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13 pages, 1280 KiB

Open AccessArticle

CD4-Positive T-Cell Responses to MOG Peptides in MOG Antibody-Associated Disease

by Hirohiko Ono, Tatsuro Misu, Chihiro Namatame, Yuki Matsumoto, Yoshiki Takai, Shuhei Nishiyama, Hiroshi Kuroda, Toshiyuki Takahashi, Ichiro Nakashima, Kazuo Fujihara and Masashi Aoki

Int. J. Mol. Sci. 2025, 26(8), 3606; https://doi.org/10.3390/ijms26083606 - 11 Apr 2025

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Abstract

To clarify T-cell responses in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), we cultured the peripheral blood mononuclear cells of 24 patients with MOGAD and 20 with aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorders (NMOSD), and those of 17 healthy controls (HCs), in [...] Read more.

To clarify T-cell responses in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), we cultured the peripheral blood mononuclear cells of 24 patients with MOGAD and 20 with aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorders (NMOSD), and those of 17 healthy controls (HCs), in the presence of fourteen MOG peptides covering the full-length MOG, five AQP4 peptides, two myelin basic protein peptides, or two proteolipid protein peptides. Then, we measured T-cell activation markers, such as cell surface CD69 and the intracellular production of granulocyte–macrophage colony-stimulating factor (GM-CSF) and interferon-γ in CD4-positive T-cells, with a flow cytometer. The expression of CD69 in response to MOG p16–40 and MOG p181–205 was significantly higher (Stimulation Index > 2) in MOGAD than in HCs. Also, CD69 for AQP4 p21–40, AQP4 p211–230, and MOG p166–190 were significantly increased in NMOSD than in HCs. Intracellular GM-CSF production responding to MOG p16–40 was significantly higher in MOGAD than in HCs (p < 0.05), although intracellular interferon-γ was not elevated. None of the responses to the other peptides were different between the groups. The present study showed subtle CD4-positive T-cell activation elicited by some MOG peptides alone in patients with MOGAD. Further studies of cytokines or other stimulation and alternative assay markers and metrics are needed to delineate the immunopathological roles of T-cells in MOGAD. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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23 pages, 9260 KiB

Open AccessArticle

Neuroprotective and Anti-Inflammatory Effects of Dimethyl Fumarate, Monomethyl Fumarate, and Cannabidiol in Neurons and Microglia

by Alicia Sánchez-Sanz, María José Coronado-Albi, Rafael Muñoz-Viana, Antonio García-Merino and Antonio J. Sánchez-López

Int. J. Mol. Sci. 2024, 25(23), 13082; https://doi.org/10.3390/ijms252313082 - 5 Dec 2024

Cited by 1 | Viewed by 1294

Abstract

Dimethyl fumarate (DMF) is an immunomodulatory treatment for multiple sclerosis (MS) that can cross the blood–brain barrier, presenting neuroprotective potential. Its mechanism of action is not fully understood, and there is a need to characterize whether DMF or its bioactive metabolite monomethyl fumarate [...] Read more.

Dimethyl fumarate (DMF) is an immunomodulatory treatment for multiple sclerosis (MS) that can cross the blood–brain barrier, presenting neuroprotective potential. Its mechanism of action is not fully understood, and there is a need to characterize whether DMF or its bioactive metabolite monomethyl fumarate (MMF) exerts neuroprotective properties. Moreover, the combination of adjuvant agents such as cannabidiol (CBD) could be relevant to enhance neuroprotection. The aim of this study was to compare the neuroprotective and immunomodulatory effects of DMF, MMF, and CBD in neurons and microglia in vitro. We found that DMF and CBD, but not MMF, activated the Nrf2 antioxidant pathway in neurons. Similarly, only DMF and CBD, but not MMF, prevented the LPS-induced activation of the inflammatory pathway NF-kB in microglia. Additionally, the three drugs inhibited the production of nitric oxide in microglia and protected neurons against apoptosis. Transcriptomically, DMF modulated a greater number of inflammatory and Nrf2-related genes compared to MMF and CBD in both neurons and microglia. Our results show that DMF and MMF, despite being structurally related, present differences in their mechanisms of action that could be relevant for the achievement of neuroprotection in MS patients. Additionally, CBD shows potential as a neuroprotective agent. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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15 pages, 4413 KiB

Open AccessArticle

Gene Expression and Alternative Splicing Analysis in a Large-Scale Multiple Sclerosis Study

by Müge Sak, Julia H. Chariker, Juw Won Park and Eric Christian Rouchka

Int. J. Mol. Sci. 2024, 25(22), 11957; https://doi.org/10.3390/ijms252211957 - 7 Nov 2024

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Abstract

Multiple Sclerosis (MS) is an autoimmune neurodegenerative disease affecting approximately 3 million people globally. Despite rigorous research on MS, aspects of its development and progression remain unclear. We utilized a publicly available RNA-seq dataset (GSE138614) consisting of the post-mortem white matter tissues of [...] Read more.

