attention. Multiple sclerosis (MS) is a rare autoimmune disease of the central nervous system, which can lead to non-traumatic disability among young adults. However, the exact pathogenesis is still unclear, and there is no therapy to cure MS. Studies have shown that MDSCs can play an important immunomodulatory role in MS and experimental autoimmune encephalomyelitis (EAE) model through multiple pathways. This article reviews the origin and characteristics of MDSCs and their role in MS/EAE, with the aim of proposing new strategies for investigating the pathogenesis and treatment of MS.

BACKGROUND:Factors associated with relapse course and disability in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remain incompletely understood. OBJECTIVES:To identify clinical and modifiable factors associated with relapse and disability in MOGAD. METHODS:In this ambispective multicentre cohort study using data from the Chinese Neuroimmunological Diseases (NIDBase) cohort (21 Chinese centres; January 2020-December 2024), 173 MOGAD patients with ≥ 12-month follow-up were analysed. Time to first relapse and time to disability, defined as Expanded Disability Status Scale (EDSS) score ≥ 2 confirmed outside acute relapse periods, were analysed using Cox regression. Nonlinear associations were assessed using restricted cubic splines. RESULTS:Older age at onset and smoking history were associated with increased disability risk. Smoking was also associated with relapse risk, although its association was attenuated and no longer statistically significant after adjustment. BMI showed nonlinear associations with both relapse and disability outcomes. CONCLUSIONS:In MOGAD, older age at onset, smoking, and BMI may influence prognosis. These findings support further investigation of modifiable lifestyle and metabolic factors in prognostic stratification.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by recurrent optic neuritis and myelitis. Blood-brain barrier (BBB) disruption is a key pathological feature of NMOSD, but the role of neutrophil extracellular traps (NETs) in this process remains poorly defined. Serum proteomic profiling in patients with acute NMOSD revealed enrichment of the NET formation pathway. Neutrophils from these patients showed an increased propensity for NETosis, accompanied by elevated myeloperoxidase-DNA complexes, neutrophil elastase-DNA complexes, and cell-free DNA in serum, as well as increased neutrophil elastase-DNA complex levels in cerebrospinal fluid. In a murine NMOSD model, neutrophil depletion, peptidylarginine deiminase 4 inhibition (Cl-amidine), and NET degradation (DNase I) each attenuated astrocyte loss, demyelination, neuroinflammation, and BBB disruption. In vitro, patient-derived NETs downregulated tight junction proteins in bEnd.3 endothelial cells through mechanisms associated with myeloperoxidase and neutrophil elastase, while c-Jun N-terminal kinase inhibition mitigated NET-induced endothelial barrier disruption. Together, these findings suggest that aberrant NETosis may contribute to BBB disruption in acute NMOSD and support further investigation of NET-associated pathways as potential therapeutic targets.

Natural killer (NK) cells and myeloid-derived suppressor cells (MDSCs) are implicated in neuromyelitis optica spectrum disorder (NMOSD), but their potential interplay remains unclear. In this study, we identified an increased frequency of polymorphonuclear MDSCs (PMN-MDSCs) and a decreased frequency of NK cells in NMOSD patients. In patients during remission, CD155 expression on PMN-MDSCs and TIGIT expression on NK cells were elevated, while NK cell activating receptors NKp30 and NKp46 were downregulated. The Expanded Disability Status Scale score correlated positively with MDSC and NKp46+ NK cell frequencies, but negatively with TIGIT+ NK cells. In vitro, PMN-MDSCs suppressed NK cell function through both soluble mediators and the contact-dependent CD155/TIGIT axis, as evidenced by reduced IFN-γ secretion and receptor modulation. This suppression was reversed by blocking CD155 or TIGIT. These findings suggest that PMN-MDSCs could inhibit NK cell function in NMOSD potentially via the CD155/TIGIT axis.

Background Fibrinogen deposition in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS), but its peripheral dynamics and hepatic contribution remain unclear. Methods We integrated a retrospective analysis of 100 MS patients with longitudinal proteomic and transcriptomic profiling of experimental autoimmune encephalomyelitis (EAE) mice, validated by flow cytometry, western blotting, and AAV8-mediated liver-specific fibrinogen overexpression. Results MS patients during relapse showed reduced plasma fibrinogen (2.43 ± 0.61 vs. 2.79 ± 0.60 g/L, P < 0.001) and altered hepatic indices. In EAE, fibrinogen chains and complement–coagulation cascades peaked at the pre-onset phase but declined at peak disease, coinciding with hepatic transcriptional exhaustion. Cross-tissue analysis identified hepatic activity as a major driver of plasma proteome remodeling (VIP = 1.32) with increased hepatic CD45⁺Ly6G⁺CD11b⁺ neutrophils. Liver-specific fibrinogen overexpression induced intrahepatic neutrophil recruitment and CNS fibrinogen deposition. Conclusions Hepatic fibrinogen synthesis precedes CNS deposition, revealing a liver–CNS axis in early neuroinflammation.

