Research

22 pages, 4994 KiB

Open AccessArticle

Targeted RNAseq Revealed the Gene Expression Signature of Ferroptosis-Related Processes Associated with Disease Severity in Patients with Multiple Sclerosis

by Ljiljana Stojkovic, Ivan Jovanovic, Evica Dincic, Ana Djordjevic, Jovana Kuveljic, Tamara Djuric, Aleksandra Stankovic, Slobodan Vojinovic and Maja Zivkovic

Int. J. Mol. Sci. 2024, 25(5), 3016; https://doi.org/10.3390/ijms25053016 - 05 Mar 2024

Viewed by 690

Abstract

Detrimental molecular processes in multiple sclerosis (MS) lead to the cellular accumulation of lipid peroxidation products and iron in the CNS, which represents the main driving force for ferroptosis. Ferroptosis is an iron-dependent form of regulated cell death, with proposed roles in neurodegeneration, [...] Read more.

Detrimental molecular processes in multiple sclerosis (MS) lead to the cellular accumulation of lipid peroxidation products and iron in the CNS, which represents the main driving force for ferroptosis. Ferroptosis is an iron-dependent form of regulated cell death, with proposed roles in neurodegeneration, oligodendrocyte loss and neuroinflammation in the pathogenesis of MS. Ferroptosis-related gene expression signature and molecular markers, which could reflect MS severity and progression, are currently understudied in humans. To tackle these challenges, we have applied a curated approach to create and experimentally analyze a comprehensive panel of ferroptosis-related genes covering a wide range of biological processes associated with ferroptosis. We performed the first ferroptosis-related targeted RNAseq on PBMCs from highly distinctive MS phenotype groups: mild relapsing–remitting (RR) (n = 24) and severe secondary progressive (SP) (n = 24), along with protein detection of GPX4 and products of lipid peroxidation (MDA and 4-HNE). Out of 138 genes, 26 were differentially expressed genes (DEGs), indicating changes in both pro- and anti-ferroptotic genes, representing a molecular signature associated with MS severity. The top three DEGs, as non-core ferroptosis genes, CDKN1A, MAP1B and EGLN2, were replicated by qPCR to validate findings in independent patient groups (16 RR and 16 SP MS). Co-expression and interactions of DEGs were presented as additional valuable assets for deeper understanding of molecular mechanisms and key targets related to MS severity. Our study integrates a wide genetic signature and biochemical markers related to ferroptosis in easily obtainable PBMCs of MS patients with clinical data and disease severity, thus providing novel molecular markers which can complement disease-related changes in the brain and undergo further research as potential therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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20 pages, 5216 KiB

Open AccessArticle

The Utility of Miniaturized Adsorbers in Exploring the Cellular and Molecular Effects of Blood Purification: A Pilot Study with a Focus on Immunoadsorption in Multiple Sclerosis

by Andreas Körtge, Anne Breitrück, Sandra Doß, Jacqueline Hofrichter, Sophie-Charlotte Nelz, Horst Krüsemann, Reinhold Wasserkort, Brit Fitzner, Michael Hecker, Steffen Mitzner and Uwe Klaus Zettl

Int. J. Mol. Sci. 2024, 25(5), 2590; https://doi.org/10.3390/ijms25052590 - 23 Feb 2024

Viewed by 594

Abstract

Immunoadsorption (IA) has proven to be clinically effective in the treatment of steroid-refractory multiple sclerosis (MS) relapses, but its mechanism of action remains unclear. We used miniaturized adsorber devices with a tryptophan-immobilized polyvinyl alcohol (PVA) gel sorbent to mimic the IA treatment of [...] Read more.

Immunoadsorption (IA) has proven to be clinically effective in the treatment of steroid-refractory multiple sclerosis (MS) relapses, but its mechanism of action remains unclear. We used miniaturized adsorber devices with a tryptophan-immobilized polyvinyl alcohol (PVA) gel sorbent to mimic the IA treatment of patients with MS in vitro. The plasma was screened before and after adsorption with regard to disease-specific mediators, and the effect of the IA treatment on the migration of neutrophils and the integrity of the endothelial cell barrier was tested in cell-based models. The in vitro IA treatment with miniaturized adsorbers resulted in reduced plasma levels of cytokines and chemokines. We also found a reduced migration of neutrophils towards patient plasma treated with the adsorbers. Furthermore, the IA-treated plasma had a positive effect on the endothelial cell barrier’s integrity in the cell culture model. Our findings suggest that IA results in a reduced infiltration of cells into the central nervous system by reducing leukocyte transmigration and preventing blood–brain barrier breakdown. This novel approach of performing in vitro blood purification therapies on actual patient samples with miniaturized adsorbers and testing their effects in cell-based assays that investigate specific hypotheses of the pathophysiology provides a promising platform for elucidating the mechanisms of action of those therapies in various diseases. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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17 pages, 2225 KiB

