Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Quantifying neuronal damage is a critical step for patient care. Neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are the most promising serum biomarkers reflecting neuronal damage and astroglial activation, respectively. This study analyzed sNfL and sGFAP in 177 MS patients and 71 healthy controls (HCs) using SIMOA technology, classifying patients as responders (Rs) or non-responders (NRs) based on “No Evidence of Disease Activity 3” (NEDA-3) status during two years of treatment. Longitudinal analyses were performed for Dimethyl fumarate (DMF) and Ocrelizumab (OCRE) treatment. Biomarker–age correlation analysis in HCs confirmed correlation between both NfL and GFAP, with age and cut-off values specific for age decades being calculated. Both biomarkers were higher in MS patients compared to HCs. sNfL showed a significant increase in NR patients overall. In contrast, sGFAP was elevated in the low-to-moderate-efficacy treatment agents (LETAs) NR group and also in the DMF NR subgroup, suggesting that it monitors persistent astrogliosis. Longitudinal analysis showed that both biomarkers decreased during DMF treatment after one year. During OCRE treatment, sNfL rapidly reduced to HC levels within one year, while sGFAP decreased only after two years. This highlights that OCRE acts differently on the pathological processes linked to the two biomarkers.

Background: Multiple sclerosis (MS) treatment response varies significantly, hindering effective management and necessitating better predictive biomarkers. Pharmacogenomics offers a promising avenue to identify genetic markers that, combined with clinico-demographic predictors, could enhance personalized therapeutic decisions. Objectives: This multi-center study investigated genetic determinants of response to interferon-beta (IFN-β) and glatiramer acetate (GA) in European ancestry patients with relapsing–remitting MS (RRMS). Methods: After harmonization and quality control, we tested over 6 million genetic variants. We used negative binomial regression, meta-analysis, and gene-set enrichment to link variants, genes, and biological pathways to treatment response. Results: In 679 GA and 1614 IFN-β patients, the top GA variant was rs2053696A in MAP3 K1 ( p = 3.97*10 ⁻⁹ ), involved in key signaling pathways. Another significant GA signal was in WWOX. For IFN-β, no genome-wide significant variants were found, but suggestive signals emerged near ZMIZ1, ZCCHC7, and other genes linked to immune function and interferon signaling. Gene-set analysis revealed IL-17 regulation for GA and ion channel pathways for IFN-β. Conclusion: This study identified novel genetic variants for GA response, implicating genes in crucial pathways. For IFN-β, suggestive signals point to immune and interferon-related genes. These findings enhance our understanding of genetic influences on RRMS treatment response, while highlighting pharmacogenomic research challenges.

Background/Objectives: Gut microbiota (GM) dysbiosis has been implicated in multiple sclerosis (MS) pathogenesis, influencing inflammation and neurodegeneration, but findings remain inconsistent due to environmental and methodological variability. This study aimed to identify possible microbial biomarkers of MS status and disease severity by profiling gut microbiota and short-chain fatty acid (SCFA) patterns in people with relapsing–remitting MS (pwRRMS), using household-matched healthy controls (HC) to minimize environmental variability. Methods: Twenty-four pwRRMS and their respective household-matched healthy controls (HC) were enrolled, with dietary and lifestyle habits monitored. GM composition was assessed by 16S rRNA gene sequencing, and fecal SCFAs were quantified using gas chromatography–mass spectrometry. PwRRMS were stratified by Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS). Results: β-diversity did not differ between groups. However, α-diversity was significantly reduced in pwRRMS, particularly in those with greater disability. Reduced diversity was associated with lower abundance of butyrate-producing genera (Roseburia, Faecalibacterium, Coprococcus) and enrichment of Oscillibacter and UBA1819, alongside a downward trend in fecal butyrate and propionate levels. Conclusions: RRMS and greater disease severity are associated with gut microbial alterations characterized by reduced SCFA-producing bacteria. Despite limitations including small sample size and sex imbalance, the household-matched design strengthens internal validity. Our findings highlight the potential of targeting the gut microbiota, an accessible compartment within the gut–brain axis, for MS management.

Background/Objectives: Retinitis pigmentosa (RP) is characterized by progressive degeneration of photoreceptors, with increasing evidence supporting the involvement of inflammation in disease progression. Aqueous humor (AH) reflects the intraocular microenvironment and represents an accessible source for biochemical analysis. This study aimed to characterize the profile of the main inflammatory proteins and bioactive lipids in the AH of RP patients and to compare it with healthy subjects. Methods: The AH was analyzed for cytokines using multiplex immunoassays and for lipid species using liquid chromatography–mass spectrometry. The concentrations of the analyzed molecules were compared between RP patients and the control group and then correlated with age and ellipsoid zone (EZ) width in RP patients. Results: A total of 26 RP patients and 13 controls were recruited. Significantly elevated levels of the pro-inflammatory IL-6 and a significant decrease in vascular endothelial growth factor (VEGF) were found in RP patients compared to controls. In RP patients, lipidomic analysis demonstrated significant increases in medium- and long-chain sphingomyelins (SMs) and very-long-chain unsaturated phosphatidylcholines (PCs). Higher levels of Cer 16:0, PC 32:0, and PC 34:0 were significantly associated with greater EZ preservation in RP patients. Additionally, in RP patients, VEGF and GM-CSF levels increased significantly with age, while IL-8 showed a non-significant decreasing trend. Conclusions: By integrating proteomic and, for the first time, lipidomic analyses of AH, we identified significant alterations in pro-inflammatory cytokines and bioactive lipid species in RP patients compared to controls, further highlighting a link between inflammatory activity, patient age, and disease stage. These preliminary findings need further validation in larger longitudinal cohorts to confirm the clinical utility of these bioactive mediators as potential disease biomarkers.

Epstein–Barr virus (EBV) is causally associated with various malignancies and autoimmune diseases. It establishes a lifelong latent infection in host B-lymphocytes, and can strategically manipulate host cell metabolism and cell-to-cell communication via extracellular particles (EPs). While EBV-induced changes in fatty acid and mevalonate pathways are documented, the role of the sphingolipid network in this process remains poorly understood. In this study, we characterized both the EP and the cellular sphingolipid signatures of three EBV-infected (EBV+) lymphoblastoid cell lines compared to three EBV-negative (EBV−) counterparts. Lipidomic analysis revealed a profound metabolic redirection in EBV+ cells, characterized by reduced ceramide and sphingomyelin levels, and a significant upregulation of glycosphingolipids (GSLs), particularly hexosylceramide and globotrialosylceramide. Furthermore, EBV+ cells released larger, more heterogeneous EPs that are significantly enriched in GSLs and in the viral non-coding RNA EBER1. Our findings suggest that EBV-induced reshaping of sphingolipid metabolism correlates with altered physical properties of the secretome, potentially contributing to viral pathogenesis and microenvironmental manipulation.

Background and ObjectivesPediatric-onset multiple sclerosis (PedMS) provides a unique opportunity to investigate MS pathogenesis because of the short interval between environmental exposures and di...