Multiple Sclerosis (MS) is an autoimmune neurodegenerative disease affecting approximately 3 million people globally. Despite rigorous research on MS, aspects of its development and progression remain unclear. We utilized a publicly available RNA-seq dataset (GSE138614) consisting of the post-mortem white matter tissues of five donors without any neurological disorders and ten MS patient donors. We investigated gene expression levels correlated with tissue inflammation and alternative splicing to identify possible pathological isoforms in MS tissues. We identified RNA-binding motifs, differentially expressed RNA-binding proteins, and single-nucleotide polymorphisms (SNPs) to unravel possible mechanisms of alternative splicing. Genes with expression changes that were positively correlated with tissue inflammation were enriched in the immune system and receptor interaction pathways. Genes showing a negative correlation were enriched in nervous system development and in metabolic pathways. A comparison of normal-appearing white matter (NAWM) and active or chronic active lesions within the same donors identified genes playing roles in immunity, white matter injury repair, and remyelination. We identified exon skipping events and spontaneous SNPs in membrane-associated ring-CH-type finger-1 (MARCHF1), UDP glycosyltransferase-8 (UGT8), and other genes important in autoimmunity and neurodegeneration. Overall, we identified unique genes, pathways, and novel splicing events that can be further investigated as potential novel drug targets for MS treatment. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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11 pages, 2886 KiB

Open AccessArticle

The Neuroprotective Effect of Erythropoietin on the Optic Nerve and Spinal Cord in Rats with Experimental Autoimmune Encephalomyelitis through the Activation of the Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway

by Gloria Aleida Pérez-Carranza, Juliana Marisol Godínez-Rubí, María Guadalupe Márquez-Rosales, Mario Eduardo Flores-Soto, Oscar Kurt Bitzer-Quintero, Ana Cristina Ramírez-Anguiano and Luis Javier Ramírez-Jirano

Int. J. Mol. Sci. 2024, 25(17), 9476; https://doi.org/10.3390/ijms25179476 - 31 Aug 2024

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Abstract

Experimental autoimmune encephalomyelitis is a demyelinating disease that causes paralysis in laboratory rats. This condition lacks treatment that reverses damage to the myelin sheaths of neuronal cells. Therefore, in this study, treatment with EPO as a neuroprotective effect was established to evaluate the [...] Read more.

Experimental autoimmune encephalomyelitis is a demyelinating disease that causes paralysis in laboratory rats. This condition lacks treatment that reverses damage to the myelin sheaths of neuronal cells. Therefore, in this study, treatment with EPO as a neuroprotective effect was established to evaluate the ERK 1/2 signaling pathway and its participation in the EAE model. EPO was administered in 5000 U/Kg Sprague Dawley rats. U0126 was used as an inhibitor of the ERK 1/2 pathway to demonstrate the possible activation of this pathway in the model. Spinal cord and optic nerve tissues were evaluated using staining techniques such as H&E and the Luxol Fast Blue myelin-specific technique, as well as immunohistochemistry of the ERK 1/2 protein. The EPO-treated groups showed a decrease in cellular sampling in the spinal cord tissues but mainly in the optic nerve, as well as an increase in the expression of the ERK 1/2 protein in both tissues. The findings of this study suggest that EPO treatment reduces cellular death in EAE-induced rats by regulating the ERK pathway. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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11 pages, 1220 KiB

Open AccessArticle

An IL-5 Single-Nucleotide Polymorphism Influences Neuroinflammation and Prospective Disease Activity in Multiple Sclerosis

by Ettore Dolcetti, Fabio Buttari, Antonio Bruno, Federica Azzolini, Luana Gilio, Angela Borrelli, Veronica Di Caprio, Gianluca Lauritano, Giovanni Galifi, Stefano Gambardella, Rosangela Ferese, Emiliano Giardina, Valentina Rovella, Roberto Furlan, Annamaria Finardi, Alessandra Musella, Sara Balletta, Georgia Mandolesi, Diego Centonze and Mario Stampanoni Bassi