Open AccessArticle

Deep Flow Cytometry Unveils Distinct Immune Cell Subsets in Inducible T Cell Co-Stimulator Ligand (ICOSL)- and ICOS-Knockout Mice during Experimental Autoimmune Encephalomyelitis

by Davide Raineri, Hugo Abreu, Beatrice Vilardo, Natasa Kustrimovic, Chiara Venegoni, Giuseppe Cappellano and Annalisa Chiocchetti

Int. J. Mol. Sci. 2024, 25(5), 2509; https://doi.org/10.3390/ijms25052509 - 21 Feb 2024

Viewed by 665

Abstract

The inducible T cell co-stimulator ligand (ICOSL), expressed by antigen presenting cells, binds to the inducible T cell co-stimulator (ICOS) on activated T cells. Improper function of the ICOS/ICOSL pathway has been implicated in several autoimmune diseases, including multiple sclerosis (MS). Previous studies [...] Read more.

The inducible T cell co-stimulator ligand (ICOSL), expressed by antigen presenting cells, binds to the inducible T cell co-stimulator (ICOS) on activated T cells. Improper function of the ICOS/ICOSL pathway has been implicated in several autoimmune diseases, including multiple sclerosis (MS). Previous studies showed that ICOS-knockout (KO) mice exhibit severe experimental autoimmune encephalomyelitis (EAE), the animal model of MS, but data on ICOSL deficiency are not available. In our study, we explored the impact of both ICOS and ICOSL deficiencies on MOG_35-55 -induced EAE and its associated immune cell dynamics by employing ICOSL-KO and ICOS-KO mice with a C57BL/6J background. During EAE resolution, MOG-driven cytokine levels and the immunophenotype of splenocytes were evaluated by ELISA and multiparametric flow cytometry, respectively. We found that both KO mice exhibited an overlapping and more severe EAE compared to C57BL/6J mice, corroborated by a reduction in memory/regulatory T cell subsets and interleukin (IL-)17 levels. It is noteworthy that an unsupervised analysis showed that ICOSL deficiency modifies the immune response in an original way, by affecting T central and effector memory (T_CM, T_EM), long-lived CD4⁺ T_EM cells, and macrophages, compared to ICOS-KO and C57BL/6J mice, suggesting a role for other binding partners to ICOSL in EAE development, which deserves further study. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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14 pages, 2033 KiB

Open AccessArticle

Quantiferon Monitor Testing Sheds Light on Immune System Disparities between Multiple Sclerosis Patients and Healthy Individuals

by Ilona Součková, Ondřej Souček, Jan Krejsek, Oldřich Vyšata, David Matyáš, Marek Peterka, Michal Novotný, Pavel Kunc and Zbyšek Pavelek

Int. J. Mol. Sci. 2024, 25(4), 2179; https://doi.org/10.3390/ijms25042179 - 11 Feb 2024

Viewed by 676

Abstract

The aim of this study was to conduct QuantiFERON Monitor (QFM) testing in patients with multiple sclerosis (MS), which is used to monitor the state of the immune system through the non-specific stimulation of leukocytes followed by determining the level of interferon-gamma (IFN-γ) [...] Read more.

The aim of this study was to conduct QuantiFERON Monitor (QFM) testing in patients with multiple sclerosis (MS), which is used to monitor the state of the immune system through the non-specific stimulation of leukocytes followed by determining the level of interferon-gamma (IFN-γ) released from activated cells. Additionally, we tested the level of selected cytokines (IFN-α, IFN-γ, IL-1α, IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-6, IL-7, IL-10, IL-15, IL-33, VEGF) from stimulated blood samples to further understand the immune response. This study builds upon a previously published study, utilizing activated serum samples that were initially used for IFN-γ determination. However, our current focus shifts from IFN-γ to exploring other cytokines that could provide further insights into the immune response. A screening was conducted using Luminex technology, which yielded promising results. These results were then further elaborated upon using ELISA to provide a more detailed understanding of the cytokine profiles involved. This study, conducted from August 2019 to June 2023, included 280 participants: 98 RRMS patients treated with fingolimod (fMS), 96 untreated patients with progressive MS (pMS), and 86 healthy controls (HC). Our results include Violin plots showing elevated IL-1α in pMS and fMS. Statistical analysis indicated significant differences in the interleukin levels between groups, with IL-1ra and age as key predictors in differentiating HC from pMS and IL-1ra, IL-1α, age, and EDSS in distinguishing pMS from fMS. These findings suggest cytokines’ potential as biomarkers in MS progression and treatment response. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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17 pages, 3121 KiB

