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New Molecular Mechanisms in Multiple Sclerosis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 71500

Special Issue Editors

Neurology Department, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Universitätsklinikum Essen, Hufelandstr. 55, 45147 Essen, Germany
Interests: neuroimmunology; multiple sclerosis (clinical/experimental); stroke (clinical/experimental); thromboinflammation; neuroprotection; neuroimaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multiple Sclerosis (MS) is one of the most exciting, emerging fields in neurology. Recent pathophysiological insights, derived from both animal models and clinical studies, paved the way for the regulatory approval of novel MS treatments, most recently cladribin was approved for active MS patients and the novel B-cell depleting antibody ocrelizumab showed promising results in phase III trials in relapsing-remitting (RRMS) and early primary progressive MS (PPMS). Some of these compounds possibly act beyond their well-established immunomodulatory properties, for instance, by inducing direct neuroprotection or neuroregeneration (e.g., Anti-LINGO-1). Of note, even childhood MS has been recognized as a significant medical problem demonstrating axonal degeneration early in the disease course and novel therapies are increasingly tested for this population. Significant clinical effects could be recently demonstrated for fingolimod in juvenile MS. However, important, unmet medical needs remain and the quest for even more sophisticated neuroprotective treatment strategies continues. For example, promising preclinical data exist regarding the modulation of certain ion channels expressed on immune cells, B cell function in PPMS, and the functional state of the blood–brain-barrier. Additionally, the search for novel biomarkers predicting treatment responses and/or disease progression is ongoing. Improved imaging techniques, such as diffusion tensor imaging or optical coherence tomography, have helped gain in vivo insights into the pathophysiological processes directly acting in MS patients.

The upcoming Special Issue on " New Molecular Mechanisms in Multiple Sclerosis" will cover all molecular aspects of this most prevalent neuroimmunological disease. We invite authors to submit original articles or state-of-the art reviews on MS pathophysiology, therapy, epidemiology, environmental factors, and imaging. All contributions will undergo a rapid, fair, and concise review process to minimize publication times.

We look forward to receiving your valuable submissions.

Prof. Dr. Christoph Kleinschnitz
Prof. Dr. Sven G. Meuth
Guest Editors

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Keywords

  • Multiple Sclerosis
  • therapy
  • epidemiology
  • animal models
  • molecular mechanisms
  • environmental factors

Published Papers (14 papers)

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Research

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13 pages, 2546 KiB  
Article
Differential Transcription of SOCS5 and SOCS7 in Multiple Sclerosis Patients Treated with Interferon Beta or Glatiramer Acetate
by Emmanuel Rojas-Morales, Gerardo Santos-López, Samuel Hernández-Cabañas, Raúl Arcega-Revilla, Nora Rosas-Murrieta, Carolina Jasso-Miranda, Elie Girgis El-Kassis, Julio Reyes-Leyva and Virginia Sedeño-Monge
Int. J. Mol. Sci. 2020, 21(1), 218; https://doi.org/10.3390/ijms21010218 - 28 Dec 2019
Cited by 4 | Viewed by 2683
Abstract
The participation of proinflammatory cytokines in the progression of Multiple Sclerosis (MS) has been well documented. Cytokines activate the JAK-STAT pathway, in which the suppressors of cytokine signaling (SOCS) exert a negative feedback. This paper analyzes the levels of SOCS5 and SOCS7 transcripts, [...] Read more.