Early correction of childhood malocclusion is timely managing morphological, structural, and functional abnormalities at different dentomaxillofacial developmental stages. The selection of appropriate imaging examination and comprehensive radiological diagnosis and analysis play an important role in early correction of childhood malocclusion. This expert consensus is a collaborative effort by multidisciplinary experts in dentistry across the nation based on the current clinical evidence, aiming to provide general guidance on appropriate imaging examination selection, comprehensive and accurate imaging assessment for early orthodontic treatment patients.

Human brucellosis, caused by Brucella, is an infectious disease with specific endemic regions, especially in pastoral areas, and may affect multiple organ systems. Neurological involvement, namely neurobrucellosis, occurs in very few of these patients. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent type of autoimmune encephalitis and is usually associated with tumors or herpes simplex virus infections. However, the link between the two disease entities is unknown. In this report, we present a rare case of a 29-year-old Chinese man with anti-NMDAR encephalitis associated with neurobrucellosis, with the detection of anti-NMDAR antibodies by cell-based assay and Brucella melitensis by metagenomic next-generation sequencing in his cerebrospinal fluid sample. The patient improved after antimicrobial treatment and immunotherapies, including steroids and intravenous immunoglobulin. This case implicates Brucella infection as a possible trigger for the production of anti-NMDAR antibodies, and prospective studies should reveal whether there is a casual relationship between brucellosis and anti-NMDAR antibodies.

BACKGROUND:Fibrinogen deposition in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS), but its peripheral dynamics and hepatic contribution remain unclear. METHODS:We integrated a retrospective analysis of 100 MS patients with longitudinal proteomic and transcriptomic profiling of experimental autoimmune encephalomyelitis (EAE) mice, validated by flow cytometry, western blotting, and AAV8-mediated liver-specific fibrinogen overexpression. RESULTS:MS patients during relapse showed reduced plasma fibrinogen (2.43 ± 0.61 vs. 2.79 ± 0.60 g/L, P < 0.001) and altered hepatic indices. In EAE, fibrinogen chains and complement-coagulation cascades peaked at the pre-onset phase but declined at peak disease, coinciding with hepatic transcriptional exhaustion. Cross-tissue analysis identified hepatic activity as a major driver of plasma proteome remodeling (Variable importance in projection (VIP) = 1.32) with increased hepatic CD45⁺Ly6G⁺CD11b⁺ neutrophils. Liver-specific fibrinogen overexpression induced intrahepatic neutrophil recruitment and CNS fibrinogen deposition. CONCLUSIONS:Hepatic fibrinogen synthesis precedes CNS deposition, revealing a liver-CNS axis in early neuroinflammation.

To evaluate the efficacy and safety of low-dose rituximab (RTX) strategy in patients with neuromyelitis optica spectrum disorder (NMOSD) over a period exceeding 5 years and to investigate the impact of treatment compliance on clinical outcomes. We conducted a retrospective analysis of 81 NMOSD patients who received low-dose RTX at Tangdu Hospital from January 2014 to December 2019. The treatment protocol involved an induction phase of 100 mg weekly for three weeks, followed by maintenance doses of 100 mg every six months. Demographic characteristics, the expanded disability status scale (EDSS) scores, annualized relapse rates (ARR), number and date of attacks, and adverse events were collected. The influence of compliance on treatment efficacy was assessed using multivariable Cox regression and propensity score-weighted analysis. Over the follow-up period, 32.1

Primary familial brain calcification (PFBC) is a genetic neurological disease, yet no effective treatment is currently available. Here, we identified five novel intronic variants in SLC20A2 gene from six PFBC families. Three of these variants increased aberrant SLC20A2 pre-mRNA splicing by altering the binding affinity of splicing machineries to newly characterized cryptic exons, ultimately causing premature termination of SLC20A2 translation. Inhibiting the cryptic-exon incorporation with splice-switching ASOs increased the expression levels of functional SLC20A2 in cells carrying SLC20A2 mutations. Moreover, by knocking in a humanized SLC20A2 intron 2 sequence carrying a PFBC-associated intronic variant, the SLC20A2-KI mice exhibited increased inorganic phosphate (Pi) levels in cerebrospinal fluid (CSF) and progressive brain calcification. Intracerebroventricular administration of ASOs to these SLC20A2-KI mice reduced CSF Pi levels and suppressed brain calcification. Together, our findings expand the genetic etiology of PFBC and demonstrate ASO-mediated splice modulation as a potential therapy for PFBC patients with SLC20A2 haploinsufficiency.

