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New Advances and Challenges in Multiple Sclerosis: Pathophysiology and Therapeutic...
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New Advances and Challenges in Multiple Sclerosis: Pathophysiology and Therapeutic Strategies

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 30558

Special Issue Editor

Dr. Diego Clemente

E-Mail Website
Guest Editor
Neuroimmuno-Repair Group, National Hospital for Paraplegics, Toledo, Spain
Interests: multiple sclerosis; biomarkers; remyelination; immunoregulatory cells

Special Issue Information

Dear Colleagues,

Multiple sclerosis (MS) is the most common neurological disease, being especially dramatic for debuting mainly in young adults and for not having a cure. The treatments available to date address the immune component of the disease, are mostly effective in the relapsing-remitting MS (RR-MS) variant, and are almost totally ineffective in the progressive forms of MS. Therefore, the search for molecular/cellular factors capable of differentiating at the pathophysiological level the intrinsic reasons for these differences, is of vital importance in the search for new treatments for people with MS. On the other hand, the existence of recovery phases in RRMS patients points to the existence of spontaneous self-correcting phenomena of the inflammatory episode that lead to neuro-repair of the damaged tissue. Although significant advances have been made in the treatment and management of MS, there are still many open questions coming from the neuroscientific but also the immunological side of the disease, the answers to which would open the door to new therapeutic strategies to improve the quality of life of people with MS. The aim of this Special Issue of Biomedicines is to provide an overview of the pathophysiologic role of newer and older molecular mechanisms of MS together with the presentation of insights for the consecution of new therapeutic strategies. Moreover, it will focus on biomarkers to help in the accurate disease monitoring. Both original articles and reviews will be considered for publication in this Special Issue.

Dr. Diego Clemente
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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • Therapy
  • immune system
  • nervous system
  • myelin
  • remyelination
  • biomarker
  • T cells
  • oligodendrocytes
  • histopathology
  • B cells
  • immunoregulation

Published Papers (7 papers)