The participation of proinflammatory cytokines in the progression of Multiple Sclerosis (MS) has been well documented. Cytokines activate the JAK-STAT pathway, in which the suppressors of cytokine signaling (SOCS) exert a negative feedback. This paper analyzes the levels of SOCS5 and SOCS7 transcripts, quantified by RT-qPCR, in MS patients, and the concentrations of proinflammatory cytokines, IFN-γ, IL17, and IL6, determined by ELISA. Samples of peripheral blood were obtained from MS patients in the relapsing–remitting phase, treated with IFN-β or glatiramer acetate (GA), and from healthy individuals. SOCS7 mRNA was significantly higher in patients treated with GA (1.36 ± 0.23) than in those treated with IFN-β (0.65 ± 0.1). Regarding gender, the level of SOCS5 and SOCS7 transcripts were similar between MS and healthy females; in MS males, the level of SOCS7 transcripts were significantly lower (0.59 ± 0.03) than in healthy males (1.008 ± 0.05). Plasmatic levels of IFN-γ were significantly higher in MS patients (60 pg/mL, range 0–160) than in healthy subjects (0 range, 0–106). The same pattern was observed in MS patients treated with IFN-β (68 pg/mL, range 0–160) compared to patients treated with GA (51 pg/mL, range 0–114), and in MS females (64 pg/mL, range 0–161) compared to healthy females (0, range 0–99). We hypothesize that the increase in SOCS7 transcription in patients treated with GA could partially explain the action mechanism of this drug, while the increase in the concentration of IFN-γ in MS patients could help elucidate the immunopathology of the disease. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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17 pages, 2258 KiB  
Article
Relationship of Iron Metabolism and Short-Term Cuprizone Treatment of C57BL/6 Mice
by Edina Pandur, Ramóna Pap, Edit Varga, Gergely Jánosa, Sámuel Komoly, Judit Fórizs and Katalin Sipos
Int. J. Mol. Sci. 2019, 20(9), 2257; https://doi.org/10.3390/ijms20092257 - 07 May 2019
Cited by 19 | Viewed by 3500
Abstract
One of the models to investigate the distinct mechanisms contributing to neurodegeneration in multiple sclerosis is based on cuprizone (CZ) intoxication. CZ is toxic to mature oligodendrocytes and produces demyelination within the central nervous system but does not cause direct neuronal damage. The [...] Read more.
One of the models to investigate the distinct mechanisms contributing to neurodegeneration in multiple sclerosis is based on cuprizone (CZ) intoxication. CZ is toxic to mature oligodendrocytes and produces demyelination within the central nervous system but does not cause direct neuronal damage. The CZ model is suitable for better understanding the molecular mechanism of de- and remyelination processes of oligodendrocytes. CZ is a copper chelating agent and it also affects the iron metabolism in brain and liver tissues. To determine the early effect of CZ treatment on iron homeostasis regulation, cytosolic and mitochondrial iron storage, as well as some lipid metabolism genes, we investigated the expression of respective iron homeostasis and lipid metabolism genes of the corpus callosum (CC) and the liver after short-term CZ administration. In the present study C57BL/6 male mice aged four weeks were fed with standard rodent food premixed with 0.2 w/w% CZ for two or eight days. The major findings of our experiments are that short-term CZ treatment causes significant changes in iron metabolism regulation as well as in the expression of myelin and lipid synthesis-related genes, even before apparent demyelination occurs. Both in the CC and the liver the iron uptake, utilization and storage are modified, though not always the same way or to the same extent in the two organs. Understanding the role of iron in short-term and long-term CZ intoxication could provide a partial explanation of the discrepant signs of acute and chronic MS. These could contribute to understanding the development of multiple sclerosis and might provide a possible drug target. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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16 pages, 22827 KiB  
Article
The Genetic Background of Mice Influences the Effects of Cigarette Smoke on Onset and Severity of Experimental Autoimmune Encephalomyelitis
by Gaby Enzmann, Roberto Adelfio, Aurélie Godel, Neda Haghayegh Jahromi, Silvia Tietz, Sabrina S. Burgener, Urban Deutsch, Hartmut Wekerle, Charaf Benarafa and Britta Engelhardt
Int. J. Mol. Sci. 2019, 20(6), 1433; https://doi.org/10.3390/ijms20061433 - 21 Mar 2019
Cited by 3 | Viewed by 3595
Abstract
Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults leading to severe disability. Besides genetic traits, environmental factors contribute to MS pathogenesis. Cigarette smoking increases the risk of MS in an HLA-dependent fashion, but [...] Read more.
