Search Results (3,656)

The human immune system consists of two main components: innate and adaptive immunity. To date, research on the pathogenesis of autoimmune neurological diseases has primarily focused on the role of adaptive immunity. However, growing evidence highlights the significant contribution of innate immune mechanisms in the development of neurological disorders. The aim of this article is to present the current state of knowledge regarding the involvement of innate immunity in the pathogenesis and treatment of selected autoimmune neurological diseases: multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), MOG antibody-associated disease (MOGAD), myasthenia gravis (MG), and chronic inflammatory demyelinating polyneuropathy (CIDP). A literature review was conducted, including both experimental and clinical data on the activity of innate immune effector cells—such as dendritic cells, macrophages, microglia, and natural killer (NK) cells—as well as plasma proteins, including the complement system. Relevant clinical and preclinical studies on targeted therapies affecting these components were also identified. All analyzed diseases demonstrate the involvement of innate immune elements in the initiation and maintenance of the inflammatory process. Furthermore, it has been shown that therapies targeting these components may offer clinical benefits. Full article

Diffusion basis spectrum imaging–derived restricted fraction (DBSI-RF) isolates the low apparent diffusion coefficient water signal attributed to cellular crowding. It is therefore proposed as a putative magnetic resonance imaging (MRI) marker of neuroinflammation. The purpose of this narrative review is to evaluate animal and human studies that compared DBSI-RF with histopathological benchmarks and clinical parameters. Across inflammatory demyelination, viral encephalitis, traumatic brain injury, and neurodegenerative disorders, DBSI-RF correlated moderately to strongly with immune cell density and distinguished inflammation from demyelinating or axonal pathology. In acute multiple sclerosis, combined isotropic fractions predicted lesion evolution, clinical subtypes, and deep-learning models that included DBSI-RF classified lesion subtypes with high accuracy. DBSI-RF might also be used to track putative neuroinflammation associated with psychosocial stress, mood disorders, and anxiety disorders. The strengths of the method include sensitivity to subclinical changes and the concurrent mapping of coexisting edema, demyelination, and axon loss. Limitations include non-specific etiology features, a demanding acquisition protocol, and limited large-scale human validation. Overall, DBSI-RF may demonstrate a promising diagnostic and prognostic accuracy, warranting standardized, multicenter, prospective trials and external validation. Full article

Accurate segmentation of multiple sclerosis (MS) lesions from 3D MRI scans is essential for diagnosis, disease monitoring, and treatment planning. However, this task remains challenging due to the sparsity, heterogeneity, and subtle appearance of lesions, as well as the difficulty in obtaining high-quality annotations. In this study, we propose Efficient-Net3D-UNet, a deep learning framework that combines compound-scaled MBConv3D blocks with a lesion-aware patch sampling strategy to improve volumetric segmentation performance across multi-modal MRI sequences (FLAIR, T1, and T2). The model was evaluated against a conventional 3D U-Net baseline using standard metrics including Dice similarity coefficient, precision, recall, accuracy, and specificity. On a held-out test set, EfficientNet3D-UNet achieved a Dice score of 48.39%, precision of 49.76%, and recall of 55.41%, outperforming the baseline 3D U-Net, which obtained a Dice score of 31.28%, precision of 32.48%, and recall of 43.04%. Both models reached an overall accuracy of 99.14%. Notably, EfficientNet3D-UNet also demonstrated faster convergence and reduced overfitting during training. These results highlight the potential of EfficientNet3D-UNet as a robust and computationally efficient solution for automated MS lesion segmentation, offering promising applicability in real-world clinical settings. Full article

Neuroinflammation is a key response to disturbed CNS homeostasis, largely mediated by activated microglia, and excessive microglia-driven inflammation can negatively impact neurogenesis. ZEB1 plays a crucial role in neurogenesis and brain development by influencing neural stem cell (NSC) maintenance, proliferation, and differentiation. This study aimed to evaluate how the knockdown of ZEB1 influences the behavior of NSCs in inflammatory environments. NSCs were isolated from the subventricular zone of rats, and ZEB1 knockdown was achieved using ZEB1 siRNA. A conditioned medium derived from lipopolysaccharide-activated microglia was utilized to induce inflammatory responses in NSCs. The silencing of ZEB1 in NSCs significantly reduced the expression of ZEB1. Furthermore, ZEB1 knockdown in NSCs resulted in a significant decrease in neurosphere formation, cell migration ability, reactive oxygen species generation, and various cytokine levels under both non-inflammatory and inflammatory conditions. These findings reveal the regulatory role of ZEB1 in the modulation of NSC behavior, suggesting that targeting ZEB1 may provide a potential therapeutic strategy for neuroinflammatory CNS disorders. Full article