Open AccessArticle

A Blood Test for the Diagnosis of Multiple Sclerosis

by Paola Giuliano, Giuliana La Rosa, Serena Capozzi, Emanuele Cassano, Simona Damiano, Francesco Habetswallner, Rosa Iodice, Maurizio Marra, Luigi Michele Pavone, Mario Quarantelli, Giuseppe Vitelli, Mariarosaria Santillo and Roberto Paternò

Int. J. Mol. Sci. 2024, 25(3), 1696; https://doi.org/10.3390/ijms25031696 - 30 Jan 2024

Viewed by 950

Abstract

Multiple sclerosis (MS) is an autoimmune chronic disease characterized by inflammation and demyelination of the central nervous system (CNS). Despite numerous studies conducted, valid biomarkers enabling a definitive diagnosis of MS are not yet available. The aim of our study was to identify [...] Read more.

Multiple sclerosis (MS) is an autoimmune chronic disease characterized by inflammation and demyelination of the central nervous system (CNS). Despite numerous studies conducted, valid biomarkers enabling a definitive diagnosis of MS are not yet available. The aim of our study was to identify a marker from a blood sample to ease the diagnosis of MS. In this study, since there is evidence connecting the serotonin pathway to MS, we used an ELISA (Enzyme-Linked Immunosorbent Assay) to detect serum MS-specific auto-antibodies (auto-Ab) against the extracellular loop 1 (ECL-1) of the 5-hydroxytryptamine (5-HT) receptor subtype 2A (5-HT2A). We utilized an ELISA format employing poly-D-lysine as a pre-coating agent. The binding of 208 serum samples from controls, both healthy and pathological, and of 104 serum samples from relapsing–remitting MS (RRMS) patients was tested. We observed that the serum-binding activity in control cohort sera, including those with autoimmune and neurological diseases, was ten times lower compared to the RRMS patient cohort (p = 1.2 × 10⁻⁴⁷), with a sensitivity and a specificity of 98% and 100%, respectively. These results show that in the serum of patients with MS there are auto-Ab against the serotonin receptor type 2A which can be successfully used in the diagnosis of MS due to their high sensitivity and specificity. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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15 pages, 1911 KiB

Open AccessArticle

Response to Fingolimod in Multiple Sclerosis Patients Is Associated with a Differential Transcriptomic Regulation

by Alicia Sánchez-Sanz, Rafael Muñoz-Viana, Julia Sabín-Muñoz, Irene Moreno-Torres, Beatriz Brea-Álvarez, Ofir Rodríguez-De la Fuente, Antonio García-Merino and Antonio J. Sánchez-López

Int. J. Mol. Sci. 2024, 25(3), 1372; https://doi.org/10.3390/ijms25031372 - 23 Jan 2024

Viewed by 839

Abstract

Fingolimod is an immunomodulatory sphingosine-1-phosphate (S1P) analogue approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The identification of biomarkers of clinical responses to fingolimod is a major necessity in MS to identify optimal responders and avoid the risk of disease progression in [...] Read more.

Fingolimod is an immunomodulatory sphingosine-1-phosphate (S1P) analogue approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The identification of biomarkers of clinical responses to fingolimod is a major necessity in MS to identify optimal responders and avoid the risk of disease progression in non-responders. With this aim, we used RNA sequencing to study the transcriptomic changes induced by fingolimod in peripheral blood mononuclear cells of MS-treated patients and their association with clinical response. Samples were obtained from 10 RRMS patients (five responders and five non-responders) at baseline and at 12 months of fingolimod therapy. Fingolimod exerted a vast impact at the transcriptional level, identifying 7155 differentially expressed genes (DEGs) compared to baseline that affected the regulation of numerous signaling pathways. These DEGs were predominantly immune related, including genes associated with S1P metabolism, cytokines, lymphocyte trafficking, master transcription factors of lymphocyte functions and the NF-kB pathway. Responder and non-responder patients exhibited a differential transcriptomic regulation during treatment, with responders presenting a higher number of DEGs (6405) compared to non-responders (2653). The S1P, NF-kB and TCR signaling pathways were differentially modulated in responder and non-responder patients. These transcriptomic differences offer the potential of being exploited as biomarkers of a clinical response to fingolimod. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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14 pages, 3033 KiB

