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Insights in Multiple Sclerosis (MS) and Neuroimmunology

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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: 30 April 2024 | Viewed by 14214

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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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

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 mechanisms of neurodegeneration in MS has expanded in the last several years. Furthermore, with the development and implementation of more precise technologies, including sequencing and advanced imaging, we are coming closer to defining processes that lead to damage of 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 with emphasis on 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 particular emphasis on immunological mediators. Original articles may also include potential therapies to combat neurodegeneration in MS.

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 100 words) can be sent to the Editorial Office for announcement on this website.

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

Published Papers (9 papers)

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Research

Jump to: Review

18 pages, 3967 KiB

Open AccessArticle

Plasma Lipidomic Profiling Using Mass Spectrometry for Multiple Sclerosis Diagnosis and Disease Activity Stratification (LipidMS)

by Seyed Siyawasch Justus Lattau, Lisa-Marie Borsch, Kristina auf dem Brinke, Christian Klose, Liza Vinhoven, Manuel Nietert and Dirk Fitzner

Int. J. Mol. Sci. 2024, 25(5), 2483; https://doi.org/10.3390/ijms25052483 - 20 Feb 2024

Viewed by 800

Abstract

This investigation explores the potential of plasma lipidomic signatures for aiding in the diagnosis of Multiple Sclerosis (MS) and evaluating the clinical course and disease activity of diseased patients. Plasma samples from 60 patients with MS (PwMS) were clinically stratified to either a relapsing-remitting (RRMS) or a chronic progressive MS course and 60 age-matched controls were analyzed using state-of-the-art direct infusion quantitative shotgun lipidomics. To account for potential confounders, data were filtered for age and BMI correlations. The statistical analysis employed supervised and unsupervised multivariate data analysis techniques, including a principal component analysis (PCA), a partial least squares discriminant analysis (oPLS-DA) and a random forest (RF). To determine whether the significant absolute differences in the lipid subspecies have a relevant effect on the overall composition of the respective lipid classes, we introduce a class composition visualization (CCV). We identified 670 lipids across 16 classes. PwMS showed a significant increase in diacylglycerols (DAG), with DAG 16:0;0_18:1;0 being proven to be the lipid with the highest predictive ability for MS as determined by RF. The alterations in the phosphatidylethanolamines (PE) were mainly linked to RRMS while the alterations in the ether-bound PEs (PE O-) were found in chronic progressive MS. The amount of CE species was reduced in the CPMS cohort whereas TAG species were reduced in the RRMS patients, both lipid classes being relevant in lipid storage. Combining the above mentioned data analyses, distinct lipidomic signatures were isolated and shown to be correlated with clinical phenotypes. Our study suggests that specific plasma lipid profiles are not merely associated with the diagnosis of MS but instead point toward distinct clinical features in the individual patient paving the way for personalized therapy and an enhanced understanding of MS pathology. Full article

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

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14 pages, 6771 KiB

Open AccessArticle

Uncovering Novel Extracellular Matrix Transcriptome Alterations in Lesions of Multiple Sclerosis

by Erin Laurel Stephenson, Rajiv William Jain, Samira Ghorbani, Rianne Petra Gorter, Charlotte D’Mello and Voon Wee Yong

Int. J. Mol. Sci. 2024, 25(2), 1240; https://doi.org/10.3390/ijms25021240 - 19 Jan 2024

Viewed by 844

Abstract

The extracellular matrix (ECM) of the central nervous system (CNS) is an interconnected network of proteins and sugars with critical roles in both homeostasis and disease. In neurological diseases, excessive ECM deposition and remodeling impact both injury and repair. CNS lesions of multiple sclerosis (MS), a chronic inflammatory and degenerative disease, cause prominent alterations of the ECM. However, there are a lack of data investigating how the multitude of ECM members change in relation to each other and how this affects the MS disease course. Here, we evaluated ECM changes in MS lesions compared to a control brain using databases generated in-house through spatial mRNA-sequencing and through a public resource of single-nucleus RNA sequencing previously published by Absinta and colleagues. These results underline the importance of publicly available datasets to find new targets of interest, such as the ECM. Both spatial and public datasets demonstrated widespread changes in ECM molecules and their interacting proteins, including alterations to proteoglycans and glycoproteins within MS lesions. Some of the altered ECM members have been described in MS, but other highly upregulated members, including the SPARC family of proteins, have not previously been highlighted. SPARC family members are upregulated in other conditions by reactive astrocytes and may influence immune cell activation and MS disease course. The profound changes to the ECM in MS lesions deserve more scrutiny as they impact neuroinflammation, injury, and repair. Full article

