Cellular and Molecular Mechanisms in Pathogenesis of Multiple Sclerosis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 78311

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Special Issue Editor

1. Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506, USA
2. Department of Neuroscience and the Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, WV 26506, USA
Interests: multiple sclerosis; stroke; neuroinflammation; myeloid cells
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Dear Colleagues,

Multiple sclerosis (MS) is one of the most common neurological disorders in young adults. The etiology of MS is not known, but it is generally accepted that it is autoimmune in nature. Our knowledge of the pathogenesis of MS has increased tremendously in the past decade through clinical studies and the use of experimental autoimmune encephalomyelitis (EAE), a model that has been widely used for MS research. Major advances in the field, such as understanding the roles of pathogenic Th17 cells, myeloid cells, and B cells in MS/EAE, as well as cytokine and chemokine signaling that controls neuroinflammation have led to the development of potential and clinically approved disease-modifying agents (DMAs).

There are many aspects related to the initiation, relapse and remission, and progression of MS that are yet to be elucidated. For instance, what are the genetic and environmental risk factors that promote the initiation of MS and how do these factors impact the immune system? What factors drive the progression of MS and what are the roles of peripheral immune cells in disease progression? How do the CNS-infiltrated immune cells interact with the CNS-resident glial cells when the disease progresses? What is the role of microbiome in MS? Can we develop animal models that better represent subcategories of MS? Understanding the cellular and molecular mechanisms that govern the pathogenesis of MS will help to develop novel and more specific therapeutic strategies that will ultimately improve clinical outcomes of the treatments. This Special Issue welcomes original research articles, clinical reports, and review articles that investigate the cellular and molecular basis of MS.

Dr. Edwin Wan
Guest Editor

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Keywords

  • multiple sclerosis
  • experimental autoimmune encephalomyelitis
  • disease-modifying agents
  • demyelination
  • neuroinflammation
  • cytokine and chemokine signaling

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Published Papers (10 papers)

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Editorial

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3 pages, 166 KiB  
Editorial
Cellular and Molecular Mechanisms in the Pathogenesis of Multiple Sclerosis
by Edwin C. K. Wan
Cells 2020, 9(10), 2223; https://doi.org/10.3390/cells9102223 - 1 Oct 2020
Cited by 3 | Viewed by 2306
Abstract
Multiple sclerosis (MS) is one of the most common neurological disorders in young adults [...] Full article