Open AccessArticle

Transient Receptor Potential Vanilloid 4-Dependent Microglial Function in Myelin Injury and Repair

by Jameson P. Holloman, Sophia H. Dimas, Angela S. Archambault, Fabia Filipello, Lixia Du, Jing Feng, Yonghui Zhao, Bryan Bollman, Laura Piccio, Andrew J. Steelman, Hongzhen Hu and Gregory F. Wu

Int. J. Mol. Sci. 2023, 24(23), 17097; https://doi.org/10.3390/ijms242317097 - 04 Dec 2023

Viewed by 1044

Abstract

Microglia are found pathologically at all stages of multiple sclerosis (MS) lesion development and are hypothesized to contribute to both inflammatory injury and neuroprotection in the MS brain. Transient receptor potential vanilloid 4 (TRPV4) channels are widely expressed, play an important role as [...] Read more.

Microglia are found pathologically at all stages of multiple sclerosis (MS) lesion development and are hypothesized to contribute to both inflammatory injury and neuroprotection in the MS brain. Transient receptor potential vanilloid 4 (TRPV4) channels are widely expressed, play an important role as environmental sensors, and are involved in calcium homeostasis for a variety of cells. TRPV4 modulates myeloid cell phagocytosis in the periphery and microglial motility in the central nervous system. We hypothesized that TRPV4 deletion would alter microglia phagocytosis in vitro and lessen disease activity and demyelination in experimental autoimmune encephalitis (EAE) and cuprizone-induced demyelination. We found that genetic deletion of TRPV4 led to increased microglial phagocytosis in vitro but did not alter the degree of demyelination or remyelination in the cuprizone mouse model of MS. We also found no difference in disease in EAE following global or microglia-specific deletion of Trpv4. Additionally, lesioned and normal appearing white matter from MS brains exhibited similar TRPV4 expression compared to healthy brain tissue. Taken together, these findings indicate that TRPV4 modulates microglial activity but does not impact disease activity in mouse models of MS, suggesting a muted and/or redundant role in MS pathogenesis. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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16 pages, 2049 KiB

Open AccessArticle

Metabolomics of Cerebrospinal Fluid Amino and Fatty Acids in Early Stages of Multiple Sclerosis

by Michal Židó, David Kačer, Karel Valeš, Denisa Zimová and Ivana Štětkářová

Int. J. Mol. Sci. 2023, 24(22), 16271; https://doi.org/10.3390/ijms242216271 - 13 Nov 2023

Viewed by 905

Abstract

Multiple sclerosis (MS) is a demyelinating and neurodegenerative autoimmune disease of the central nervous system (CNS) damaging myelin and axons. Diagnosis is based on the combination of clinical findings, magnetic resonance imaging (MRI) and analysis of cerebrospinal fluid (CSF). Metabolomics is a systematic [...] Read more.

Multiple sclerosis (MS) is a demyelinating and neurodegenerative autoimmune disease of the central nervous system (CNS) damaging myelin and axons. Diagnosis is based on the combination of clinical findings, magnetic resonance imaging (MRI) and analysis of cerebrospinal fluid (CSF). Metabolomics is a systematic study that allows us to track amounts of different metabolites in a chosen medium. The aim of this study was to establish metabolomic differences between the cerebrospinal fluid of patients in the early stages of multiple sclerosis and healthy controls, which could potentially serve as markers for predicting disease activity. We collected CSF from 40 patients after the first attack of clinical symptoms who fulfilled revised McDonald criteria of MS, and the CSF of 33 controls. Analyses of CSF samples were performed by using the high-performance liquid chromatography system coupled with a mass spectrometer with a high-resolution detector. Significant changes in concentrations of arginine, histidine, spermidine, glutamate, choline, tyrosine, serine, oleic acid, stearic acid and linoleic acid were observed. More prominently, Expanded Disability Status Scale values significantly correlated with lower concentrations of histidine. We conclude that these metabolites could potentially play a role as a biomarker of disease activity and predict presumable inflammatory changes. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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21 pages, 3592 KiB