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

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17 pages, 1686 KiB

Open AccessArticle

Serum Reactive Antibodies against the N-Methyl-D-Aspartate Receptor NR2 Subunit—Could They Act as Potential Biomarkers?

by Maria S. Hadjiagapiou, George Krashias, Christina Christodoulou, Marios Pantzaris and Anastasia Lambrianides

Int. J. Mol. Sci. 2023, 24(22), 16170; https://doi.org/10.3390/ijms242216170 - 10 Nov 2023

Viewed by 921

Abstract

Synaptic dysfunction and disrupted communication between neuronal and glial cells play an essential role in the underlying mechanisms of multiple sclerosis (MS). Earlier studies have revealed the importance of glutamate receptors, particularly the N-methyl-D-aspartate (NMDA) receptor, in excitotoxicity, leading to abnormal synaptic transmission and damage of neurons. Our study aimed to determine whether antibodies to the NR2 subunit of NMDAR are detected in MS patients and evaluate the correlation between antibody presence and clinical outcome. Furthermore, our focus extended to examine a possible link between NR2 reactivity and anti-coagulant antibody levels as pro-inflammatory molecules associated with MS. A cross-sectional study was carried out, including 95 patients with MS and 61 age- and gender-matched healthy controls (HCs). The enzyme-linked immunosorbent assay was used to detect anti-NR2 antibodies in serum samples of participants along with IgG antibodies against factor (F)VIIa, thrombin, prothrombin, FXa, and plasmin. According to our results, significantly elevated levels of anti-NR2 antibodies were detected in MS patients compared to HCs (p < 0.05), and this holds true when we compared the Relapsing-Remitting MS course with HCs (p < 0.05). A monotonically increasing correlation was found between NR2 seropositivity and advanced disability (r_s = 0.30; p < 0.01), anti-NR2 antibodies and disease worsening (r_s = 0.24; p < 0.05), as well as between antibody activity against NR2 and thrombin (r_s = 0.33; p < 0.01). The presence of anti-NR2 antibodies in MS patients was less associated with anti-plasmin IgG antibodies [OR:0.96 (95%CI: 0.92–0.99); p < 0.05]; however, such an association was not demonstrated when analyzing only RRMS patients. In view of our findings, NR2-reactive antibodies may play, paving the way for further research into their potential as biomarkers and therapeutic targets in MS. Full article

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

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12 pages, 1649 KiB

Open AccessArticle

A Comparison of Two Analytical Approaches for the Quantification of Neurofilament Light Chain, a Biomarker of Axonal Damage in Multiple Sclerosis

by Anna Pafiti, George Krashias, John Tzartos, Socrates Tzartos, Christos Stergiou, Eftychia Gaglia, Irene Smoleski, Christina Christodoulou, Marios Pantzaris and Anastasia Lambrianides

Int. J. Mol. Sci. 2023, 24(13), 10787; https://doi.org/10.3390/ijms241310787 - 28 Jun 2023

Cited by 3 | Viewed by 1359

Abstract

Neurofilament light chain (NfL), is a neuron-specific cytoskeletal protein detected in extracellular fluid following axonal damage. Extensive research has focused on NfL quantification in CSF, establishing it as a prognostic biomarker of disability progression in Multiple Sclerosis (MS). Our study used a new commercially available Enzyme-Linked Immunosorbent Assay (ELISA) kit and Single Molecular Array (Simoa) advanced technology to assess serum NfL levels in MS patients and Healthy Controls (HC). Verifying the most accurate, cost-effective methodology will benefit its application in clinical settings. Blood samples were collected from 54 MS patients and 30 HC. Protocols accompanying the kits were followed. The ELISA thershold was set as 3 S.D. above the mean of the HC. For Simoa, the Z-score calculation created by Jens Kuhle’s group was applied (with permission). Samples exceeding the threshold or z-score ≥1.5 indicated subclinical disease activity. To our knowledge, this is the first study to find strong-positive correlation between ELISA and Simoa for the quantification of NfL in serum (r = 0.919). Despite the strong correlation, Simoa has better analytical sensitivity and can detect small changes in samples making it valuable in clinical settings. Further research is required to evaluate whether serum NfL quantification using ELISA could be utilized to predict disability progression. Full article

