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Insights in Multiple Sclerosis (MS) and Neuroimmunology: 2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (20 October 2025) | Viewed by 13074

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Prof. Dr. Michael C. Levin

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Department of Medicine, Neurology Division, University of Saskatchewan, Saskatoon, SK S7N 0X8, Canada
Interests: neurology; neuroscience; multiple sclerosis; RNA-binding proteins; neurodegeneration
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue on “Insights in Multiple Sclerosis (MS) and Neuroimmunology”.

Neurodegeneration, defined as damage to neurons, oligodendrocytes, and axons, is now acknowledged to be the primary driver of disability in multiple sclerosis (MS) patients. Therefore, research into the mechanisms of neurodegeneration in MS has expanded over the past several years. Furthermore, with the development and implementation of more precise technologies, including sequencing and advanced imaging, we can more confidently define processes that cause damage to neurons, oligodendrocytes, and axons in MS.

For this Special Issue on ‘Insights in Multiple Sclerosis (MS) and Neuroimmunology’, we accept both reviews and original articles that explore the mechanisms of neurodegeneration, including those with an immunological mediator (i.e., macrophages, T-cells, B-cells, astrocytes, etc.). Reviews should highlight the most recent findings with regard to this topic, as well as emphasize novel approaches that are helping to advance this area of research. Original articles should demonstrate potential mechanisms of neurodegeneration, including damage to neurons, oligodendrocytes, and axons, in any MS models, including in vitro, in vivo, and in situ systems with a particular emphasis on immunological mediators. Original articles may also include potential therapies to combat neurodegeneration in MS.

This Special Issue is supervised by Prof. Dr. Michael C. Levin and assisted by Dr. Catherine Hutchinson. We warmly welcome the submission of short communications, original research articles, and review articles.

Prof. Dr. Michael C. Levin
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neurodegeneration
neuroimmunology
macrophage
T-cell
B-cell
antibody
neurons
oligodendrocytes
axon
axonal damage
cell death
multiple sclerosis

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Published Papers (9 papers)

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Research

Jump to: Review

26 pages, 2679 KB

Open AccessArticle

EBV Early Lytic Antigens, EBNA2 and PDL-1, in Progressive Multiple Sclerosis Brain: A Coordinated Contribution to Viral Immune Evasion

by Lucia Benincasa, Barbara Rosicarelli, Chiara Meloni and Barbara Serafini

Int. J. Mol. Sci. 2026, 27(1), 437; https://doi.org/10.3390/ijms27010437 - 31 Dec 2025

Viewed by 462

Abstract

Epstein-Barr virus (EBV) infection shows the strongest causative association with multiple sclerosis (MS), but its contribution to disease progression and the mechanisms allowing for viral persistence in the MS brain are still elusive. Studies in post-mortem MS brain tissue indicate an ongoing yet ineffective antiviral immune reaction in advanced stages of the disease. EBV has evolved strategies to evade immune recognition and clearance by the host immune system during both the latency and lytic phase of its life cycle. Recent evidence demonstrates that cells expressing EBV latent membrane protein (LMP) 2A exploit the PD-1/PDL1 inhibitory immune checkpoint to escape immune surveillance and maintain a persistent latent infection in the MS brain. This study investigated whether the virus also utilizes this inhibitory mechanism during other phases of the viral life cycle. By using multiple immunostainings on highly inflamed MS brain tissues containing meningeal tertiary lymphoid structures (TLSs), we analyzed PD-L1 expression on EBV-infected cells expressing EBNA2, five EBV lytic gene products, BZLF1, BHRF1, BMRF1, BALF2, and gp350/220, as well as on follicular dendritic cells within the TLSs. This is the first study describing in secondary progressive MS brain tissue the expression and the cellular and tissue distribution of PD-L1 on EBV-infected cells being in different stages of the viral life cycle, and confirms the meningeal TLSs as immune-permissive habitats favoring the maintenance of an intracerebral EBV reservoir. Full article

(This article belongs to the Special Issue Insights in Multiple Sclerosis (MS) and Neuroimmunology: 2nd Edition)