Research

Jump to: Editorial, Review

18 pages, 3533 KiB  
Article
Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis
by Alessandra Musella, Antonietta Gentile, Livia Guadalupi, Francesca Romana Rizzo, Francesca De Vito, Diego Fresegna, Antonio Bruno, Ettore Dolcetti, Valentina Vanni, Laura Vitiello, Silvia Bullitta, Krizia Sanna, Silvia Caioli, Sara Balletta, Monica Nencini, Fabio Buttari, Mario Stampanoni Bassi, Diego Centonze and Georgia Mandolesi
Cells 2020, 9(5), 1290; https://doi.org/10.3390/cells9051290 - 22 May 2020
Cited by 25 | Viewed by 4851
Abstract
Future treatments of multiple sclerosis (MS), a chronic autoimmune neurodegenerative disease of the central nervous system (CNS), aim for simultaneous early targeting of peripheral immune function and neuroinflammation. Sphingosine-1-phosphate (S1P) receptor modulators are among the most promising drugs with both “immunological” and “non-immunological” [...] Read more.
Future treatments of multiple sclerosis (MS), a chronic autoimmune neurodegenerative disease of the central nervous system (CNS), aim for simultaneous early targeting of peripheral immune function and neuroinflammation. Sphingosine-1-phosphate (S1P) receptor modulators are among the most promising drugs with both “immunological” and “non-immunological” actions. Selective S1P receptor modulators have been recently approved for MS and shown clinical efficacy in its mouse model, the experimental autoimmune encephalomyelitis (EAE). Here, we investigated the anti-inflammatory/neuroprotective effects of ozanimod (RPC1063), a S1P1/5 modulator recently approved in the United States for the treatment of MS, by performing ex vivo studies in EAE brain. Electrophysiological experiments, supported by molecular and immunofluorescence analysis, revealed that ozanimod was able to dampen the EAE glutamatergic synaptic alterations, through attenuation of local inflammatory response driven by activated microglia and infiltrating T cells, the main CNS-cellular players of EAE synaptopathy. Electrophysiological studies with selective S1P1 (AUY954) and S1P5 (A971432) agonists suggested that S1P1 modulation is the main driver of the anti-excitotoxic activity mediated by ozanimod. Accordingly, in vivo intra-cerebroventricular treatment of EAE mice with AUY954 ameliorated clinical disability. Altogether these results strengthened the relevance of S1P1 agonists as immunomodulatory and neuroprotective drugs for MS therapy. Full article
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16 pages, 4389 KiB  
Article
A Clonal NG2-Glia Cell Response in a Mouse Model of Multiple Sclerosis
by Sonsoles Barriola, Fernando Pérez-Cerdá, Carlos Matute, Ana Bribián and Laura López-Mascaraque
Cells 2020, 9(5), 1279; https://doi.org/10.3390/cells9051279 - 21 May 2020
Cited by 9 | Viewed by 3730
Abstract
NG2-glia, also known as oligodendrocyte precursor cells (OPCs), have the potential to generate new mature oligodendrocytes and thus, to contribute to tissue repair in demyelinating diseases like multiple sclerosis (MS). Once activated in response to brain damage, NG2-glial cells proliferate, and they acquire [...] Read more.
NG2-glia, also known as oligodendrocyte precursor cells (OPCs), have the potential to generate new mature oligodendrocytes and thus, to contribute to tissue repair in demyelinating diseases like multiple sclerosis (MS). Once activated in response to brain damage, NG2-glial cells proliferate, and they acquire a reactive phenotype and a heterogeneous appearance. Here, we set out to investigate the distribution and phenotypic diversity of NG2-glia relative to their ontogenic origin, and whether there is a clonal NG2-glial response to lesion in an experimental autoimmune encephalomyelitis (EAE) murine model of MS. As such, we performed in utero electroporation of the genomic lineage tracer, StarTrack, to follow the fate of NG2-glia derived from single progenitors and to evaluate their response to brain damage after EAE induction. We then analyzed the dispersion of the NG2-glia derived clonally from single pallial progenitors in the brain of EAE mice. In addition, we examined several morphological parameters to assess the degree of NG2-glia reactivity in clonally-related cells. Our results reveal the heterogeneity of these progenitors and their cell progeny in a scenario of autoimmune demyelination, revealing the ontogenic phenomena at play in these processes. Full article
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15 pages, 1805 KiB  
Article
The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model