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

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11 pages, 958 KiB

Open AccessArticle

CSF Markers of Oxidative Stress Are Associated with Brain Atrophy and Iron Accumulation in a 2-Year Longitudinal Cohort of Early MS

by Andrea Burgetova, Petr Dusek, Tomas Uher, Manuela Vaneckova, Martin Vejrazka, Romana Burgetova, Dana Horakova, Barbora Srpova, Marta Kalousova, Libuse Noskova, Katerina Levova, Jan Krasensky and Lukas Lambert

Int. J. Mol. Sci. 2023, 24(12), 10048; https://doi.org/10.3390/ijms241210048 - 12 Jun 2023

Viewed by 1116

Abstract

In this prospective longitudinal study, we quantified regional brain volume and susceptibility changes during the first two years after the diagnosis of multiple sclerosis (MS) and identified their association with cerebrospinal fluid (CSF) markers at baseline. Seventy patients underwent MRI (T1 and susceptibility weighted images processed to quantitative susceptibility maps, QSM) with neurological examination at the diagnosis and after two years. In CSF obtained at baseline, the levels of oxidative stress, products of lipid peroxidation, and neurofilaments light chain (NfL) were determined. Brain volumetry and QSM were compared with a group of 58 healthy controls. In MS patients, regional atrophy was identified in the striatum, thalamus, and substantia nigra. Magnetic susceptibility increased in the striatum, globus pallidus, and dentate and decreased in the thalamus. Compared to controls, MS patients developed greater atrophy of the thalamus, and a greater increase in susceptibility in the caudate, putamen, globus pallidus and a decrease in the thalamus. Of the multiple calculated correlations, only the decrease in brain parenchymal fraction, total white matter, and thalamic volume in MS patients negatively correlated with increased NfL in CSF. Additionally, negative correlation was found between QSM value in the substantia nigra and peroxiredoxin-2, and QSM value in the dentate and lipid peroxidation levels. Full article

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

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13 pages, 3699 KiB

Open AccessArticle

3-Dimensional Immunostaining and Automated Deep-Learning Based Analysis of Nerve Degeneration

by Sienna S. Drake, Marc Charabati, Tristan Simas, Yu Kang T. Xu, Etienne J. P. Maes, Shan Shan Shi, Jack Antel, Alexandre Prat, Barbara Morquette and Alyson E. Fournier

Int. J. Mol. Sci. 2022, 23(23), 14811; https://doi.org/10.3390/ijms232314811 - 26 Nov 2022

Cited by 1 | Viewed by 2324

Abstract

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease driven by inflammation and demyelination in the brain, spinal cord, and optic nerve. Optic neuritis, characterized by inflammation and demyelination of the optic nerve, is a symptom in many patients with MS. The optic nerve is the highway for visual information transmitted from the retina to the brain. It contains axons from the retinal ganglion cells (RGCs) that reside in the retina, myelin forming oligodendrocytes and resident microglia and astrocytes. Inflammation, demyelination, and axonal degeneration are also present in the optic nerve of mice subjected to experimental autoimmune encephalomyelitis (EAE), a preclinical mouse model of MS. Monitoring the optic nerve in EAE is a useful strategy to study the presentation and progression of pathology in the visual system; however, current approaches have relied on sectioning, staining and manual quantification. Further, information regarding the spatial load of lesions and inflammation is dependent on the area of sectioning. To better characterize cellular pathology in the EAE model, we employed a tissue clearing and 3D immunolabelling and imaging protocol to observe patterns of immune cell infiltration and activation throughout the optic nerve. Increased density of TOPRO staining for nuclei captured immune cell infiltration and Iba1 immunostaining was employed to monitor microglia and macrophages. Axonal degeneration was monitored by neurofilament immunolabelling to reveal axonal swellings throughout the optic nerve. In parallel, we developed a convolutional neural network with a UNet architecture (CNN-UNet) called BlebNet for automated identification and quantification of axonal swellings in whole mount optic nerves. Together this constitutes a toolkit for 3-dimensional immunostaining to monitor general optic nerve pathology and fast automated quantification of axonal defects that could also be adapted to monitor axonal degeneration and inflammation in other neurodegenerative disease models. Full article