Open AccessArticle

Multiple Sclerosis-Associated Gut Microbiome in the Israeli Diverse Populations: Associations with Ethnicity, Gender, Disability Status, Vitamin D Levels, and Mediterranean Diet

by Zehavit Nitzan, Elsebeth Staun-Ram, Anat Volkowich and Ariel Miller

Int. J. Mol. Sci. 2023, 24(19), 15024; https://doi.org/10.3390/ijms241915024 - 09 Oct 2023

Cited by 2 | Viewed by 1232

Abstract

Microbiome dysbiosis is increasingly being recognized as implicated in immune-mediated disorders including multiple sclerosis (MS). The microbiome is modulated by genetic and environmental factors including lifestyle, diet, and drug intake. This study aimed to characterize the MS-associated gut microbiome in the Israeli populations [...] Read more.

Microbiome dysbiosis is increasingly being recognized as implicated in immune-mediated disorders including multiple sclerosis (MS). The microbiome is modulated by genetic and environmental factors including lifestyle, diet, and drug intake. This study aimed to characterize the MS-associated gut microbiome in the Israeli populations and to identify associations with demographic, dietary, and clinical features. The microbiota from 57 treatment-naive patients with MS (PwMS) and 43 age- and gender-matched healthy controls (HCs) was sequenced and abundance compared. Associations between differential microbes with demographic or clinical characteristics, as well as diet and nutrient intake, were assessed. While there was no difference in α- or β-diversity of the microbiome, we identified 40 microbes from different taxonomic levels that differ in abundance between PwMS and HCs, including Barnesiella, Collinsella, Egerthella, Mitsuokella, Olsenella Romboutsia, and Succinivibrio, all enhanced in PwMS, while several members of Lacnospira were reduced. Additional MS-differential microbes specific to ethnicity were identified. Several MS-specific microbial patterns were associated with gender, vitamin D level, Mediterranean diet, nutrient intake, or disability status. Thus, PwMS have altered microbiota composition, with distinctive patterns related to geographic locations and population. Microbiome dysbiosis seem to be implicated in disease progression, gender-related differences, and vitamin D-mediated immunological effects recognized in MS. Dietary interventions may be beneficial in restoring a “healthy microbiota” as part of applying comprehensive personalized therapeutic strategies for PwMS. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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25 pages, 4653 KiB

Open AccessArticle

An Animal Model for Chronic Meningeal Inflammation and Inflammatory Demyelination of the Cerebral Cortex

by Lukas Simon Enz, Anne Winkler, Claudia Wrzos, Boris Dasen, Stefan Nessler, Christine Stadelmann and Nicole Schaeren-Wiemers

Int. J. Mol. Sci. 2023, 24(18), 13893; https://doi.org/10.3390/ijms241813893 - 09 Sep 2023

Viewed by 900

Abstract

Modeling chronic cortical demyelination allows the study of long-lasting pathological changes observed in multiple sclerosis such as failure of remyelination, chronically disturbed functions of oligodendrocytes, neurons and astrocytes, brain atrophy and cognitive impairments. We aimed at generating an animal model for studying the [...] Read more.

Modeling chronic cortical demyelination allows the study of long-lasting pathological changes observed in multiple sclerosis such as failure of remyelination, chronically disturbed functions of oligodendrocytes, neurons and astrocytes, brain atrophy and cognitive impairments. We aimed at generating an animal model for studying the consequences of chronic cortical demyelination and meningeal inflammation. To induce long-lasting cortical demyelination and chronic meningeal inflammation, we immunized female Lewis rats against myelin oligodendrocyte glycoprotein (MOG) and injected lentiviruses for continuing overexpression of the cytokines TNFα and IFNγ in the cortical brain parenchyma. Immunization with MOG and overexpression of TNFα and IFNγ led to widespread subpial demyelination and meningeal inflammation that were stable for at least 10 weeks. We demonstrate here that immunization with MOG is necessary for acute as well as chronic cortical demyelination. In addition, long-lasting overexpression of TNFα and IFNγ in the brain parenchyma is sufficient to induce chronic meningeal inflammation. Our model simulates key features of chronic cortical demyelination and inflammation, reminiscent of human multiple sclerosis pathology. This will allow molecular, cellular and functional investigations for a better understanding of the adaptation mechanisms of the cerebral cortex in multiple sclerosis. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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20 pages, 3593 KiB