Multiple sclerosis (MS) is the most common inflammatory disorder of the central nervous system (CNS) in young adults leading to severe disability. Besides genetic traits, environmental factors contribute to MS pathogenesis. Cigarette smoking increases the risk of MS in an HLA-dependent fashion, but the underlying mechanisms remain unknown. Here, we explored the effect of cigarette smoke exposure on spontaneous and induced models of experimental autoimmune encephalomyelitis (EAE) by evaluating clinical disease and, when relevant, blood leukocytes and histopathology. In the relapsing-remitting (RR) transgenic model in SJL/J mice, we observed very low incidence in both smoke-exposed and control groups. In the optico-spinal encephalomyelitis (OSE) double transgenic model in C57BL/6 mice, the early onset of EAE prevented a meaningful evaluation of the effects of cigarette smoke. In EAE models induced by immunization, daily exposure to cigarette smoke caused a delayed onset of EAE followed by a protracted disease course in SJL/J mice. In contrast, cigarette smoke exposure ameliorated the EAE clinical score in C57BL/6J mice. Our exploratory studies therefore show that genetic background influences the effects of cigarette smoke on autoimmune neuroinflammation. Importantly, our findings expose the challenge of identifying an animal model for studying the influence of cigarette smoke in MS. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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12 pages, 3253 KiB  
Article
Fumaric Acids Directly Influence Gene Expression of Neuroprotective Factors in Rodent Microglia
by Jessica Kronenberg, Kaweh Pars, Marina Brieskorn, Chittappen K. Prajeeth, Sandra Heckers, Philipp Schwenkenbecher, Thomas Skripuletz, Refik Pul, Andreas Pavlou and Martin Stangel
Int. J. Mol. Sci. 2019, 20(2), 325; https://doi.org/10.3390/ijms20020325 - 15 Jan 2019
Cited by 19 | Viewed by 4000
Abstract
Dimethylfumarate (DMF) has been approved the for treatment of relapsing-remitting multiple sclerosis. The mode of action of DMF and its assumed active primary metabolite monomethylfumarate (MMF) is still not fully understood, notably for brain resident cells. Therefore we investigated potential direct effects of [...] Read more.
Dimethylfumarate (DMF) has been approved the for treatment of relapsing-remitting multiple sclerosis. The mode of action of DMF and its assumed active primary metabolite monomethylfumarate (MMF) is still not fully understood, notably for brain resident cells. Therefore we investigated potential direct effects of DMF and MMF on microglia and indirect effects on oligodendrocytes. Primary rat microglia were differentiated into M1-like, M2-like and M0 phenotypes and treated in vitro with DMF or MMF. The gene expression of pro-inflammatory and anti-inflammatory factors such as growth factors (IGF-1), interleukins (IL-10, IL-1β), chemokines (CCl3, CXCL-10) as well as cytokines (TGF-1β, TNFα), iNOS, and the mannose receptor (MRC1) was examined by determining their transcription level with qPCR, and on the protein level by ELISA and FACS analysis. Furthermore, microglia function was determined by phagocytosis assays and indirect effects on oligodendroglial proliferation and differentiation. DMF treatment of M0 and M1-like polarized microglia demonstrated an upregulation of gene expression for IGF-1 and MRC1, but not on the protein level. While the phagocytic activity remained unchanged, DMF and MMF treated microglia supernatants led to an enhanced proliferation of oligodendrocyte precursor cells (OPC). These results suggest that DMF has anti-inflammatory effects on microglia which may result in enhanced proliferation of OPC. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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13 pages, 3886 KiB  
Article
Myelination in Multiple Sclerosis Lesions Is Associated with Regulation of Bone Morphogenetic Protein 4 and Its Antagonist Noggin
by Kim Harnisch, Sarah Teuber-Hanselmann, Nicole Macha, Fabian Mairinger, Lena Fritsche, Daniel Soub, Edgar Meinl and Andreas Junker
Int. J. Mol. Sci. 2019, 20(1), 154; https://doi.org/10.3390/ijms20010154 - 03 Jan 2019
Cited by 23 | Viewed by 5559
Abstract
Remyelination is a central aspect of new multiple sclerosis (MS) therapies, in which one aims to alleviate disease symptoms by improving axonal protection. However, a central problem is mediators expressed in MS lesions that prevent effective remyelination. Bone morphogenetic protein4 (BMP4) inhibits the [...] Read more.