Background Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease affecting the central nervous system (CNS). NMOSD pathogenesis involves systemic inflammation. However, a causal relationship between circulating cytokine levels and NMOSD remains unclear.Methods Mendelian randomization (MR) approaches were used to investigate the potential association between genetically determined circulating 19 inflammatory cytokines and 12 chemokines levels and the risk of developing NMOSD.Results After Bonferroni correction, the risk of aquaporin 4-antibody (AQP4-ab)-positive NMOSD was suggested to be causally associated with the circulating levels of three cytokines, including interleukin (IL)-4 [odds ratio (OR): 11.01, 95% confidence interval (CI): 1.16-104.56, P = 0.037], IL-24 (OR: 161.37; 95% CI: 2.46-10569.21, P = 0.017), and C-C motif chemokine 19 (CCL19) (OR: 6.87, 95% CI: 1.78-26.93, P = 0.006).Conclusion These findings suggest that a genetic predisposition to higher levels of IL-4, IL-24, and CCL19 may exert a causal effect on the risk of AQP4-ab-positive NMOSD. Further studies are warranted to clarify how these cytokines affect the development of AQP4-ab-positive NMOSD.

Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35-55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system primarily mediated by CD4+ T helper cells. This study investigated the dynamic changes of natural killer (NK) cells and follicular T helper (Tfh) cells and their associations in relapsing-remitting MS patients. The findings revealed inverse relationships between NK cells and CD4+ T cells or Tfh cells. Specifically, CD56dim NK cells, not CD56bright NK cells, were negatively correlated with CD4+ T cells and Tfh cells. However, no significant correlations were found between NK cells and sNfL levels or EDSS scores. The ratio of CD56dim NK cells to circulating Tfh (cTfh) cells demonstrated superior discriminatory ability in distinguishing relapsing MS patients from healthy controls (HCs) and remitting patients, as determined by receiver operating characteristic (ROC) analysis. Following treatment with immunosuppressants or disease-modifying therapies (DMTs), a significant increase in the CD56dim NK/cTfh ratio was observed. These findings suggest that the CD56dim NK/cTfh ratio holds promise as a prognostic indicator for clinical relapse and treatment response in MS.

Multiple sclerosis (MS) was defined as a rare disease in China due to its low prevalence. For a long time, interferon β was the only approved disease-modifying therapy (DMT). Since the first oral DMT was approved in 2018, DMT approval accelerated, and seven DMTs were approved within 5 years. With an increasing number of DMTs being prescribed in clinical practice, it is necessary to discuss the standardized MS treatment algorithms depending on the disease activity and DMT availability. In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country.

Microglia, which are the resident macrophages of the central nervous system, are an important part of the inflammatory response that occurs after cerebral ischemia. Vav guanine nucleotide exchange factor 1 (Vav1) is a guanine nucleotide exchange factor that is related to microglial activation. However, how Vav1 participates in the inflammatory response after cerebral ischemia/reperfusion injury remains unclear. In this study, we subjected rats to occlusion and reperfusion of the middle cerebral artery and subjected the BV-2 microglia cell line to oxygen-glucose deprivation/reoxygenation to mimic cerebral ischemia/reperfusion in vivo and in vitro, respectively. We found that Vav1 levels were increased in the brain tissue of rats subjected to occlusion and reperfusion of the middle cerebral artery and in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation. Silencing Vav1 reduced the cerebral infarct volume and brain water content, inhibited neuronal loss and apoptosis in the ischemic penumbra, and improved neurological function in rats subjected to occlusion and reperfusion of the middle cerebral artery. Further analysis showed that Vav1 was almost exclusively localized to microglia and that Vav1 downregulation inhibited microglial activation and the NOD-like receptor pyrin 3 (NLRP3) inflammasome in the ischemic penumbra, as well as the expression of inflammatory factors. In addition, Vav1 knockdown decreased the inflammatory response exhibited by BV-2 cells after oxygen-glucose deprivation/reoxygenation. Taken together, these findings show that silencing Vav1 attenuates inflammation and neuronal apoptosis in rats subjected to cerebral ischemia/reperfusion through inhibiting the activation of microglia and NLRP3 inflammasome.