Int. J. Mol. Sci. 2024, 25(16), 9108; https://doi.org/10.3390/ijms25169108 - 22 Aug 2024

Cited by 1 | Viewed by 1150

Abstract

(1) Multiple sclerosis (MS) is identified by a complex interaction between central inflammation and neurodegeneration. Genetic individual variability could play a significative role in clinical presentation. The interleukin-5 (IL-5) rs2069812 single-nucleotide polymorphism (SNP) seems to define the clinical course of Th2 autoimmune diseases, [...] Read more.

(1) Multiple sclerosis (MS) is identified by a complex interaction between central inflammation and neurodegeneration. Genetic individual variability could play a significative role in clinical presentation. The interleukin-5 (IL-5) rs2069812 single-nucleotide polymorphism (SNP) seems to define the clinical course of Th2 autoimmune diseases, while its role in MS has never been investigated. (2) In a group of 230 patients diagnosed with relapsing–remitting MS (RR-MS) or progressive MS (P-MS) and controls (IC), rs2069812 polymorphism, cerebrospinal fluid (CSF) levels of inflammatory mediators, and clinical and demographic characteristics were determined. In RR-MS patients, No Evidence of Disease Activity (NEDA-3) at three years of follow-up was detected. (3) We identified higher levels of proinflammatory cytokines, particularly IL-2 (median [IQR], RR-MS = 0.2 [0–0.7]; P-MS = 0.1 [0–1.6]; IC = 0.1 [0.0–0.1]; p < 0.005), IL-6 (RR-MS = 0.9 [0.3–2.3]; P-MS = 0.8 [0.1–2.7]; IC = 0.1 [0.0–0.5]; p < 0.005), IL-12 (RR-MS = 0.5 [0–1.1]; P-MS = 0.5 [0–1.1]; IC = 0.0 [0.0–0.3]; p < 0.005), and GM-CSF (RR-MS = 15.6 [4.8–26.4]; P-MS = 14 [3.3–29.7]; IC = 8.9 [4.7–11.7]; p < 0.005) in MS patients compared with IC. Conversely, anti-inflammatory cytokines, specifically IL-5 (RR-MS = 0.65 [0–2.4]; P-MS = 0.1 [0–0.8]; IC = 1.7 [0.6–2.8]; p < 0.005) and IL-1ra (RR-MS = 14.7 [4.9–26.4]; P-MS = 13.1 [4.7–22.2]; IC = 27.8 [17.7–37.6]; p < 0.005) were higher in controls. According to rs2069812, in MS patients, the T-allele was associated with higher concentrations of proinflammatory mediators (IL-2, CT/TT = 0.2 [0.0–2.0]; CC = 0.1 [0.0–0.4], p = 0.015; IL-6, CT/TT = 1.2 [0.4–3.2] vs. CC = 0.7 [0.1–1.7], p = 0.007; IL-15, CT/TT = 0.1 [0.0–9.5] vs. CC = 0.0 [0.0–0.1], p = 0.019; and GM-CSF, CT/TT = 0.1 [0.0–0.6] vs. CC = 0.05 [0.0–0.1], p < 0.001), and CC was associated with anti-inflammatory mediators (IL-5, CT/TT = 0.03 [0.0–1.9] vs. CC = 1.28 [0.0–2.7], p = 0.001; IL-1ra, CT/TT = 12.1 [4.1–25.9] vs. CC = 18.1 [12.1–26.9], p = 0.006). We found the same differences in RR-MS patients (IL-2, T-allele median [IQR] = 0.3 [0.0–2.0] vs. C-allele, median [IQR] = 0.04 [0.0–0.3]; p = 0.005; IL-6, T-allele, median [IQR] = 1.3 [0.4–3.3] vs. C-allele, median [IQR] = 0.6 [0.03–1.5]; p = 0.001; IL-15, T-allele, median [IQR] = 0.1 [0.0–9.5] vs. C-allele, median [IQR] = 0.0 [0.0–0.1]; p = 0.008; GM-CSF, T-allele, median [IQR] = 0.1 [0.0–97.9] vs. C-allele, median [IQR] = 0.0 [0.0–0.001]; p < 0.001; IL-5, T-allele, median [IQR] = 0.02 [0.0–2.2] vs. C-allele, median [IQR] = 1.5 [0.0–2.9]; p = 0.016; and IL-1ra, T-allele, median [IQR] = 12.1 [4.3–26.4] vs. C-allele, median [IQR] = 18.5 [12.7–28.3]; p = 0.006) but not in P-MS, except for IL-5 (T-allele, median [IQR] = 0.1 [0–0.23] vs. C-allele, median [IQR] = 0.6 [0.0–2.5]; p = 0.022). Finally, we identified an association between CC in RR-MS patients and NEDA-3 after three years of follow-up (p = 0.007). (4) We describe, for the first time, the role of an SNP of the IL-5 gene in regulating central neuroinflammation and influencing clinical course in MS patients. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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14 pages, 2991 KiB