Introduction: Multiple sclerosis (MS) is a chronic neurodegenerative disease that entails high costs, progressive disability, and reduced quality of life (QoL). Telerehabilitation (TR), supported by new technologies, is emerging as an alternative or complement to in-person rehabilitation, potentially lowering socioeconomic impact and improving QoL. Aim: The objective of this study was to evaluate the effect of TR on the QoL of people with MS compared with in-person rehabilitation or no intervention. Materials and methods: A systematic review of randomized clinical trials was conducted (March–May 2025) following PRISMA guidelines. Searches were run in the PubMed-Medline, EMBASE, PEDro, Web of Science, and Dialnet databases. Methodological quality was assessed with the CASP scale, risk of bias with the Risk of Bias 2 tool, and evidence level and grade of recommendation with the Oxford Classification. The protocol was registered in PROSPERO (CRD420251110353). Results: Of the 151 articles initially found, 12 RCTs (598 total patients) met the inclusion criteria. Interventions included (a) four studies employing video-controlled exercise (one involving Pilates to improve fitness, another involving exercise to improve fatigue and general health, and two using exercises focused on the pelvic floor muscles); (b) three studies using a monitoring app to improve manual dexterity, symptom control, and increased physical activity; (c) two studies implementing an augmented reality system to treat cognitive deficits and sexual disorders, respectively; (d) one platform with a virtual reality headset for motor and cognitive training; (e) one study focusing on video-controlled motor imagery, along with the use of a pain management app; (f) a final study addressing cognitive training and pain reduction. Studies used eight different scales to assess QoL, finding similar improvements between groups in eight of the trials and statistically significant improvements in favor of TR in four. The included trials were of good methodological quality, with a moderate-to-low risk of bias and good levels of evidence and grades of recommendation. Conclusions: TR was more effective in improving the QoL of people with MS than no intervention, was as effective as in-person treatment in patients with EDSS ≤ 6, and appeared to be more effective than in-person intervention in patients with EDSS between 5.5 and 7.5 in terms of QoL. It may also eliminate some common barriers to accessing such treatments. Full article

Vitamin D₃ plays a pivotal role not only in bone health but also in the functioning of the nervous system, particularly in the context of age-related neurodegenerative diseases such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Vitamin D₃ deficiency has been associated with cognitive decline, heightened inflammation, and shortened leukocyte telomere length, which may contribute to accelerated cellular aging. Therapeutic interventions involving vitamin D₃ have been reported in selected clinical studies and meta-analyses to potentially enhance cognitive function, decrease amyloid β biomarkers, and prolong telomere length, although heterogeneity remains across study designs and populations. Furthermore, vitamin D₃ has been shown to influence the expression of genes implicated in DNA repair and oxidative stress response, including NRF2, OGG1, MYH, and MTH1. This narrative review synthesizes current knowledge on the molecular mechanisms of vitamin D₃ action in the context of neuroprotection and discusses potential directions for future research, including its possible therapeutic applications in neurodegenerative diseases. Full article