Remyelination is a central aspect of new multiple sclerosis (MS) therapies, in which one aims to alleviate disease symptoms by improving axonal protection. However, a central problem is mediators expressed in MS lesions that prevent effective remyelination. Bone morphogenetic protein4 (BMP4) inhibits the development of mature oligodendrocytes in cell culture and also blocks the expression of myelin proteins. Additionally, numerous studies have shown that Noggin (SYM1)—among other physiological antagonists of BMP4—plays a prominent role in myelin formation in the developing but also the adult central nervous system. Nonetheless, neither BMP4 nor Noggin have been systematically studied in human MS lesions. In this study, we demonstrated by transcript analysis and immunohistochemistry that BMP4 is expressed by astrocytes and microglia/macrophages in association with inflammatory infiltrates in MS lesions, and that astrocytes also express BMP4 in chronic inactive lesions that failed to remyelinate. Furthermore, the demonstration of an increased expression of Noggin in so-called shadow plaques (i.e., remyelinated lesions with thinner myelin sheaths) in comparison to chronically inactive demyelinated lesions implies that antagonizing BMP4 is associated with successful remyelination in MS plaques in humans. However, although BMP4 is strongly overexpressed in inflammatory lesion areas, its levels are also elevated in remyelinated lesion areas, which raises the possibility that BMP4 signaling itself may be required for remyelination. Therefore, remyelination might be influenced by a small number of key factors. Manipulating these molecules, i.e., BMP4 and Noggin, could be a promising therapeutic approach for effective remyelination. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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16 pages, 1790 KiB  
Article
The miRNA Expression Profile of Experimental Autoimmune Encephalomyelitis Reveals Novel Potential Disease Biomarkers
by Shivaprasad H. Venkatesha, Steven Dudics, Yang Song, Anup Mahurkar and Kamal D. Moudgil
Int. J. Mol. Sci. 2018, 19(12), 3990; https://doi.org/10.3390/ijms19123990 - 11 Dec 2018
Cited by 24 | Viewed by 4065
Abstract
Multiple sclerosis (MS) is a debilitating autoimmune disease affecting over 2.3 million people worldwide, and it is characterized by inflammation and demyelination of nerve cells. The currently available biomarkers for the diagnosis and management of MS have inherent limitations, therefore, additional new biomarkers [...] Read more.
Multiple sclerosis (MS) is a debilitating autoimmune disease affecting over 2.3 million people worldwide, and it is characterized by inflammation and demyelination of nerve cells. The currently available biomarkers for the diagnosis and management of MS have inherent limitations, therefore, additional new biomarkers are needed. We studied the microRNA (miRNA) profile of splenocytes of mice having experimental autoimmune encephalomyelitis (EAE), a model of human MS. A miRNA-microarray analysis revealed increased expression of nine miRNAs (let-7e, miR-23b, miR-31, miR-99b, miR-125a, miR-146b, miR-155, miR-193b, and miR-221) following EAE development. Interestingly, serum levels of miR-99b, miR-125a, and miR-146b were significantly higher in EAE mice compared to normal mice. Bioinformatics analysis revealed the experimentally validated as well as predicted gene targets of specific miRNAs that are important for disease progression in MS. Specifically, we observed inverse correlation in the levels of miR-99b versus LIF, and between miR-125a versus BDNF and LIF. Our results suggest that above-mentioned miRNAs may play a crucial role in the pathogenesis of MS, and that miR-99b, miR-125a, and miR-146b in particular may serve as useful biomarkers for disease activity. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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9 pages, 1008 KiB  
Article
The Persisting Significance of Oligoclonal Bands in the Dawning Era of Kappa Free Light Chains for the Diagnosis of Multiple Sclerosis
by Philipp Schwenkenbecher, Franz Felix Konen, Ulrich Wurster, Konstantin Fritz Jendretzky, Stefan Gingele, Kurt-Wolfram Sühs, Refik Pul, Torsten Witte, Martin Stangel and Thomas Skripuletz
Int. J. Mol. Sci. 2018, 19(12), 3796; https://doi.org/10.3390/ijms19123796 - 29 Nov 2018
Cited by 34 | Viewed by 4098
Abstract
The latest revision of the McDonald criteria of 2017 considers the evidence of an intrathecal immunoglobulin (IgG) synthesis as a diagnostic criterion for dissemination in time in multiple sclerosis. While the detection of oligoclonal bands is considered as the gold standard, determination of [...] Read more.