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Research

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24 pages, 11140 KiB  
Article
Comparative Profiling of TG2 and Its Effectors in Human Relapsing Remitting and Progressive Multiple Sclerosis
by Damien D. Pearse, Andrew B. Hefley, Alejo A. Morales and Mousumi Ghosh
Biomedicines 2022, 10(6), 1241; https://doi.org/10.3390/biomedicines10061241 - 26 May 2022
Cited by 4 | Viewed by 1842
Abstract
Multiple Sclerosis (MS) is a chronic CNS autoimmune disease characterized by immune-mediated demyelination, axon loss, and disability. Dysregulation of transglutaminase-2 (TG2) has been implicated in disease initiation and progression. Herein, TG2 expression in post-mortem human brain tissue from Relapsing Remitting MS (RRMS) or [...] Read more.
Multiple Sclerosis (MS) is a chronic CNS autoimmune disease characterized by immune-mediated demyelination, axon loss, and disability. Dysregulation of transglutaminase-2 (TG2) has been implicated in disease initiation and progression. Herein, TG2 expression in post-mortem human brain tissue from Relapsing Remitting MS (RRMS) or Progressive MS (PMS) individuals were examined and correlated with the presence of TG2 binding partners and effectors implicated in the processes of inflammation, scar formation, and the antagonism of repair. Tissues from Relapsing-Remitting Multiple Sclerosis (RRMS; n = 6), Progressive Multiple Sclerosis (PMS; n = 5), and non-MS control (n = 6) patients underwent immunohistochemistry for TG2, PLA2, COX-2, FN, CSPG, and HSPG. TG2 was strongly upregulated in active RRMS and PMS lesions, within blood vessels and the perivascular tissue of sclerotic plaques. TG2 colocalization was observed with GFAP+ astrocytes and ECM, including FN, HSPG, and CSPG, which also increased in either RRMS or PMS lesions. Although TG2 was not colocalized with inflammatory mediators COX-2 and PLA2, or the macrophage-microglia marker Iba1, its increased expression correlated with their elevation in active RRMS and PMS lesions. In summary, the correlation of strong TG2 induction in either RRMS or PMS with some of its binding partners but not others implicates potentially different roles for TG2 in disparate MS forms that may warrant further investigation. Full article
(This article belongs to the Special Issue New Advances and Challenges in Multiple Sclerosis: Pathophysiology and Therapeutic Strategies)
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11 pages, 1402 KiB  
Article
Epstein-Barr Virus Load Correlates with Multiple Sclerosis-Associated Retrovirus Envelope Expression
by Silvia Pérez-Pérez, María Inmaculada Domínguez-Mozo, María Ángel García-Martínez, Rubén Ballester-González, Israel Nieto-Gañán, Rafael Arroyo and Roberto Alvarez-Lafuente
Biomedicines 2022, 10(2), 387; https://doi.org/10.3390/biomedicines10020387 - 05 Feb 2022
Cited by 7 | Viewed by 2522
Abstract
pHERV-W ENV and syncytin-1, the envelope proteins of the human endogenous retrovirus W family (HERV-W), have been proposed as etiological factors for MS development. In addition, herpesviruses, such as the Epstein-Barr virus (EBV) and the human herpesvirus 6A/B (HHV-6A/B), have been also strongly [...] Read more.
pHERV-W ENV and syncytin-1, the envelope proteins of the human endogenous retrovirus W family (HERV-W), have been proposed as etiological factors for MS development. In addition, herpesviruses, such as the Epstein-Barr virus (EBV) and the human herpesvirus 6A/B (HHV-6A/B), have been also strongly associated with the disease. This work aims to study the possible link between viral loads and antibody titers against EBV and HHV-6A/B and the pHERV-W ENV/syncytin-1 protein/gene expression. For this purpose, we conducted a 12-month longitudinal study involving 98 RRMS patients. Peripheral blood samples were obtained from each patient. Serum antibody titers against EBV and HHV-6A/B were determined by ELISA, while viral loads were analyzed using qPCR. HLA MS-related alleles were also genotyped. pHERV-W ENV/syncytin-1 protein and gene expression levels in immune cells were assessed by flow cytometry and qPCR, respectively. We found that the 12-month variation of the pHERV-W ENV gene expression levels positively correlated with the variation of the EBV viral load, especially in those patients with high baseline EBV loads. Therefore, these results could support previous studies pointing to the transactivation of pHERV-W ENV by EBV. However, further studies are needed to better understand this possible relationship. Full article
(This article belongs to the Special Issue New Advances and Challenges in Multiple Sclerosis: Pathophysiology and Therapeutic Strategies)
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12 pages, 1000 KiB  
Article
Are Neurophysiological Biomarkers Able to Discriminate Multiple Sclerosis Clinical Subtypes?
by Daniele Belvisi, Matteo Tartaglia, Giovanna Borriello, Viola Baione, Sebastiano Giuseppe Crisafulli, Valeria Zuccoli, Giorgio Leodori, Antonio Ianniello, Gabriele Pasqua, Patrizia Pantano, Alfredo Berardelli, Carlo Pozzilli and Antonella Conte
Biomedicines 2022, 10(2), 231; https://doi.org/10.3390/biomedicines10020231 - 21 Jan 2022
Cited by 4 | Viewed by 2332
Abstract
Secondary progressive multiple sclerosis (SPMS) subtype is retrospectively diagnosed, and biomarkers of the SPMS are not available. We aimed to identify possible neurophysiological markers exploring grey matter structures that could be used in clinical practice to better identify SPMS. Fifty-five people with MS [...] Read more.
Secondary progressive multiple sclerosis (SPMS) subtype is retrospectively diagnosed, and biomarkers of the SPMS are not available. We aimed to identify possible neurophysiological markers exploring grey matter structures that could be used in clinical practice to better identify SPMS. Fifty-five people with MS and 31 healthy controls underwent a transcranial magnetic stimulation protocol to test intracortical interneuron excitability in the primary motor cortex and somatosensory temporal discrimination threshold (STDT) to test sensory function encoded in cortical and deep grey matter nuclei. A logistic regression model was used to identify a combined neurophysiological index associated with the SP subtype. We observed that short intracortical inhibition (SICI) and STDT were the only variables that differentiated the RR from the SP subtype. The logistic regression model provided a formula to compute the probability of a subject being assigned to an SP subtype based on age and combined SICI and STDT values. While only STDT correlated with disability level at baseline evaluation, both SICI and STDT were associated with disability at follow-up. SICI and STDT abnormalities reflect age-dependent grey matter neurodegenerative processes that likely play a role in SPMS pathophysiology and may represent easily accessible neurophysiological biomarkers for the SPMS subtype. Full article
(This article belongs to the Special Issue New Advances and Challenges in Multiple Sclerosis: Pathophysiology and Therapeutic Strategies)
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19 pages, 26657 KiB  
Article
Profiling of Plasma Extracellular Vesicle Transcriptome Reveals That circRNAs Are Prevalent and Differ between Multiple Sclerosis Patients and Healthy Controls
by Leire Iparraguirre, Ainhoa Alberro, Thomas B. Hansen, Tamara Castillo-Triviño, Maider Muñoz-Culla and David Otaegui
Biomedicines 2021, 9(12), 1850; https://doi.org/10.3390/biomedicines9121850 - 07 Dec 2021
Cited by 12 | Viewed by 2475
Abstract
(1) Background: Extracellular vesicles (EVs) are released by most cell types and are implicated in several biological and pathological processes, including multiple sclerosis (MS). Differences in the number and cargo of plasma-derived EVs have been described in MS. In this work, we have [...] Read more.
(1) Background: Extracellular vesicles (EVs) are released by most cell types and are implicated in several biological and pathological processes, including multiple sclerosis (MS). Differences in the number and cargo of plasma-derived EVs have been described in MS. In this work, we have characterised the EV RNA cargo of MS patients, with particular attention to circular RNAs (circRNAs), which have attracted increasing attention for their roles in physiology and disease and their biomarker potential. (2) Methods: Plasma-derived EVs were isolated by differential centrifugation (20 patients, 8 controls), and RNA-Sequencing was used to identify differentially expressed linear and circRNAs. (3) Results: We found differences in the RNA type distribution, circRNAs being enriched in EVs vs. leucocytes. We found a number of (corrected p-value < 0.05) circRNA significantly DE between the groups. Nevertheless, highly structured circRNAs are preferentially retained in leukocytes. Differential expression analysis reports significant differences in circRNA and linear RNA expression between MS patients and controls, as well as between different MS types. (4) Conclusions: Plasma derived EV RNA cargo is not a representation of leukocytes’ cytoplasm but a message worth studying. Moreover, our results reveal the interest of circRNAs as part of this message, highlighting the importance of further understanding RNA regulation in MS. Full article
(This article belongs to the Special Issue New Advances and Challenges in Multiple Sclerosis: Pathophysiology and Therapeutic Strategies)
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9 pages, 1459 KiB  
Article
Pre-Existing Humoral Immunological Memory Is Retained in Patients with Multiple Sclerosis Receiving Cladribine Therapy
by Tobias Moser, Ciara O’Sullivan, Christian Puttinger, Julia Feige, Georg Pilz, Elisabeth Haschke-Becher, Janne Cadamuro, Hannes Oberkofler, Wolfgang Hitzl, Andrea Harrer, Jörg Kraus, Eugen Trinka and Peter Wipfler
Biomedicines 2021, 9(11), 1584; https://doi.org/10.3390/biomedicines9111584 - 31 Oct 2021
Cited by 6 | Viewed by 2174
Abstract
Cladribine (CLAD) is a lymphodepleting agent approved for active relapsing multiple sclerosis (MS). The impact of CLAD on the adaptive humoral immune system has not sufficiently been studied. This study aimed to assess the influence of CLAD treatment on specific antibody titers to [...] Read more.
Cladribine (CLAD) is a lymphodepleting agent approved for active relapsing multiple sclerosis (MS). The impact of CLAD on the adaptive humoral immune system has not sufficiently been studied. This study aimed to assess the influence of CLAD treatment on specific antibody titers to common pathogens. We included 18 MS patients treated with CLAD. Serum IgG antibody levels to measles, mumps, rubella, hepatitis B and varicella zoster virus (VZV), as well as diphtheria and tetanus toxins, were measured prior to the initiation of treatment and at 12 and 24 months after first CLAD administration. Moreover, specimens were longitudinally analyzed regarding absolute blood concentrations of IgG and main lymphocyte subsets. No reduction in antibody levels against measles, mumps, rubella, VZV, hepatitis B, diphtheria toxin and tetanus toxin associated with CLAD treatment was observed. Loss of seroprotection occurred in <1%. We found no significant impact of CLAD on absolute serum IgG levels. Absolute lymphocyte counts were significantly reduced at the end of each treatment year (p < 0.00001 and p < 0.000001). This study suggests that CLAD does not interfere with the pre-existing humoral immunologic memory in terms of pathogen-specific antibody titers. Full article
(This article belongs to the Special Issue New Advances and Challenges in Multiple Sclerosis: Pathophysiology and Therapeutic Strategies)
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Review