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that affects women more frequently than men. This sex gap has widened over the past century, and appears to be shaped by lifestyle factors more than biological factors. This narrative review examines the evidence for sex-specific differences in lifestyle risk factors and their impact on both MS susceptibility and disease progression, with implications for diagnosis, monitoring, and treatment. Smoking, obesity, vitamin D deficiency, ultraviolet radiation exposure, and Epstein–Barr virus infection all interact with sex-related biological pathways to influence MS risk. Women appear to be more vulnerable to the pathogenic effects of smoking and obesity, both independently and in synergy with genetic risk alleles, while vitamin D and UV exposure confer stronger protective effects in females than in males. EBV infection also exhibits sex-dependent immune responses, shaped by hormonal regulation and host–virus genetic interactions. Sex-related lifestyle factors also modulate MS progression. Women experience more inflammatory activity and relapses, whereas men more often develop a progressive phenotype with greater neurodegeneration. Hormonal changes during female reproductive phases, such as pregnancy, breastfeeding, menopause, and hormone-based therapies, critically influence disease activity and progression in MS. Obesity, smoking, vitamin D status, diet, and gut microbiota further interact with sex hormones and genetic background, contributing to variable disease trajectories, also modulated by social determinants such as education level. These findings underscore the need to integrate into clinical practice the evaluation of lifestyle factors in a sex-specific way for diagnosis, monitoring, and treatment of MS. Full article

Interferons (IFNs) are key cytokines at the intersection of innate and adaptive immunity. While their antiviral and antitumor roles are well recognized, emerging evidence implicates IFNs—particularly types I, II, and III—in the initiation and progression of autoimmune diseases (ADs). This review synthesizes current data on IFN biology, their immunoregulatory and pathogenic mechanisms, and their contributions to distinct AD phenotypes. We conducted a comprehensive review of peer-reviewed literature on IFNs and autoimmune diseases, focusing on publications indexed in PubMed and Scopus. Studies on molecular pathways, immune cell interactions, disease-specific IFN signatures, and clinical correlations were included. Data were extracted and thematically organized by IFN type, signaling pathway, and disease context, with emphasis on rheumatic and systemic autoimmune disorders. Across systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, idiopathic inflammatory myopathies, multiple sclerosis, type 1 diabetes, psoriasis, and inflammatory bowel diseases, IFNs were consistently associated with aberrant activation of pattern recognition receptors, sustained expression of interferon-stimulated genes (ISGs), and dysregulated T cell and B cell responses. Type I IFNs often preceded clinical onset, suggesting a triggering role, whereas type II and III IFNs modulated disease course and severity. Notably, IFNs exhibited dual immunostimulatory and immunosuppressive effects, contingent on tissue context, cytokine milieu, and disease stage. IFNs are central mediators in autoimmune pathogenesis, functioning as both initiators and amplifiers of chronic inflammation. Deciphering the context-dependent effects of IFN signaling may inform targeted therapeutic strategies and advance precision immunomodulation in autoimmune diseases. Full article

Background: Preliminary evidence supports high-intensity functional training (HIFT) for improving various health outcomes in non-disabled adults with overweight/obesity. It remains unknown whether HIFT produces similar benefits in individuals who are overweight/obese and also have a mobility disability (e.g., spinal cord injury, multiple sclerosis)—a population disproportionately affected by obesity-related health conditions and systemic barriers to exercise. This pilot study aimed to evaluate the feasibility and preliminary effects of a 24-week HIFT intervention, delivered at community sites by certified trainers, for adults with mobility disabilities (MDs) who were overweight/obese. Methods: Twenty adults with MD and overweight/obesity (self-reported BMI 25–46 kg/m²) enrolled in a 24-week HIFT intervention (3 days/wk, 60 min sessions) delivered at four community-based facilities by certified trainers. Feasibility indicators included recruitment, retention, and attendance; adverse events were tracked. Effect sizes (Cohen’s d) were calculated for changes in obesity-related measures, physical function, work capacity, and psychological measures from baseline to post-intervention. Results: Feasibility targets were met, with a recruitment rate of 72.2%, 76.9% retention, and 80.7% attendance. Thirteen adverse events occurred. Effects on obesity-related measures ranged from negligible to moderate, with stable weight/BMI, reduced waist circumference (45% ≥ 3 cm decrease), decreased body fat, and increased lean mass. Functional outcome effects ranged from small to large and included grip strength, balance, and walking speed. Large improvements were observed for the endurance, speed, work capacity, and self-reported physical function. Conclusions: A community-based HIFT program is feasible and may improve health outcomes in adults with MD and overweight/obesity. Full article