Open AccessArticle

Mineralocorticoid Receptor Signaling in Peripheral Blood Cells in Patients with Multiple Sclerosis

by Franziska Küstermann, Kathy Busse, Johannes Orthgieß, Muriel Stoppe, Sarah Haars and Florian Then Bergh

Int. J. Mol. Sci. 2024, 25(16), 8883; https://doi.org/10.3390/ijms25168883 - 15 Aug 2024

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Abstract

Multiple sclerosis (MS) is associated with alterations in neuroendocrine function, primarily the hypothalamic–pituitary–adrenal axis, including lower expression of the glucocorticoid receptor (GR) and its target genes in peripheral blood mononuclear cells (PBMC) or full blood. We previously found reduced mineralocorticoid receptor (MR) expression [...] Read more.

Multiple sclerosis (MS) is associated with alterations in neuroendocrine function, primarily the hypothalamic–pituitary–adrenal axis, including lower expression of the glucocorticoid receptor (GR) and its target genes in peripheral blood mononuclear cells (PBMC) or full blood. We previously found reduced mineralocorticoid receptor (MR) expression in MS patients’ peripheral blood. MS is being treated with a widening variety of disease-modifying treatments (DMT), some of which have similar efficacy but different mechanisms of action; body-fluid biomarkers to support the choice of the optimal initial DMT and/or to indicate an unsatisfactory response before clinical activity are unavailable. Using cell culture of volunteers’ PBMCs and subsequent gene expression analysis (microarray and qPCR validation), we identified the mRNA expression of OTUD1 to represent MR signaling. The MR and MR target gene expression levels were then measured in full blood samples. In 119 MS (or CIS) patients, the expression of both MR and OTUD1 was lower than in 42 controls. The expression pattern was related to treatment, with the MR expression being particularly low in patients treated with fingolimod. While MR signaling may be involved in the therapeutic effects of some disease-modifying treatments, MR and OTUD1 expression can complement the neuroendocrine assessment of MS disease course. If confirmed, such assessment may support clinical decision-making. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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17 pages, 4081 KiB

Open AccessArticle

Humanized-Aquaporin-4-Expressing Rat Created by Gene-Editing Technology and Its Use to Clarify the Pathology of Neuromyelitis Optica Spectrum Disorder

by Chihiro Namatame, Yoichiro Abe, Yoshiki Miyasaka, Yoshiki Takai, Yuki Matsumoto, Toshiyuki Takahashi, Tomoji Mashimo, Tatsuro Misu, Kazuo Fujihara, Masato Yasui and Masashi Aoki

Int. J. Mol. Sci. 2024, 25(15), 8169; https://doi.org/10.3390/ijms25158169 - 26 Jul 2024

Cited by 2 | Viewed by 1714

Abstract

Conventional rodent neuromyelitis optica spectrum disorder (NMOSD) models using patient-derived immunoglobulin G (IgG) are potentially affected by the differences between the human and rodent aquaporin-4 (AQP4) extracellular domains (ECDs). We hypothesized that the humanization of AQP4 ECDs would make the rodent model lesions [...] Read more.