The latest revision of the McDonald criteria of 2017 considers the evidence of an intrathecal immunoglobulin (IgG) synthesis as a diagnostic criterion for dissemination in time in multiple sclerosis. While the detection of oligoclonal bands is considered as the gold standard, determination of kappa free light chains might be a promising tool as a less technically demanding and cost saving method. However, data on the direct comparison between kappa free light chains and oligoclonal bands are limited and no study to date has used the highly sensitive method of polyacrylamide gels with consecutive silver staining for the demonstration of oligoclonal bands. Furthermore, the impact of the revised McDonald criteria of 2017 on the role of kappa free light chains as a biomarker has not been investigated. Nephelometry was used to determine kappa free light chains in cerebrospinal fluid (CSF) and serum from 149 patients with their first demyelinating event between 2010 and 2015. Clinical data, kappa free light chains, and oligoclonal band status were compared at the time of initial diagnosis and after follow-up to identify converters from clinically isolated syndrome to multiple sclerosis. An elevated kappa free light chain index (>5.9) was found in 79/83 patients (95%) with multiple sclerosis diagnosed at baseline, slightly less frequent than oligoclonal bands (98.8%). 18/25 (72%) patients who converted from clinically isolated syndrome to multiple sclerosis showed an elevated kappa free light chain index compared to 20/25 (80%) patients with positive oligoclonal bands. In patients with stable clinically isolated syndrome 7/41 (17%) displayed an elevated kappa free light chain index against 11/41 (27%) oligoclonal band positive patients. Only two patients with stable clinically isolated syndrome showed an elevated kappa free light chain index but were oligoclonal bands negative. In conclusion, determination of the kappa free light chain index is a promising diagnostic approach to assess intrathecal immunoglobulin synthesis in multiple sclerosis. Nevertheless, oligoclonal bands are highly prevalent in multiple sclerosis and can detect an intrathecal synthesis of IgG even when the kappa free light chain index is below the threshold. We consider sequential use of both methods as reasonable. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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18 pages, 2461 KiB  
Article
Investigating the Role of MicroRNA and Transcription Factor Co-regulatory Networks in Multiple Sclerosis Pathogenesis
by Nicoletta Nuzziello, Laura Vilardo, Paride Pelucchi, Arianna Consiglio, Sabino Liuni, Maria Trojano and Maria Liguori
Int. J. Mol. Sci. 2018, 19(11), 3652; https://doi.org/10.3390/ijms19113652 - 20 Nov 2018
Cited by 39 | Viewed by 5147
Abstract
MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a cohort of pediatric MS (PedMS) patients, we applied a combined molecular and computational approach in order to [...] Read more.
MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a cohort of pediatric MS (PedMS) patients, we applied a combined molecular and computational approach in order to verify published data in patients with adult-onset MS (AOMS). Six out of the 13 selected miRNAs (miR-320a, miR-125a-5p, miR-652-3p, miR-185-5p, miR-942-5p, miR-25-3p) were significantly upregulated in PedMS and AOMS patients, suggesting that they may be considered circulating biomarkers distinctive of the disease independently from age. A computational and unbiased miRNA-based screening of target genes not necessarily associated to MS was then performed in order to provide an extensive view of the genetic mechanisms underlying the disease. A comprehensive MS-specific miRNA-TF co-regulatory network was hypothesized; among others, SP1, RELA, NF-κB, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Interestingly, NF-κB and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflammatory and immune cells. Further functional analysis will be performed on the identified critical hubs. Above all, in our view, this approach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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17 pages, 3882 KiB  
Article
Endothelial Microsomal Prostaglandin E Synthetase-1 Upregulates Vascularity and Endothelial Interleukin-1β in Deteriorative Progression of Experimental Autoimmune Encephalomyelitis
by Takako Takemiya, Marumi Kawakami and Chisen Takeuchi
Int. J. Mol. Sci. 2018, 19(11), 3647; https://doi.org/10.3390/ijms19113647 - 19 Nov 2018
Cited by 2 | Viewed by 3565
Abstract
Microsomal prostaglandin E synthetase-1 (mPGES-1) is an inducible terminal enzyme for the production of prostaglandin E2 (PGE2). In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, mPGES-1 is induced in vascular endothelial cells (VECs) around inflammatory foci and [...] Read more.