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disorder characterized by progressive demyelination and axonal degeneration within the central nervous system, driven by complex genomic and epigenomic dysregulation. Its pathogenesis involves aberrant DNA methylation patterns at CpG islands of numbers of genes like OLIG1 and OLIG2 disrupting protein expression at myelin with compromised oligodendrocyte differentiation. Furthermore, histone modifications, particularly H3K4me3 and H3K27ac, alter the promoter regions of genes responsible for myelination, affecting myelin synthesis. MS exhibits chromosomal instability and copy number variations in immune-regulatory gene loci, contributing to the elevated expression of genes for pro-inflammatory cytokines (TNF-α, IL-6) and reductions in anti-inflammatory molecules (IL-10, TGF-β1). Vitamin D deficiency correlates with compromised immune regulation through hypermethylation and reduced chromatin accessibility of vitamin D receptor (VDR) dysfunction and is reported to be associated with dopaminergic neuronal loss. Vitamin D supplementation demonstrates therapeutic potential through binding with VDR, which facilitates nuclear translocation and subsequent transcriptional activation of target genes via vitamin D response elements (VDREs), resulting in suppression of NF-κB signalling, enhancement of regulatory T-cell (T_reg) responses due to upregulation of specific genes like FOXP3, downregulation of pro-inflammatory pathways, and potential restoration of the chromatin accessibility of oligodendrocyte-specific gene promoters, which normalizes oligodendrocyte activity. Identification of differentially methylated regions (DMRs) and differentially expressed genes (DEGs) that are in proximity to VDR-mediated gene regulation supports vitamin D supplementation as a promising, economically viable, and sustainable therapeutic strategy for MS. This systematic review integrates clinical evidence and eventual bioinformatical meta-analyses that reference transcriptome and methylome profiling and identify prospective molecular targets that represent potential genetic and epigenetic biomarkers for personalized therapeutic intervention. Full article

Selective and potent inhibitors of the NAD⁺-dependent deacetylase Sirt2 represent a valuable epigenetic strategy for the treatment of currently incurable diseases such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and multiple sclerosis. Guided by molecular docking and MM/GBSA validation studies, a lead structure-based hybridization strategy was developed, resulting in a series of very effective Sirt2 inhibitors. With RW-93, we present a highly potent and subtype selective Sirt2 inhibitor (IC₅₀ = 16 nM), which as a next generation SirReal-type inhibitor significantly surpasses established Sirt2 inhibitors and contributes to the extension of the current SAR profile. The structural modification strategy employed in this study proved to be highly promising, resulting in the identification of the most potent low-molecular-weight Sirt2 inhibitor reported to date, providing a promising target for further medicinal chemistry-driven SAR studies. Full article

Autoimmune diseases result from dysregulated immune responses that mistakenly attack the body’s own tissues, causing chronic inflammation and progressive damage. Macrophages, with their remarkable plasticity, play key roles in both promoting and resolving inflammation, with pro-inflammatory M1 and anti-inflammatory M2 states shaping disease outcomes. Macrophage-derived exosomes have emerged as important mediators of intercellular communication, reflecting the functional state of their parent cells while influencing recipient cell behavior. Exosomes from M1 macrophages amplify inflammation through cytokines and microRNAs, whereas M2-derived exosomes support tissue repair and immune regulation. Studies in rheumatoid arthritis, lupus, multiple sclerosis, inflammatory bowel disease, type 1 diabetes, and psoriasis highlight their dual roles in pathology and resolution. In addition, macrophage exosomes can be engineered to deliver targeted therapeutic molecules, offering cell-free interventions with advantages in specificity, biocompatibility, and immunomodulation. This review summarizes current insights into macrophage-derived exosomes, their role in autoimmune pathogenesis, and emerging strategies to harness their therapeutic potential, highlighting their promise as precision-guided treatments for autoimmune diseases. Full article