Conventional rodent neuromyelitis optica spectrum disorder (NMOSD) models using patient-derived immunoglobulin G (IgG) are potentially affected by the differences between the human and rodent aquaporin-4 (AQP4) extracellular domains (ECDs). We hypothesized that the humanization of AQP4 ECDs would make the rodent model lesions closer to human NMOSD pathology. Humanized-AQP4-expressing (hAQP4) rats were generated using genome-editing technology, and the human AQP4-specific monoclonal antibody (mAb) or six patient-derived IgGs were introduced intraperitoneally into hAQP4 rats and wild-type Lewis (WT) rats after immunization with myelin basic protein and complete Freund’s adjuvant. Human AQP4-specific mAb induced astrocyte loss lesions specifically in hAQP4 rats. The patient-derived IgGs also induced NMOSD-like tissue-destructive lesions with AQP4 loss, demyelination, axonal swelling, complement deposition, and marked neutrophil and macrophage/microglia infiltration in hAQP4 rats; however, the difference in AQP4 loss lesion size and infiltrating cells was not significant between hAQP4 and WT rats. The patient-derived IgGs bound to both human and rat AQP4 M23, suggesting their binding to the shared region of human and rat AQP4 ECDs. Anti-AQP4 titers positively correlated with AQP4 loss lesion size and neutrophil and macrophage/microglia infiltration. Considering that patient-derived IgGs vary in binding sites and affinities and some of them may not bind to rodent AQP4, our hAQP4 rat is expected to reproduce NMOSD-like pathology more accurately than WT rats. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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15 pages, 2220 KiB

Open AccessArticle

Tissue Hypoxia and Associated Innate Immune Factors in Experimental Autoimmune Optic Neuritis

by Zhiyuan Yang, Cristina Marcoci, Hatice Kübra Öztürk, Eleni Giama, Ayse Gertrude Yenicelik, Ondřej Slanař, Christopher Linington, Roshni Desai and Kenneth J. Smith

Int. J. Mol. Sci. 2024, 25(5), 3077; https://doi.org/10.3390/ijms25053077 - 6 Mar 2024

Cited by 3 | Viewed by 2497

Abstract

Visual loss in acute optic neuritis is typically attributed to axonal conduction block due to inflammatory demyelination, but the mechanisms remain unclear. Recent research has highlighted tissue hypoxia as an important cause of neurological deficits and tissue damage in both multiple sclerosis (MS) [...] Read more.

Visual loss in acute optic neuritis is typically attributed to axonal conduction block due to inflammatory demyelination, but the mechanisms remain unclear. Recent research has highlighted tissue hypoxia as an important cause of neurological deficits and tissue damage in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) and, here, we examine whether the optic nerves are hypoxic in experimental optic neuritis induced in Dark Agouti rats. At both the first and second peaks of disease expression, inflamed optic nerves labelled significantly for tissue hypoxia (namely, positive for hypoxia inducible factor-1α (HIF1α) and intravenously administered pimonidazole). Acutely inflamed nerves were also labelled significantly for innate markers of oxidative and nitrative stress and damage, including superoxide, nitric oxide and 3-nitrotyrosine. The density and diameter of capillaries were also increased. We conclude that in acute optic neuritis, the optic nerves are hypoxic and come under oxidative and nitrative stress and damage. Tissue hypoxia can cause mitochondrial failure and thus explains visual loss due to axonal conduction block. Tissue hypoxia can also induce a damaging oxidative and nitrative environment. The findings indicate that treatment to prevent tissue hypoxia in acute optic neuritis may help to restore vision and protect from damaging reactive oxygen and nitrogen species. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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Review

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9 pages, 228 KiB

Open AccessReview

Do Nitrosative Stress Molecules Hold Promise as Biomarkers for Multiple Sclerosis?

by Moritz Förster, Saskia Räuber, Philipp Albrecht, Lars Wojtecki, Sven G. Meuth and David Kremer

Int. J. Mol. Sci. 2025, 26(7), 3412; https://doi.org/10.3390/ijms26073412 - 5 Apr 2025

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Abstract

Multiple sclerosis (MS), an auto-immune disease of the central nervous system (CNS) with inflammatory and neurodegenerative properties, remains an insufficiently understood disease despite more than 150 years of research. In contrast to diseases from other medical fields such as, for instance, oncology, a [...] Read more.