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20 pages, 4326 KB

Open AccessArticle

Overexpression of ITGB3 in Peripheral Blood Mononuclear Cells of Relapsing-Remitting Multiple Sclerosis Patients

by Giselle Berenice Vela Sancho, Ricardo E. Buendia-Corona, María Paulina Reyes-Mata, Mario Alberto Mireles-Ramírez, Christian Griñán-Ferré, Mercè Pallàs, Ana Laura Márquez-Aguirre, Lenin Pavon, Oscar Arias-Carrión, José de Jesús Guerrero-García and Daniel Ortuño-Sahagún

Int. J. Mol. Sci. 2025, 26(24), 12094; https://doi.org/10.3390/ijms262412094 - 16 Dec 2025

Viewed by 368

Abstract

Multiple sclerosis (MS), the most prevalent chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults, exhibits marked sexual dimorphism, with a 3:1 female-to-male ratio, but more severe symptoms and greater neurological damage in males. Increasing attention has focused on identifying circulating molecules that reflect inflammatory activity within the central nervous system and could clarify the mechanisms underlying MS. Pleiotrophin (PTN), a cytokine implicated in autoimmune and neurological diseases, is significantly elevated in patients with relapsing-remitting MS (RRMS). To explore the potential contribution of PTN and its receptors to neuroinflammatory signaling, we quantified the mRNA expression of PTN receptors in peripheral blood mononuclear cells from RRMS patients compared to untreated RRMS patients and healthy control subjects. We further performed an in silico molecular docking and molecular dynamics analysis to assess the possible functional significance of PTN-receptor interactions. Our results show a significant overexpression of integrin subunit beta-3 (ITGB3) mRNA in peripheral blood mononuclear cells from RRMS patients compared to healthy control subjects. Molecular docking shows that PTN could binds to the metal ion-dependent adhesion site domain of ITGB3 via Mg²⁺/Ca²⁺-mediated stabilization and has a higher binding affinity than fibrinogen, the canonical endogenous ligand. These findings suggest that ITGB3 could be a dynamically regulated integrin receptor in RRMS that may participate in PTN-driven neuroinflammatory pathways in peripheral blood immune cells, influenced by disease stage, sex, and immunotherapy. While our results support the biological plausibility of PTN–ITGB3 engagement, they remain hypothesis-generating and require functional validation. The integration of molecular expression data and computational modeling underscores the potential involvement of ITGB3 as a possible participant in MS and warrants further investigation of its clinical and mechanistic role. Full article

(This article belongs to the Special Issue Insights in Multiple Sclerosis (MS) and Neuroimmunology: 2nd Edition)

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14 pages, 1024 KB

Open AccessArticle

Modulation of Paraoxonase 1 Activity and Asymmetric Dimethylarginine by Immunomodulatory Therapies in Multiple Sclerosis

by Lilla Racz, Hajnalka Lorincz, Ildiko Seres, Laszlo Kardos, Gyorgy Paragh and Tunde Csepany

Int. J. Mol. Sci. 2025, 26(19), 9728; https://doi.org/10.3390/ijms26199728 - 6 Oct 2025

Viewed by 663

Abstract

Background: Neurodegeneration is present from the earliest stages of multiple sclerosis [MS], and oxidative stress together with mitochondrial dysfunction are key contributors to neuronal injury and disease progression. Objective: To investigate the role of the antioxidant enzyme paraoxonase 1 (PON1) and serum asymmetric dimethylarginine (ADMA) levels in MS across different disease subtypes and immunomodulatory treatments. Methods: Serum lipid levels and PON1 activity were measured and compared by disease subtype and treatment in a single-center MS cohort (N = 262; CIS = 10, RRMS = 208, PPMS = 19, SPMS = 25; 110 untreated, 152 treated) and in 91 healthy controls. ADMA levels were assessed in sera from 79 MS patients (19 untreated, 60 treated) and 31 age-matched controls. Results: Median serum paraoxonase (PON) and arylesterase (ARE) activity levels were 83.8 and 127.2 IU/L in MS patients versus 85.9 and 136.9 IU/L in controls, with no significant difference for PON (p = 0.191) but a significant reduction in ARE [p = 0.003]. PON activity differed significantly among disease subtypes (p = 0.023), with the highest levels in CIS. PON and ARE activity also varied across treatment groups (p = 0.038 and p = 0.034, respectively), with longitudinal analysis indicating a measurable effect of immunomodulatory therapy on PON activity at 10 years (p = 0.0136). Significant differences in enzyme activity were observed between untreated and interferon-treated patients (PON p = 0.0055, ARE p = 0.0001), with trends toward differences in ARE under natalizumab and fingolimod. ADMA levels were lower in MS patients than controls (p < 0.0001) and differed among treatment subgroups (natalizumab, dimethyl fumarate, glatiramer acetate, untreated RRMS). Conclusions: PON1 activity and ADMA levels differ between MS subgroups and under immunomodulatory treatments. Long-term therapy was associated with increased PON1 activity, while highly effective immunomodulators reduced ADMA levels. These changes may contribute to the treatment-related reduction in disease activity and attenuation of neurodegenerative processes in MS. Full article