Open AccessArticle

DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes

by Alexandre Xavier, Vicki E. Maltby, Ewoud Ewing, Maria Pia Campagna, Sean M. Burnard, Jesper N. Tegner, Mark Slee, Helmut Butzkueven, Ingrid Kockum, Lara Kular, Ausimmune/AusLong Investigators Group, Vilija G. Jokubaitis, Trevor Kilpatrick, Lars Alfredsson, Maja Jagodic, Anne-Louise Ponsonby, Bruce V. Taylor, Rodney J. Scott, Rodney A. Lea and Jeannette Lechner-Scott

Int. J. Mol. Sci. 2023, 24(16), 12576; https://doi.org/10.3390/ijms241612576 - 08 Aug 2023

Cited by 3 | Viewed by 1567

Abstract

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease [...] Read more.

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10⁻²⁹) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10⁻¹⁷). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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20 pages, 6063 KiB

Open AccessArticle

Global DNA Methylation and Hydroxymethylation Levels in PBMCs Are Altered in RRMS Patients Treated with IFN-β and GA—A Preliminary Study

by María Paulina Reyes-Mata, Mario Alberto Mireles-Ramírez, Christian Griñán-Ferré, Mercè Pallàs, Lenin Pavón, José de Jesús Guerrero-García and Daniel Ortuño-Sahagún

Int. J. Mol. Sci. 2023, 24(10), 9074; https://doi.org/10.3390/ijms24109074 - 22 May 2023

Viewed by 2022

Abstract

Multiple sclerosis (MS) is a chronic disease affecting the central nervous system (CNS) due to an autoimmune attack on axonal myelin sheaths. Epigenetics is an open research topic on MS, which has been investigated in search of biomarkers and treatment targets for this [...] Read more.

Multiple sclerosis (MS) is a chronic disease affecting the central nervous system (CNS) due to an autoimmune attack on axonal myelin sheaths. Epigenetics is an open research topic on MS, which has been investigated in search of biomarkers and treatment targets for this heterogeneous disease. In this study, we quantified global levels of epigenetic marks using an ELISA-like approach in Peripheral Blood Mononuclear Cells (PBMCs) from 52 patients with MS, treated with Interferon beta (IFN-β) and Glatiramer Acetate (GA) or untreated, and 30 healthy controls. We performed media comparisons and correlation analyses of these epigenetic markers with clinical variables in subgroups of patients and controls. We observed that DNA methylation (5-mC) decreased in treated patients compared with untreated and healthy controls. Moreover, 5-mC and hydroxymethylation (5-hmC) correlated with clinical variables. In contrast, histone H3 and H4 acetylation did not correlate with the disease variables considered. Globally quantified epigenetic DNA marks 5-mC and 5-hmC correlate with disease and were altered with treatment. However, to date, no biomarker has been identified that can predict the potential response to therapy before treatment initiation. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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Review

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15 pages, 802 KiB

Open AccessReview

Adverse Childhood Experiences and the Risk of Multiple Sclerosis Development: A Review of Potential Mechanisms

by Karine Eid, Marte-Helene Bjørk, Nils Erik Gilhus and Øivind Torkildsen

Int. J. Mol. Sci. 2024, 25(3), 1520; https://doi.org/10.3390/ijms25031520 - 26 Jan 2024

Viewed by 1565

Abstract

Adverse childhood experiences (ACEs), such as abuse, neglect, and household dysfunction, contribute to long-term systemic toxic stress and inflammation that may last well into adulthood. Such early-life stressors have been associated with increased susceptibility to multiple sclerosis (MS) in observational studies and with [...] Read more.

Adverse childhood experiences (ACEs), such as abuse, neglect, and household dysfunction, contribute to long-term systemic toxic stress and inflammation that may last well into adulthood. Such early-life stressors have been associated with increased susceptibility to multiple sclerosis (MS) in observational studies and with the development of experimental autoimmune encephalomyelitis in animal models. In this review, we summarize the evidence for an ACE-mediated increase in MS risk, as well as the potential mechanisms for this association. ACEs dysregulate neurodevelopment, stress responses, and immune reactivity; they also alter the interplay between the immune system and neural networks. All of this may be relevant for MS risk. We further discuss how ACEs induce epigenetic changes and how the toxic stress caused by ACEs may reactivate the Epstein-Barr Virus (EBV), a key risk factor for MS. We conclude by suggesting new initiatives to obtain further insights into this topic. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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25 pages, 1809 KiB