by Gabriele Di Sante, Susanna Amadio, Beatrice Sampaolese, Maria Elisabetta Clementi, Mariagrazia Valentini, Cinzia Volonté, Patrizia Casalbore, Francesco Ria and Fabrizio Michetti
Cells 2020, 9(3), 748; https://doi.org/10.3390/cells9030748 - 18 Mar 2020
Cited by 27 | Viewed by 4827
Abstract
S100B is an astrocytic protein acting either as an intracellular regulator or an extracellular signaling molecule. A direct correlation between increased amount of S100B and demyelination and inflammatory processes has been demonstrated. The aim of this study is to investigate the possible role [...] Read more.
S100B is an astrocytic protein acting either as an intracellular regulator or an extracellular signaling molecule. A direct correlation between increased amount of S100B and demyelination and inflammatory processes has been demonstrated. The aim of this study is to investigate the possible role of a small molecule able to bind and inhibit S100B, pentamidine, in the modulation of disease progression in the relapsing–remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the central nervous system, we observed that pentamidine is able to delay the acute phase of the disease and to inhibit remission, resulting in an amelioration of clinical score when compared with untreated relapsing–remitting experimental autoimmune encephalomyelitis mice. Moreover, we observed a significant reduction of proinflammatory cytokines expression levels in the brains of treated versus untreated mice, in addition to a reduction of nitric oxide synthase activity. Immunohistochemistry confirmed that the inhibition of S100B was able to modify the neuropathology of the disease, reducing immune infiltrates and partially protecting the brain from the damage. Overall, our results indicate that pentamidine targeting the S100B protein is a novel potential drug to be considered for multiple sclerosis treatment. Full article
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33 pages, 3648 KiB  
Article
Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis
by Monokesh K. Sen, Mohammed S. M. Almuslehi, Erika Gyengesi, Simon J. Myers, Peter J. Shortland, David A. Mahns and Jens R. Coorssen
Cells 2019, 8(11), 1314; https://doi.org/10.3390/cells8111314 - 24 Oct 2019
Cited by 24 | Viewed by 5132
Abstract
Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), [...] Read more.
Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis plus marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and no splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the ‘inside-out’ theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the ‘inside-out’ role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement. Full article
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8 pages, 890 KiB  
Article
The Neutrophil-to-Lymphocyte Ratio is Related to Disease Activity in Relapsing Remitting Multiple Sclerosis
by Emanuele D’Amico, Aurora Zanghì, Alessandra Romano, Mariangela Sciandra, Giuseppe Alberto Maria Palumbo and Francesco Patti
Cells 2019, 8(10), 1114; https://doi.org/10.3390/cells8101114 - 20 Sep 2019
Cited by 45 | Viewed by 3311
Abstract
Background: The role of the neutrophil-to-lymphocyte ratio (NLR) of peripheral blood has been investigated in relation to several autoimmune diseases. Limited studies have addressed the significance of the NLR in terms of being a marker of disease activity in multiple sclerosis (MS). Methods: [...] Read more.
Background: The role of the neutrophil-to-lymphocyte ratio (NLR) of peripheral blood has been investigated in relation to several autoimmune diseases. Limited studies have addressed the significance of the NLR in terms of being a marker of disease activity in multiple sclerosis (MS). Methods: This is a retrospective study in relapsing–remitting MS patients (RRMS) admitted to the tertiary MS center of Catania, Italy during the period of 1 January to 31 December 2018. The aim of the present study was to investigate the significance of the NLR in reflecting the disease activity in a cohort of early diagnosed RRMS patients. Results: Among a total sample of 132 patients diagnosed with RRMS, 84 were enrolled in the present study. In the association analysis, a relation between the NLR value and disease activity at onset was found (V-Cramer 0.271, p = 0.013). In the logistic regression model, the variable NLR (p = 0.03 ExpB 3.5, CI 95% 1.089–11.4) was related to disease activity at onset. Conclusion: An elevated NLR is associated with disease activity at onset in RRMS patients. More large-scale studies with a longer follow-up are needed. Full article
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Review