(This article belongs to the Special Issue Insights in Multiple Sclerosis (MS) and Neuroimmunology: 2nd Edition)

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10 pages, 1474 KB

Open AccessArticle

Exploring the Prognostic Role of Neurofilaments and SEMA3A in Multiple Sclerosis Progression

by Zbyšek Pavelek, Ondřej Souček, Jan Krejsek, Ilona Součková, Andrea Popovičová, David Matyáš, Lukáš Sobíšek and Michal Novotný

Int. J. Mol. Sci. 2025, 26(17), 8750; https://doi.org/10.3390/ijms26178750 - 8 Sep 2025

Viewed by 1080

Abstract

The transition from relapsing–remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) is characterized by an increasing neurodegenerative component. Identifying biomarkers that distinguish these disease stages is crucial for early diagnosis and treatment optimization. This study aimed to compare serum levels of progranulin, interleukin-6 (IL-6), semaphorin 3A (SEMA3A), and neurofilaments between RRMS and SPMS patients and to investigate their correlation with clinical characteristics, including disability measured by the Expanded Disability Status Scale (EDSS). This observational study included 118 MS patients (63 RRMS and 55 SPMS). Serum biomarker levels were measured using an enzyme-linked immunosorbent assay (ELISA). Statistical analyses included group comparisons using non-parametric tests and correlation analyses using Pearson’s correlation coefficient with multiple testing corrections. While demographic and clinical parameters significantly differed between groups (p < 0.001), biomarker levels showed no statistically significant differences (p > 0.05). However, in SPMS patients, SEMA3A correlated positively with neurofilaments (r = 0.359, p = 0.007), and progranulin correlated with IL-6 (r = 0.354, p = 0.008). No significant biomarker correlations with EDSS were found. Although absolute biomarker levels did not distinguish RRMS from SPMS, specific biomarker correlations may reflect processes relevant to disease progression and warrant further longitudinal validation. Full article

(This article belongs to the Special Issue Insights in Multiple Sclerosis (MS) and Neuroimmunology: 2nd Edition)

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20 pages, 1676 KB

Open AccessArticle

Combining CSF and Serum Biomarkers to Differentiate Mechanisms of Disability Worsening in Multiple Sclerosis

by Enric Monreal, José Ignacio Fernández-Velasco, Susana Sainz de la Maza, Mercedes Espiño, Noelia Villarrubia, Ernesto Roldán-Santiago, Yolanda Aladro, Juan Pablo Cuello, Lucía Ayuso-Peralta, Alexander Rodero-Romero, Juan Luís Chico-García, Fernando Rodríguez-Jorge, Ana Quiroga-Varela, Eulalia Rodríguez-Martín, Belén Pilo de la Fuente, Guillermo Martín-Ávila, María Luisa Martínez-Ginés, José Manuel García-Domínguez, Lluïsa Rubio, Sara Llufriu, Manuel Comabella, Xavier Montalban, Gary Álvarez-Bravo, José Luís Veiga-González, Jaime Masjuan, Lucienne Costa-Frossard and Luisa María Villar Show full author list Hide full author list

Int. J. Mol. Sci. 2025, 26(14), 6898; https://doi.org/10.3390/ijms26146898 - 18 Jul 2025