Multiple sclerosis (MS), an auto-immune disease of the central nervous system (CNS) with inflammatory and neurodegenerative properties, remains an insufficiently understood disease despite more than 150 years of research. In contrast to diseases from other medical fields such as, for instance, oncology, a description of its clinical and non-clinical features based on readouts such as biomarkers is still in its infancy. While, in this regard, neurofilament light chain (NfL) seems to be a promising new tool, the significant intra- and interindividual variation of this serological marker somewhat limits its widespread applicability in everyday clinical reality. This has sparked novel studies in which glial fibrillary acidic protein (GFAP) was proposed as an on-top marker serving to improve overall specificity. In this context, it was found that MS disease progression was significantly more often associated with increased levels of both NfL and GFAP compared to increased NfL levels alone. This highlights the complexity of the disease while also emphasizing the potential benefits of introducing additional markers to enhance current options. We propose that nitrosative stress markers, such as nitrate, nitrite, and nitrotyrosine (3NT), could serve this purpose effectively. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

14 pages, 2687 KiB

Open AccessReview

Is DEXI a Multiple Sclerosis Susceptibility Gene?

by Anna M. Eriksson, Nora Emini, Hanne F. Harbo and Tone Berge

Int. J. Mol. Sci. 2025, 26(3), 1175; https://doi.org/10.3390/ijms26031175 - 29 Jan 2025

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Abstract

The genetic landscape of multiple sclerosis (MS) has been extensively mapped, yielding significant insights into the molecular mechanisms of the disorder. Early studies highlighted key genes associated with the immune system, particularly T cells, as critical for MS susceptibility. Subsequent large-scale genome-wide association [...] Read more.

The genetic landscape of multiple sclerosis (MS) has been extensively mapped, yielding significant insights into the molecular mechanisms of the disorder. Early studies highlighted key genes associated with the immune system, particularly T cells, as critical for MS susceptibility. Subsequent large-scale genome-wide association studies (GWASs) identified over 200 genetic variants linked to MS, revealing a complex interplay between MS risk and genes involved in various processes within adaptive and innate immune cells, as well as brain-resident microglia. Recently, a groundbreaking GWAS pinpointed the first gene variant associated with MS disease progression, distinguishing the mechanisms driving disease onset from those influencing progression. The C-type lectin domain family 16, member A (CLEC16A) gene within the 16p13 region has consistently been shown to be associated with increased risk of developing both MS and other autoimmune disorders. Notably, several autoimmune-associated genetic variants in CLEC16A introns act as expression quantitative trait loci for the dexamethasone-induced protein (DEXI gene, adding DEXI to the growing list of MS susceptibility genes. This review explores the molecular and functional characterization of DEXI with a particular focus on recent advances in understanding its role in autoimmunity, specifically in the context of multiple sclerosis. We underscore the importance of continued molecular investigation of susceptibility loci for MS identified in genetic studies, with the goal of translating this knowledge into clinical applications. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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19 pages, 665 KiB

Open AccessReview

A Window into New Insights on Progression Independent of Relapse Activity in Multiple Sclerosis: Role of Therapies and Current Perspective

by Tommaso Guerra and Pietro Iaffaldano

Int. J. Mol. Sci. 2025, 26(3), 884; https://doi.org/10.3390/ijms26030884 - 21 Jan 2025

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Abstract

In multiple sclerosis (MS), there is significant evidence indicating that both progression independent of relapse activity (PIRA) and relapse-related worsening events contribute to the accumulation of progressive disability from the onset of the disease and throughout its course. Understanding the compartmentalized pathophysiology of [...] Read more.

In multiple sclerosis (MS), there is significant evidence indicating that both progression independent of relapse activity (PIRA) and relapse-related worsening events contribute to the accumulation of progressive disability from the onset of the disease and throughout its course. Understanding the compartmentalized pathophysiology of MS would enhance comprehension of disease progression mechanisms, overcoming the traditional distinction in phenotypes. Smoldering MS activity is thought to be maintained by a continuous interaction between the parenchymal chronic processes of neuroinflammation and neurodegeneration and the intrathecal compartment. This review provides a comprehensive and up-to-date overview of the neuropathological and immunological evidence related to the mechanisms underlying PIRA phenomena in MS, with a focus on studies investigating the impact of currently available therapies on these complex mechanisms. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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68 pages, 6003 KiB

Open AccessReview

Should We Consider Neurodegeneration by Itself or in a Triangulation with Neuroinflammation and Demyelination? The Example of Multiple Sclerosis and Beyond

by Océane Perdaens and Vincent van Pesch

Int. J. Mol. Sci. 2024, 25(23), 12637; https://doi.org/10.3390/ijms252312637 - 25 Nov 2024

Cited by 1 | Viewed by 2115

Abstract

Neurodegeneration is preeminent in many neurological diseases, and still a major burden we fail to manage in patient’s care. Its pathogenesis is complicated, intricate, and far from being completely understood. Taking multiple sclerosis as an example, we propose that neurodegeneration is neither a [...] Read more.