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15 pages, 1209 KiB  
Review
HDAC6 in Diseases of Cognition and of Neurons
by Patrizia LoPresti
Cells 2021, 10(1), 12; https://doi.org/10.3390/cells10010012 - 23 Dec 2020
Cited by 59 | Viewed by 16174
Abstract
Central nervous system (CNS) neurodegenerative diseases are characterized by faulty intracellular transport, cognition, and aggregate regulation. Traditionally, neuroprotection exerted by histone deacetylase (HDAC) inhibitors (HDACi) has been attributed to the ability of this drug class to promote histone acetylation. However, HDAC6 in the [...] Read more.
Central nervous system (CNS) neurodegenerative diseases are characterized by faulty intracellular transport, cognition, and aggregate regulation. Traditionally, neuroprotection exerted by histone deacetylase (HDAC) inhibitors (HDACi) has been attributed to the ability of this drug class to promote histone acetylation. However, HDAC6 in the healthy CNS functions via distinct mechanisms, due largely to its cytoplasmic localization. Indeed, in healthy neurons, cytoplasmic HDAC6 regulates the acetylation of a variety of non-histone proteins that are linked to separate functions, i.e., intracellular transport, neurotransmitter release, and aggregate formation. These three HDAC6 activities could work independently or in synergy. Of particular interest, HDAC6 targets the synaptic protein Bruchpilot and neurotransmitter release. In pathological conditions, HDAC6 becomes abundant in the nucleus, with deleterious consequences for transcription regulation and synapses. Thus, HDAC6 plays a leading role in neuronal health or dysfunction. Here, we review recent findings and novel conclusions on the role of HDAC6 in neurodegeneration. Selective studies with pan-HDACi are also included. We propose that an early alteration of HDAC6 undermines synaptic transmission, while altering transport and aggregation, eventually leading to neurodegeneration. Full article
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37 pages, 1278 KiB  
Review
Kynurenines in the Pathogenesis of Multiple Sclerosis: Therapeutic Perspectives
by Tamás Biernacki, Dániel Sandi, Krisztina Bencsik and László Vécsei
Cells 2020, 9(6), 1564; https://doi.org/10.3390/cells9061564 - 26 Jun 2020
Cited by 37 | Viewed by 5485
Abstract
Over the past years, an increasing amount of evidence has emerged in support of the kynurenine pathway’s (KP) pivotal role in the pathogenesis of several neurodegenerative, psychiatric, vascular and autoimmune diseases. Different neuroactive metabolites of the KP are known to exert opposite effects [...] Read more.
Over the past years, an increasing amount of evidence has emerged in support of the kynurenine pathway’s (KP) pivotal role in the pathogenesis of several neurodegenerative, psychiatric, vascular and autoimmune diseases. Different neuroactive metabolites of the KP are known to exert opposite effects on neurons, some being neuroprotective (e.g., picolinic acid, kynurenic acid, and the cofactor nicotinamide adenine dinucleotide), while others are toxic to neurons (e.g., 3-hydroxykynurenine, quinolinic acid). Not only the alterations in the levels of the metabolites but also disturbances in their ratio (quinolinic acid/kynurenic acid) have been reported in several diseases. In addition to the metabolites, the enzymes participating in the KP have been unearthed to be involved in modulation of the immune system, the energetic upkeep of neurons and have been shown to influence redox processes and inflammatory cascades, revealing a sophisticated, intertwined system. This review considers various methods through which enzymes and metabolites of the kynurenine pathway influence the immune system, the roles they play in the pathogenesis of neuroinflammatory diseases based on current evidence with a focus on their involvement in multiple sclerosis, as well as therapeutic approaches. Full article
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15 pages, 635 KiB  
Review
The Role of Granulocyte-Macrophage Colony-Stimulating Factor in Murine Models of Multiple Sclerosis
by Kelly L. Monaghan and Edwin C.K. Wan
Cells 2020, 9(3), 611; https://doi.org/10.3390/cells9030611 - 4 Mar 2020
Cited by 26 | Viewed by 7280
Abstract
Multiple sclerosis (MS) is an immune-mediated disease that predominantly impacts the central nervous system (CNS). Animal models have been used to elucidate the underpinnings of MS pathology. One of the most well-studied models of MS is experimental autoimmune encephalomyelitis (EAE). This model was [...] Read more.
Multiple sclerosis (MS) is an immune-mediated disease that predominantly impacts the central nervous system (CNS). Animal models have been used to elucidate the underpinnings of MS pathology. One of the most well-studied models of MS is experimental autoimmune encephalomyelitis (EAE). This model was utilized to demonstrate that the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a critical and non-redundant role in mediating EAE pathology, making it an ideal therapeutic target. In this review, we will first explore the role that GM-CSF plays in maintaining homeostasis. This is important to consider, because any therapeutics that target GM-CSF could potentially alter these regulatory processes. We will then focus on current findings related to the function of GM-CSF signaling in EAE pathology, including the cell types that produce and respond to GM-CSF and the role of GM-CSF in both acute and chronic EAE. We will then assess the role of GM-CSF in alternative models of MS and comment on how this informs the understanding of GM-CSF signaling in the various aspects of MS immunopathology. Finally, we will examine what is currently known about GM-CSF signaling in MS, and how this has promoted clinical trials that directly target GM-CSF. Full article
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23 pages, 1523 KiB  
Review
Memory CD4+ T Cells in Immunity and Autoimmune Diseases
by Itay Raphael, Rachel R. Joern and Thomas G. Forsthuber
Cells 2020, 9(3), 531; https://doi.org/10.3390/cells9030531 - 25 Feb 2020
Cited by 114 | Viewed by 24192
Abstract
CD4+ T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4+ Th cells [...] Read more.
CD4+ T helper (Th) cells play central roles in immunity in health and disease. While much is known about the effector function of Th cells in combating pathogens and promoting autoimmune diseases, the roles and biology of memory CD4+ Th cells are complex and less well understood. In human autoimmune diseases such as multiple sclerosis (MS), there is a critical need to better understand the function and biology of memory T cells. In this review article we summarize current concepts in the field of CD4+ T cell memory, including natural history, developmental pathways, subsets, and functions. Furthermore, we discuss advancements in the field of the newly-described CD4+ tissue-resident memory T cells and of CD4+ memory T cells in autoimmune diseases, two major areas of important unresolved questions in need of answering to advance new vaccine design and development of novel treatments for CD4+ T cell-mediated autoimmune diseases. Full article
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