Cited by 2 | Viewed by 1892

Abstract

The combined use of serum and CSF biomarkers for prognostic stratification in multiple sclerosis (MS) remains underexplored. This multicenter observational study investigated associations between serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), and CSF lipid-specific IgM oligoclonal bands (LS-OCMB) with different forms of disability worsening, such as relapse-associated worsening (RAW), active progression independent of relapse activity (aPIRA), and non-active PIRA (naPIRA). A total of 535 patients with MS were included, all sampled within one year of disease onset. Biomarkers were quantified using single-molecule array and immunoblotting techniques, and CSF cell subsets were analyzed by flow cytometry. High sNfL z-scores and LS-OCMB positivity were independently associated with increased risk of RAW and aPIRA, collectively termed inflammatory-associated worsening (IAW), while elevated sGFAP levels predicted naPIRA. Patients with both high sNfL and LS-OCMB positivity had the highest risk of IAW. Among LS-OCMB–positive patients, higher regulatory T cell percentages were associated with lower sNfL levels, suggesting a protective role. Conversely, in LS-OCMB–negative patients, sNfL levels correlated with CSF C3 concentrations. These findings support the complementary role of sNfL, sGFAP, and LS-OCMB in identifying distinct mechanisms of disease worsening and may inform early personalized management strategies in MS. Full article

(This article belongs to the Special Issue Insights in Multiple Sclerosis (MS) and Neuroimmunology: 2nd Edition)

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13 pages, 1914 KB

Open AccessArticle

Profiling Blood-Based Neural Biomarkers and Cytokines in Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis Using Single-Molecule Array Technology

by Insha Zahoor, Sajad Mir and Shailendra Giri

Int. J. Mol. Sci. 2025, 26(7), 3258; https://doi.org/10.3390/ijms26073258 - 1 Apr 2025

Cited by 6 | Viewed by 1942

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a preclinical animal model widely used to study multiple sclerosis (MS). Blood-based analytes, including cytokines and neural biomarkers are the predictors of neurodegeneration, disease activity, and disability in patients with MS. However, understudied confounding factors cause variation in reports on EAE across animal strains/studies, limiting the utility of these biomarkers for predicting disease activity. In this study, we investigated blood-based analyte profiles, including neural markers (NFL and GFAP) and cytokines (IL-6, IL-17, IL-12p70, IL-10, and TNF-α), in two clinically distinct EAE models: relapsing-remitting (RR)-EAE and chronic-EAE. Ultrasensitive single-molecule array technology (SIMOA, Quanterix) was used to profile the analytes in the blood plasma of mice at the acute, chronic, and progressive phases of disease. In both models, NFL was substantially increased during post-disease onset across all phases, with a pronounced increase observed in chronic-EAE. The leakage of GFAP into peripheral blood was also greater after disease onset in both EAE models, especially in the acute phase of chronic-EAE. Among all cytokines, only IL-10 had consistently lower levels in both EAE models throughout the course of disease. This study suggests NFL, GFAP, and IL-10 as potential translational predictors of disease activity in EAE, making them potential candidates as surrogate markers for the preclinical testing of therapeutic interventions in animal models of MS. Full article

(This article belongs to the Special Issue Insights in Multiple Sclerosis (MS) and Neuroimmunology: 2nd Edition)

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Review

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22 pages, 701 KB

Open AccessReview

The Potential of β-Synuclein-Specific Regulatory T Cell Therapy as a Treatment for Progressive Multiple Sclerosis

by Grace E. Osmond, Nevin A. John, Yi Tian Ting and Joshua D. Ooi

Int. J. Mol. Sci. 2025, 26(23), 11534; https://doi.org/10.3390/ijms262311534 - 28 Nov 2025

Viewed by 582

Abstract

Disease progression in multiple sclerosis (MS) is now known to affect many patients, even those not diagnosed with progressive subtypes. Progressive and neurodegenerative aspects of MS are poorly treated by currently available therapies. Research on new therapeutic options is needed to improve health outcomes in people with MS. This review highlights the potential for treatment using an engineered T cell receptor–regulatory T cell (TCR-Treg) therapy targeting the presynaptic protein beta-synuclein. Tregs respond to self-antigens presented on human leukocyte antigen (HLA) class II with anti-inflammatory and pro-neural healing effects, but this response is impaired in MS patients. Since the HLA-DRB1*15:01 allele is known to contribute to MS pathogenesis, a TCR specific to a known antigen presented on DRB1*15:01 can be transduced into Tregs to direct them to activate within the inflamed brain tissue. Beta-synuclein is released from neurons at a high level after neural damage, may be presented on HLA, enables homing of specific T cells to the grey matter, and is immunogenic in progressive MS patients. This review presents beta-synuclein as a disease-relevant antigen to target for therapeutic development. Full article