The primary aim of the study is to discuss the potential interactions between venetoclax and common drugs used in department of hematology and the corresponding effects on the efficacy and safety of venetoclax treatment. Here, we report an acute myeloid leukemia patient treated with venetoclax and posaconazole, and the dose of venetoclax was adjusted due to drug interactions. Clinical pharmacists actively participated in treatment of this patient to provide pharmacy care to assist clinicians to identify the venetoclax-induced liver function impairment and give timely management. The case reported here is hoped to provide reference for clinical venetoclax treatment in patients with such disease. Clinical pharmacists should actively participate in clinical treatment, actively screen potential drug interactions, strengthen cooperation and communication with doctors, provide patients with high-quality pharmaceutical services, and establish clinical pharmacists' status in the multidisciplinary treatment of tumor.

Background: Multiple sclerosis (MS) has been considered to be a T cell-dependent autoimmune disease of the central nervous system (CNS), so does the experimental autoimmune encephalomyelitis (EAE) model. Recent studies identified CD8 follicular T cells (CD8+CXCR5+ T), a subset of CD8 T cells, in antiviral, anti-tumor immunity and systemic autoimmunity, yet the role of CD8+CXCR5+ T cells in MS and EAE remains unclarified.Methods: CD8+CXCR5+ T cell frequency in peripheral blood of relapsing-remitting MS patients and healthy controls were detected by flow cytometry and analyzed the correlation with disease activity. Flow cytometry and multiplexed immunohistochemistry were performed to detect the dynamic changes and locations of CD8+CXCR5+ T cells in secondary lymphoid organs (spleens and inguinal lymph nodes) and CNS from EAE mice. RNA-seq, co-culture experiments and in vivo adoptive transfer were performed to reveal the phenotypes and functions of CD8+CXCR5+ T cells.Findings: Expansion of CD8+CXCR5+ T cells in both MS patients and EAE mice was detected during acute phase. In relapsing MS patients, elevated frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions of CNS. In EAE mice, infiltration of CD8+CXCR5+ T cells, which were positively correlated with clinical score, were found in ectopic lymphoid structures of spinal cords and germinal centers of spleens with helper cell-like and restricted cytolytic phenotypes. In vitro co-culture experiments and CD8+CXCR5+ T -adoptive mice both confirmed the potential cytotoxicity and the ability to provide B cell help of CD8+CXCR5+ T cells.Interpretation: CD8+CXCR5+ T cells expanded and infiltrated in the CNS of MS patients and EAE mice display multiple functions of CD8+ T cells and stronger pathogenic effect on demyelination.Funding: This study was supported by National Natural Science Foundation of China (grant no. 81901226 to CZ and no. 82073154 to KY).Declaration of Interest: The authors have declared no conflict of interesEthical Approval: This study was carried out in accordance with the recommendations of “the Biomedical Research Guideline involving Human Participants, National Health and Family Planning Commission of China” with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the “Air Force Medical Center Ethical Review Board of Fourth Military Medical University". All the animal experimental protocols were authorized by the Institutional Ethics Committee.

To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses. Methods A retrospective observational study was conducted in 121 patients (2016–2021) with a CNS viral infection confirmed via cerebrospinal fluid (CSF) next-generation sequencing (cohort A). Their clinical information was analysed and CSF samples were screened for autoantibodies against monkey cerebellum by tissue-based assay. In situ hybridisation was used to detect Epstein-Barr virus (EBV) in brain tissue of 8 patients with glial fibrillar acidic protein (GFAP)-IgG and nasopharyngeal carcinoma tissue of 2 patients with GFAP-IgG as control (cohort B). Results Among cohort A (male:female=79:42; median age: 42 (14–78) years old), 61 (50.4%) participants had detectable autoantibodies in CSF. Compared with other viruses, EBV increased the odds of having GFAP-IgG (OR 18.22, 95% CI 6.54 to 50.77, p<0.001). In cohort B, EBV was found in the brain tissue from two of eight (25.0%) patients with GFAP-IgG. Autoantibody-positive patients had a higher CSF protein level (median: 1126.00 (281.00–5352.00) vs 700.00 (76.70–2899.00), p<0.001), lower CSF chloride level (mean: 119.80±6.24 vs 122.84±5.26, p=0.005), lower ratios of CSF-glucose/serum-glucose (median: 0.50[0.13-0.94] vs 0.60[0.26-1.23], p =0.003), more meningitis (26/61 (42.6%) vs 12/60 (20.0%), p=0.007) and higher follow-up modified Rankin Scale scores (1 (0–6) vs 0 (0–3), p=0.037) compared with antibody-negative patients. A Kaplan-Meier analysis revealed that autoantibody-positive patients experienced significantly worse outcomes (p=0.031). Conclusions Autoimmune responses are found at the onset of viral encephalitis. EBV in the CNS increases the risk for autoimmunity to GFAP.