Neurodegeneration is preeminent in many neurological diseases, and still a major burden we fail to manage in patient’s care. Its pathogenesis is complicated, intricate, and far from being completely understood. Taking multiple sclerosis as an example, we propose that neurodegeneration is neither a cause nor a consequence by itself. Mitochondrial dysfunction, leading to energy deficiency and ion imbalance, plays a key role in neurodegeneration, and is partly caused by the oxidative stress generated by microglia and astrocytes. Nodal and paranodal disruption, with or without myelin alteration, is further involved. Myelin loss exposes the axons directly to the inflammatory and oxidative environment. Moreover, oligodendrocytes provide a singular metabolic and trophic support to axons, but do not emerge unscathed from the pathological events, by primary myelin defects and cell apoptosis or secondary to neuroinflammation or axonal damage. Hereby, trophic failure might be an overlooked contributor to neurodegeneration. Thus, a complex interplay between neuroinflammation, demyelination, and neurodegeneration, wherein each is primarily and secondarily involved, might offer a more comprehensive understanding of the pathogenesis and help establishing novel therapeutic strategies for many neurological diseases and beyond. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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27 pages, 2334 KiB

Open AccessReview

An Overview of Multiple Sclerosis In Vitro Models

by Joanna Czpakowska, Mateusz Kałuża, Piotr Szpakowski and Andrzej Głąbiński

Int. J. Mol. Sci. 2024, 25(14), 7759; https://doi.org/10.3390/ijms25147759 - 16 Jul 2024

Cited by 1 | Viewed by 3691

Abstract

Multiple sclerosis (MS) still poses a challenge in terms of complex etiology, not fully effective methods of treatment, and lack of healing agents. This neurodegenerative condition considerably affects the comfort of life by causing difficulties with movement and worsening cognition. Neuron, astrocyte, microglia, [...] Read more.

Multiple sclerosis (MS) still poses a challenge in terms of complex etiology, not fully effective methods of treatment, and lack of healing agents. This neurodegenerative condition considerably affects the comfort of life by causing difficulties with movement and worsening cognition. Neuron, astrocyte, microglia, and oligodendrocyte activity is engaged in multiple pathogenic processes associated with MS. These cells are also utilized in creating in vitro cellular models for investigations focusing on MS. In this article, we present and discuss a summary of different in vitro models useful for MS research and describe their development. We discuss cellular models derived from animals or humans and present in the form of primary cell lines or immortalized cell lines. In addition, we characterize cell cultures developed from induced pluripotent stem cells (iPSCs). Culture conditions (2D and 3D cultures) are also discussed. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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25 pages, 1388 KiB

Open AccessReview

CNS Resident Innate Immune Cells: Guardians of CNS Homeostasis

by Luca Muzio and Jessica Perego

Int. J. Mol. Sci. 2024, 25(9), 4865; https://doi.org/10.3390/ijms25094865 - 29 Apr 2024

Cited by 4 | Viewed by 2922

Abstract

Although the CNS has been considered for a long time an immune-privileged organ, it is now well known that both the parenchyma and non-parenchymal tissue (meninges, perivascular space, and choroid plexus) are richly populated in resident immune cells. The advent of more powerful [...] Read more.

Although the CNS has been considered for a long time an immune-privileged organ, it is now well known that both the parenchyma and non-parenchymal tissue (meninges, perivascular space, and choroid plexus) are richly populated in resident immune cells. The advent of more powerful tools for multiplex immunophenotyping, such as single-cell RNA sequencing technique and upscale multiparametric flow and mass spectrometry, helped in discriminating between resident and infiltrating cells and, above all, the different spectrum of phenotypes distinguishing border-associated macrophages. Here, we focus our attention on resident innate immune players and their primary role in both CNS homeostasis and pathological neuroinflammation and neurodegeneration, two key interconnected aspects of the immunopathology of multiple sclerosis. Full article

(This article belongs to the Special Issue Molecular Mechanism in Multiple Sclerosis and Related Disorders: 2nd Edition)

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