(This article belongs to the Special Issue Insights in Multiple Sclerosis (MS) and Neuroimmunology: 2nd Edition)

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48 pages, 950 KB

Open AccessReview

Metabolomics in Multiple Sclerosis: Advances, Challenges, and Clinical Perspectives—A Systematic Review

by Jan Smusz, Patrycja Mojsak, Paulina Matys, Anna Mirończuk, Joanna Tarasiuk, Kamil Grubczak, Aleksandra Starosz, Jan Kochanowicz, Alina Kułakowska, Katarzyna Ruszczyńska and Katarzyna Kapica-Topczewska

Int. J. Mol. Sci. 2025, 26(18), 9207; https://doi.org/10.3390/ijms26189207 - 20 Sep 2025

Cited by 2 | Viewed by 2703

Abstract

Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disorder marked by inflammation, demyelination, and neuronal loss within the central nervous system. Despite advances in diagnostics, current tools remain insufficiently sensitive and specific. Metabolomics has emerged as a promising approach to explore MS pathophysiology and discover novel biomarkers. This PRISMA-guided systematic review included 29 original studies using validated metabolomic techniques in adult patients with MS. Biological samples analyzed included serum, cerebrospinal fluid, and feces. Consistent metabolic alterations were identified across several pathways. The kynurenine pathway demonstrated a shift toward neurotoxic metabolites, alongside reductions in microbial-derived indoles, indicating inflammation and gut dysbiosis. Energy metabolism was impaired, with changes in glycolysis, tricarboxylic acid (TCA) cycle, and mitochondrial function. Lipid metabolism showed widespread dysregulation involving phospholipids, sphingolipids, endocannabinoids, and polyunsaturated fatty acids, some modulated by treatments such as ocrelizumab and interferon-β. Nitrogen metabolism was also affected, including amino acids, peptides, and nucleotides. Non-classical and xenobiotic metabolites, such as myo-inositol, further reflected host–microbiome–environment interactions. Several studies demonstrated the potential of metabolomics-based machine learning to distinguish MS subtypes. These findings highlight the value of metabolomics for biomarker discovery and support its integration into personalized therapeutic strategies in MS. Full article

(This article belongs to the Special Issue Insights in Multiple Sclerosis (MS) and Neuroimmunology: 2nd Edition)

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37 pages, 2404 KB

Open AccessReview

From Molecules to Models: miRNAs and Advanced Human Platforms of Neurodegeneration and Repair in Multiple Sclerosis

by María Muñoz-San Martín, Lucía de la Guerra-Sasián, Gabriel Gárate, Jorge Madera, Andrea González-Suárez, Nadia C. Cavada-Bustamante, Vicente González-Quintanilla and Jennifer K. Dowling

Int. J. Mol. Sci. 2025, 26(17), 8740; https://doi.org/10.3390/ijms26178740 - 8 Sep 2025

Viewed by 2174

Abstract

Beyond the potential role of microRNAs (miRNAs) as biomarkers, their participation in different biological and pathological processes observed in multiple sclerosis (MS) such as neuroinflammation, neurodegeneration and remyelination, makes them suitable candidates for therapeutic applications in neurorepair. Most studies addressing this reparative approach have been carried out using in vitro or in vivo model systems. However, functional differences between murine and human cells within the central nervous system (CNS) have been described, and certain mechanisms are distinctive in humans. The development of human models to investigate therapeutic interventions in neurological conditions including MS should be a priority to avoid failures. In this review, we provide a comprehensive summary of the advances in reparative therapeutic strategies for MS, including miRNAs and human models. We also discuss their benefits, the likely challenges they face and comment on possible mitigation strategies. Full article

(This article belongs to the Special Issue Insights in Multiple Sclerosis (MS) and Neuroimmunology: 2nd Edition)

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