(1) Background: Technological advancements provide new opportunities to objectively assess motor deficits in people with Multiple Sclerosis (PwMS). This pilot study aimed to evaluate the performance and usability of iFeel, a novel wearable system which integrates inertial sensors, instrumented shoes, and an AI-based algorithm. (2) Methods: Sixteen adult PwMS (Expanded Disability Status Scale—EDSS ≤ 6) performed motor tests (Timed 25-Foot Walk—T25FW; Timed Up and Go—TUG) both with and without the iFeel suit. Patient-reported outcomes (PROs) were also collected to assess perceived fatigue, dual-task impact, and walking difficulties. System Usability Scale (SUS) and ad hoc questionnaires have been further administered to test usability. (3) Results: No significant differences were found between the clinician and system-based scores for both T25FW (p = 0.383) and TUG (p = 0.447). Reliability analyses showed good agreement for T25FW (Intraclass Correlation Coefficient—ICC = 0.83) and excellent agreement for TUG (ICC = 0.92). Sensor-derived measures correlated strongly with PROs on fatigue, dual-task interference, and mobility. Usability was rated high (SUS: 78.6 ± 16.1), with participants reporting minimal discomfort and positive perceptions of iFeel usefulness for rehabilitation, health monitoring, and daily activities. (4) Conclusions: This pilot study provides preliminary yet promising evidence on the feasibility, usability, and perceived usefulness of the iFeel technology for motor assessment in PwMS. The findings support its further development and potential integration into clinical practice, particularly for remote or continuous motor monitoring. Full article

Background: Monocytes can commit to different phenotypes associated with specific features required in inflammation and homeostasis. Classical and alternative activation are two extremes of monocyte polarization and are both influenced by glucocorticoids (GCs). Methods: Human monocytes were sorted from the blood of healthy individuals and activated with LPS or IL-4 and IL-13, either in the absence or presence of dexamethasone (Dex). Metabolic adjustments were analyzed using Seahorse stress tests, SCENITH, and RT-qPCR. Results: LPS enhanced glycolysis and also, to a lesser extent, oxidative phosphorylation (OXPHOS), whereas addition of Dex induced a metabolic switch in favor of the latter. In contrast, activation of monocytes with IL-4 and IL-13 exclusively stimulated OXPHOS, which was suppressed by concomitant Dex treatment. The glycolytic function of monocytes matched alterations in gene expression of glucose transporters and metabolic enzymes, which were upregulated by LPS and inhibited by Dex via interference with the mTORC1 pathway but remained unaltered in response to IL-4 and IL-13. Although the dependency of classically and alternatively activated monocytes on OXPHOS and glucose usage markedly differed, modulation by GCs was limited to the latter polarization state. Conclusions: Our findings unravel a highly selective regulation of human monocyte energy metabolism by different activating stimuli as well as by GCs. Full article

Misregulation of C-C chemokine receptor 7 (CCR7) has been linked to multiple autoimmune diseases including systemic lupus erythematosus, multiple sclerosis, and ankylosing spondylitis. As a G-protein-coupled receptor, located on the cell membrane, CCR7 can be targeted by inhibiting one of its two ligands, C-C chemokine ligand 19 (CCL19), to regulate its function. In this study, we examined signaling events downstream of CCL19 binding that provide a mechanism for regulation of the immune response. We used a CCR7 antagonist, CCL19_8-83, in immune studies in vivo, as a platform for a pharmaceutical to define the molecular events that are involved in regulating the humoral adaptive immune response. We found that in the presence of a T-cell-dependent antigen, C57BL/6 mice treated during antigen exposure with CCL19_8-83 generated significantly higher levels of IgG1, the dominant isotype in extracellular bacterial infections that can activate complement, and IgG2c, the dominant isotype during viral and intracellular bacterial infections. Inhibiting ERK5 signaling downstream of CCR7 activation by CCL19, or disruption of CCL19 expression in CCL19^−/− mice, also resulted in higher levels of IgG1 when compared to control mice. Differences in levels of IL-4 or other cytokines or lymphocyte types between wild-type and ERK5-deficient T cells did not account for antibody levels. Since pertussis-toxin-induced inhibition of lymphocyte chemotaxis is linked to elevated levels of IgG, we examined the effect of ERK5 on chemotaxis to CCR7 ligand CCL19. We found that disruption of ERK5 in T cells, or global disruption of CCL19 or CCR7, inhibited chemotaxis of T cells to CCL19, a mechanism that enhances sensitization during the exposure to an immunogen. Since CCR7 and its ligands have been linked to autoimmunity, these studies may provide insight into mechanisms that can be targeted to control autoimmune responses. Full article