Open AccessReview

The Therapeutic Mechanisms of Mesenchymal Stem Cells in MS—A Review Focusing on Neuroprotective Properties

by Sonia Gavasso, Torbjørn Kråkenes, Håkon Olsen, Elisabeth Claire Evjenth, Marie Ytterdal, Jonas Bull Haugsøen and Christopher Elnan Kvistad

Int. J. Mol. Sci. 2024, 25(3), 1365; https://doi.org/10.3390/ijms25031365 - 23 Jan 2024

Cited by 1 | Viewed by 1597

Abstract

In multiple sclerosis (MS), there is a great need for treatment with the ability to suppress compartmentalized inflammation within the central nervous system (CNS) and to promote remyelination and regeneration. Mesenchymal stem cells (MSCs) represent a promising therapeutic option, as they have been [...] Read more.

In multiple sclerosis (MS), there is a great need for treatment with the ability to suppress compartmentalized inflammation within the central nervous system (CNS) and to promote remyelination and regeneration. Mesenchymal stem cells (MSCs) represent a promising therapeutic option, as they have been shown to migrate to the site of CNS injury and exert neuroprotective properties, including immunomodulation, neurotrophic factor secretion, and endogenous neural stem cell stimulation. This review summarizes the current understanding of the underlying neuroprotective mechanisms and discusses the translation of MSC transplantation and their derivatives from pre-clinical demyelinating models to clinical trials with MS patients. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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13 pages, 963 KiB

Open AccessReview

Beyond Myelin Oligodendrocyte Glycoprotein and Aquaporin-4 Antibodies: Alternative Causes of Optic Neuritis

by Giacomo Greco, Elena Colombo, Matteo Gastaldi, Lara Ahmad, Eleonora Tavazzi, Roberto Bergamaschi and Eleonora Rigoni

Int. J. Mol. Sci. 2023, 24(21), 15986; https://doi.org/10.3390/ijms242115986 - 05 Nov 2023

Viewed by 2018

Abstract

Optic neuritis (ON) is the most common cause of vision loss in young adults. It manifests as acute or subacute vision loss, often accompanied by retrobulbar discomfort or pain during eye movements. Typical ON is associated with Multiple Sclerosis (MS) and is generally [...] Read more.

Optic neuritis (ON) is the most common cause of vision loss in young adults. It manifests as acute or subacute vision loss, often accompanied by retrobulbar discomfort or pain during eye movements. Typical ON is associated with Multiple Sclerosis (MS) and is generally mild and steroid-responsive. Atypical forms are characterized by unusual features, such as prominent optic disc edema, poor treatment response, and bilateral involvement, and they are often associated with autoantibodies against aquaporin-4 (AQP4) or Myelin Oligodendrocyte Glycoprotein (MOG). However, in some cases, AQP4 and MOG antibodies will return as negative, plunging the clinician into a diagnostic conundrum. AQP4- and MOG-seronegative ON warrants a broad differential diagnosis, including autoantibody-associated, granulomatous, and systemic disorders. These rare forms need to be identified promptly, as their management and prognosis are greatly different. The aim of this review is to describe the possible rarer etiologies of non-MS-related and AQP4- and MOG-IgG-seronegative inflammatory ON and discuss their diagnoses and treatments. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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18 pages, 1129 KiB

Open AccessReview

Interaction of the Gut Microbiome and Immunity in Multiple Sclerosis: Impact of Diet and Immune Therapy

by Sudhir Kumar Yadav, Kouichi Ito and Suhayl Dhib-Jalbut

Int. J. Mol. Sci. 2023, 24(19), 14756; https://doi.org/10.3390/ijms241914756 - 29 Sep 2023

Cited by 1 | Viewed by 1611

Abstract

The bidirectional communication between the gut and central nervous system (CNS) through microbiota is known as the microbiota–gut–brain axis. The brain, through the enteric neural innervation and the vagus nerve, influences the gut physiological activities (motility, mucin, and peptide secretion), as well as [...] Read more.