Microsomal prostaglandin E synthetase-1 (mPGES-1) is an inducible terminal enzyme for the production of prostaglandin E2 (PGE2). In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, mPGES-1 is induced in vascular endothelial cells (VECs) around inflammatory foci and facilitates inflammation, demyelination, and paralysis. Therefore, we investigated the role of CD31-positive VECs in mPGES-1-mediated EAE aggravation using immunohistochemical analysis and imaging of wild-type (wt) and mPGES-1-deficient (mPGES-1−/−) mice. We demonstrated that EAE induction facilitated vascularity in inflammatory lesions in the spinal cord, and this was significantly higher in wt mice than in mPGES-1−/− mice. In addition, endothelial interleukin-1β (IL-1β) production was significantly higher in wt mice than in mPGES-1−/− mice. Moreover, endothelial PGE2 receptors (E-prostanoid (EP) receptors EP1–4) were expressed after EAE induction, and IL-1β was induced in EP receptor-positive VECs. Furthermore, IL-1 receptor 1 expression on VECs was increased upon EAE induction. Thus, increased vascularity is one mechanism involved in EAE aggravation induced by mPGES-1. Furthermore, mPGES-1 facilitated the autocrine function of VECs upon EP receptor induction and IL-1β production, modulating mPGES-1 induction in EAE. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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Review

Jump to: Research

25 pages, 705 KiB  
Review
Exploiting the Therapeutic Potential of Endogenous Immunomodulatory Systems in Multiple Sclerosis—Special Focus on the Peroxisome Proliferator-Activated Receptors (PPARs) and the Kynurenines
by Bernadett Fakan, Levente Szalardy and Laszlo Vecsei
Int. J. Mol. Sci. 2019, 20(2), 426; https://doi.org/10.3390/ijms20020426 - 19 Jan 2019
Cited by 18 | Viewed by 4664
Abstract
Multiple sclerosis (MS) is a progressive neurodegenerative disease, characterized by autoimmune central nervous system (CNS) demyelination attributable to a disturbed balance between encephalitic T helper 1 (Th1) and T helper 17 (Th17) and immunomodulatory regulatory T cell (Treg) and T helper 2 (Th2) [...] Read more.
Multiple sclerosis (MS) is a progressive neurodegenerative disease, characterized by autoimmune central nervous system (CNS) demyelination attributable to a disturbed balance between encephalitic T helper 1 (Th1) and T helper 17 (Th17) and immunomodulatory regulatory T cell (Treg) and T helper 2 (Th2) cells, and an alternatively activated macrophage (M2) excess. Endogenous molecular systems regulating these inflammatory processes have recently been investigated to identify molecules that can potentially influence the course of the disease. These include the peroxisome proliferator-activated receptors (PPARs), PPARγ coactivator-1alpha (PGC-1α), and kynurenine pathway metabolites. Although all PPARs ameliorate experimental autoimmune encephalomyelitis (EAE), recent evidence suggests that PPARα, PPARβ/δ agonists have less pronounced immunomodulatory effects and, along with PGC-1α, are not biomarkers of neuroinflammation in contrast to PPARγ. Small clinical trials with PPARγ agonists have been published with positive results. Proposed as immunomodulatory and neuroprotective, the therapeutic use of PGC-1α activation needs to be assessed in EAE/MS. The activation of indolamine 2,3-dioxygenase (IDO), the rate-limiting step of the kynurenine pathway of tryptophan (Trp) metabolism, plays crucial immunomodulatory roles. Indeed, Trp metabolites have therapeutic relevance in EAE and drugs with structural analogy to kynurenines, such as teriflunomide, are already approved for MS. Further studies are required to gain deeper knowledge of such endogenous immunomodulatory pathways with potential therapeutic implications in MS. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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16 pages, 2698 KiB  
Review
The Interaction between Viral and Environmental Risk Factors in the Pathogenesis of Multiple Sclerosis
by Rachael Eugenie Tarlinton, Timur Khaibullin, Evgenii Granatov, Ekaterina Martynova, Albert Rizvanov and Svetlana Khaiboullina
Int. J. Mol. Sci. 2019, 20(2), 303; https://doi.org/10.3390/ijms20020303 - 14 Jan 2019
Cited by 37 | Viewed by 9858
Abstract
Multiple sclerosis (MS) is a chronic debilitating inflammatory disease of unknown ethology targeting the central nervous system (CNS). MS has a polysymptomatic onset and is usually first diagnosed between the ages of 20–40 years. The pathology of the disease is characterized by immune [...] Read more.