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

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11 pages, 1926 KiB

Open AccessArticle

Targeting Signaling Pathway Downstream of RIG-I/MAVS in the CNS Stimulates Production of Endogenous Type I IFN and Suppresses EAE

by Anne K. Kronborg Hansen, Magdalena Dubik, Joanna Marczynska, Bhavya Ojha, Estanislao Nistal-Villán, Gloria González Aseguinolaza, Dina S. Arengoth, Trevor Owens and Reza Khorooshi

Int. J. Mol. Sci. 2022, 23(19), 11292; https://doi.org/10.3390/ijms231911292 - 25 Sep 2022

Cited by 1 | Viewed by 2122

Abstract

Type I interferons (IFN), including IFNβ, play a protective role in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Type I IFNs are induced by the stimulation of innate signaling, including via cytoplasmic RIG-I-like receptors. In the present study, we investigated the potential effect of a chimeric protein containing the key domain of RIG-I signaling in the production of CNS endogenous IFNβ and asked whether this would exert a therapeutic effect against EAE. We intrathecally administered an adeno-associated virus vector (AAV) encoding a fusion protein comprising RIG-I 2CARD domains (C) and the first 200 amino acids of mitochondrial antiviral-signaling protein (MAVS) (M) (AAV-CM). In vivo imaging in IFNβ/luciferase reporter mice revealed that a single intrathecal injection of AAV-CM resulted in dose-dependent and sustained IFNβ expression within the CNS. IFNβ expression was significantly increased for 7 days. Immunofluorescent staining in IFNβ-YFP reporter mice revealed extraparenchymal CD45+ cells, choroid plexus, and astrocytes as sources of IFNβ. Moreover, intrathecal administration of AAV-CM at the onset of EAE induced the suppression of EAE, which was IFN-I-dependent. These findings suggest that accessing the signaling pathway downstream of RIG-I represents a promising therapeutic strategy for inflammatory CNS diseases, such as MS. Full article

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

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Review

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12 pages, 493 KiB

Open AccessReview

Are There General Features of How Immune Responses Are Regulated That Can Provide Clues to How Remitting/Relapsing Multiple Sclerosis May Be Treated?

by Peter Alan Bretscher

Int. J. Mol. Sci. 2024, 25(5), 2726; https://doi.org/10.3390/ijms25052726 - 27 Feb 2024

Viewed by 568

Abstract

Most basic studies directed at how immune responses are regulated employ chemically “simple antigens”, usually purified proteins. The target antigens in many clinical situations, such as in autoimmunity, infectious diseases and cancer, are chemically “complex”, consisting of several distinct molecules, and they often are part of a replicating entity. We examine here the relationships between how immune responses to complex and simple antigens are regulated. This examination provides a context for considering how immune responses are regulated in those clinical situations involving complex antigens. I have proposed and discuss here a mechanism by which immune responses to the envisaged complex target antigen in remitting/relapsing multiple sclerosis go back and forth between inflammatory and non-inflammatory modes, potentially accounting for the course of this disease. This proposal makes predictions that can be tested by non-invasive means. It also leads to a suggestion for simple, non-invasive treatment. Full article

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

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12 pages, 923 KiB

Open AccessReview

Dual Role of B Cells in Multiple Sclerosis

by Gaurav Kumar and Robert C. Axtell

Int. J. Mol. Sci. 2023, 24(3), 2336; https://doi.org/10.3390/ijms24032336 - 25 Jan 2023

Cited by 5 | Viewed by 3221

Abstract

B cells have emerged as an important immune cell type that can be targeted for therapy in multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies is effective in treating MS. Yet, atacicept treatment, which blocks B-cell Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL), two cytokines important for B cell development and function, paradoxically increases disease activity in MS patients. The reason behind the failure of atacicept is not well understood. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and anti-inflammatory functions in MS. In this review, we summarize the importance of B cells in MS and discuss the different B cell subsets that perform inflammatory and anti-inflammatory functions and how therapies modulate B cell functions in MS patients. Additionally, we discuss the potential anti-inflammatory functions of BAFF and APRIL on MS disease. Full article

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

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