The bidirectional communication between the gut and central nervous system (CNS) through microbiota is known as the microbiota–gut–brain axis. The brain, through the enteric neural innervation and the vagus nerve, influences the gut physiological activities (motility, mucin, and peptide secretion), as well as the development of the mucosal immune system. Conversely, the gut can influence the CNS via intestinal microbiota, its metabolites, and gut-homing immune cells. Growing evidence suggests that gut immunity is critically involved in gut–brain communication during health and diseases, including multiple sclerosis (MS). The gut microbiota can influence the development and function of gut immunity, and conversely, the innate and adaptive mucosal immunity can influence microbiota composition. Gut and systemic immunity, along with gut microbiota, are perturbed in MS. Diet and disease-modifying therapies (DMTs) can affect the composition of the gut microbial community, leading to changes in gut and peripheral immunity, which ultimately affects MS. A high-fat diet is highly associated with gut dysbiosis-mediated inflammation and intestinal permeability, while a high-fiber diet/short-chain fatty acids (SCFAs) can promote the development of Foxp3 Tregs and improvement in intestinal barrier function, which subsequently suppress CNS autoimmunity in the animal model of MS (experimental autoimmune encephalomyelitis or EAE). This review will address the role of gut immunity and its modulation by diet and DMTs via gut microbiota during MS pathophysiology. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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Open AccessReview

Alterations of Oligodendrocyte and Myelin Energy Metabolism in Multiple Sclerosis

by Eneritz López-Muguruza and Carlos Matute

Int. J. Mol. Sci. 2023, 24(16), 12912; https://doi.org/10.3390/ijms241612912 - 18 Aug 2023

Cited by 3 | Viewed by 2390

Abstract

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration. Oligodendrocytes play a vital role in maintaining the integrity of myelin, the protective sheath around nerve fibres essential for efficient signal transmission. However, in [...] Read more.

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration. Oligodendrocytes play a vital role in maintaining the integrity of myelin, the protective sheath around nerve fibres essential for efficient signal transmission. However, in MS, oligodendrocytes become dysfunctional, leading to myelin damage and axonal degeneration. Emerging evidence suggests that metabolic changes, including mitochondrial dysfunction and alterations in glucose and lipid metabolism, contribute significantly to the pathogenesis of MS. Mitochondrial dysfunction is observed in both immune cells and oligodendrocytes within the CNS of MS patients. Impaired mitochondrial function leads to energy deficits, affecting crucial processes such as impulse transmission and axonal transport, ultimately contributing to neurodegeneration. Moreover, mitochondrial dysfunction is linked to the generation of reactive oxygen species (ROS), exacerbating myelin damage and inflammation. Altered glucose metabolism affects the energy supply required for oligodendrocyte function and myelin synthesis. Dysregulated lipid metabolism results in changes to the composition of myelin, affecting its stability and integrity. Importantly, low levels of polyunsaturated fatty acids in MS are associated with upregulated lipid metabolism and enhanced glucose catabolism. Understanding the intricate relationship between these mechanisms is crucial for developing targeted therapies to preserve myelin and promote neurological recovery in individuals with MS. Addressing these metabolic aspects may offer new insights into potential therapeutic strategies to halt disease progression and improve the quality of life for MS patients. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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8 pages, 267 KiB

Open AccessBrief Report

The CXCL13 Index as a Predictive Biomarker for Activity in Clinically Isolated Syndrome

by Steven C. Pike, Francesca Gilli and Andrew R. Pachner

Int. J. Mol. Sci. 2023, 24(13), 11050; https://doi.org/10.3390/ijms241311050 - 04 Jul 2023

Cited by 2 | Viewed by 1091

Abstract

Multiple sclerosis (MS) is a clinically heterogenous disease. Currently, we cannot identify patients with more active disease who may potentially benefit from earlier interventions. Previous data from our lab identified the CXCL13 index (I_CXCL13), a measure of intrathecal production of CXCL13, [...] Read more.

Multiple sclerosis (MS) is a clinically heterogenous disease. Currently, we cannot identify patients with more active disease who may potentially benefit from earlier interventions. Previous data from our lab identified the CXCL13 index (I_CXCL13), a measure of intrathecal production of CXCL13, as a potential biomarker to predict future disease activity in MS patients two years after diagnosis. Patients with clinically isolated syndrome (CIS) or radiologically isolated syndrome (RIS) underwent a lumbar puncture and blood draw, and the I_CXCL13 was determined. They were then followed for at least 5 years for MS activity. Patients with high I_CXCL13 were more likely to convert to clinically definite MS (82.4%) compared to those with low I_CXCL13 (10.0%). The data presented below demonstrate that this predictive ability holds true in CIS and RIS patients, and for at least five years compared to our initial two-year follow-up study. These data support the concept that I_CXCL13 has the potential to be used to guide immunomodulatory therapy in MS. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders)

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