Multiple sclerosis (MS) is a chronic debilitating inflammatory disease of unknown ethology targeting the central nervous system (CNS). MS has a polysymptomatic onset and is usually first diagnosed between the ages of 20–40 years. The pathology of the disease is characterized by immune mediated demyelination in the CNS. Although there is no clinical finding unique to MS, characteristic symptoms include sensory symptoms visual and motor impairment. No definitive trigger for the development of MS has been identified but large-scale population studies have described several epidemiological risk factors for the disease. This list is a confusing one including latitude, vitamin D (vitD) levels, genetics, infection with Epstein Barr Virus (EBV) and endogenous retrovirus (ERV) reactivation. This review will look at the evidence for each of these and the potential links between these disparate risk factors and the known molecular disease pathogenesis to describe potential hypotheses for the triggering of MS pathology. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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13 pages, 597 KiB  
Review
Vitamin D Supplementation in Central Nervous System Demyelinating Disease—Enough Is Enough
by Darius Häusler and Martin S. Weber
Int. J. Mol. Sci. 2019, 20(1), 218; https://doi.org/10.3390/ijms20010218 - 08 Jan 2019
Cited by 23 | Viewed by 7120
Abstract
The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual’s risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors [...] Read more.
The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual’s risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors are now established that influence MS, which is of enormous interest, as some of these contributing factors are relatively easy to change. In this regard, a low vitamin D status is associated with an elevated relapse frequency and worsened disease course in patients with MS. The most important question, however, is whether this association is causal or related. That supplementing vitamin D in MS is of direct therapeutic benefit, is still a matter of debate. In this manuscript, we first review the potentially immune modulating mechanisms of vitamin D, followed by a summary of current and ongoing clinical trials intended to assess whether vitamin D supplementation positively influences the outcome of MS. Furthermore, we provide emerging evidence that excessive vitamin D treatment via the T cell-stimulating effect of secondary hypercalcemia, could have negative effects in CNS demyelinating disease. This jointly merges into the balancing concept of a therapeutic window of vitamin D in MS. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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23 pages, 569 KiB  
Review
Interferon β-Mediated Protective Functions of Microglia in Central Nervous System Autoimmunity
by Stefanie Scheu, Shafaqat Ali, Ritu Mann-Nüttel, Lisa Richter, Volker Arolt, Udo Dannlowski, Tanja Kuhlmann, Luisa Klotz and Judith Alferink
Int. J. Mol. Sci. 2019, 20(1), 190; https://doi.org/10.3390/ijms20010190 - 07 Jan 2019
Cited by 23 | Viewed by 6419
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and axonal damage. It often affects young adults and can lead to neurological disability. Interferon β (IFNβ) preparations represent widely used treatment regimens for patients with [...] Read more.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and axonal damage. It often affects young adults and can lead to neurological disability. Interferon β (IFNβ) preparations represent widely used treatment regimens for patients with relapsing-remitting MS (RRMS) with therapeutic efficacy in reducing disease progression and frequency of acute exacerbations. In mice, IFNβ therapy has been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS while genetic deletion of IFNβ or its receptor augments clinical severity of disease. However, the complex mechanism of action of IFNβ in CNS autoimmunity has not been fully elucidated. Here, we review our current understanding of the origin, phenotype, and function of microglia and CNS immigrating macrophages in the pathogenesis of MS and EAE. In addition, we highlight the emerging roles of microglia as IFNβ-producing cells and vice versa the impact of IFNβ on microglia in CNS autoimmunity. We finally discuss recent progress in unraveling the underlying molecular mechanisms of IFNβ-mediated effects in EAE. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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17 pages, 530 KiB  
Review
Emerging Role of Follicular T Helper Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis
by James L. Quinn and Robert C. Axtell
Int. J. Mol. Sci. 2018, 19(10), 3233; https://doi.org/10.3390/ijms19103233 - 19 Oct 2018
Cited by 20 | Viewed by 6493
Abstract
Multiple sclerosis (MS) is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse [...] Read more.
Multiple sclerosis (MS) is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse models that Th17, B cells, and follicular T helper (TFH) cells contribute to disease. This review article describes the literature that identifies mechanisms by which Th17, TFH, and B cells cooperatively drive disease activity in MS and experimental autoimmune encephalomyelitis (EAE). The curation of this literature has identified that central nervous system (CNS) infiltrating TFH cells act with TH17 cell to contribute to an inflammatory B cell response in neuroinflammation. This demonstrates that TFH cells and their products are promising targets for therapies in MS. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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