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26 pages, 2568 KiB  
Review
Regulatory Cells in Multiple Sclerosis: From Blood to Brain
by Leticia Calahorra, Celia Camacho-Toledano, Mari Paz Serrano-Regal, María Cristina Ortega and Diego Clemente
Biomedicines 2022, 10(2), 335; https://doi.org/10.3390/biomedicines10020335 - 01 Feb 2022
Cited by 24 | Viewed by 5129
Abstract
Multiple sclerosis (MS) is a chronic, autoimmune, and neurodegenerative disease of the central nervous system (CNS) that affects myelin. The etiology of MS is unclear, although a variety of environmental and genetic factors are thought to increase the risk of developing the disease. [...] Read more.
Multiple sclerosis (MS) is a chronic, autoimmune, and neurodegenerative disease of the central nervous system (CNS) that affects myelin. The etiology of MS is unclear, although a variety of environmental and genetic factors are thought to increase the risk of developing the disease. Historically, T cells were considered to be the orchestrators of MS pathogenesis, but evidence has since accumulated implicating B lymphocytes and innate immune cells in the inflammation, demyelination, and axonal damage associated with MS disease progression. However, more recently the importance of the protective role of immunoregulatory cells in MS has become increasingly evident, such as that of myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) and B (Breg) cells, or CD56bright natural killer cells. In this review, we will focus on how peripheral regulatory cells implicated in innate and adaptive immune responses are involved in the physiopathology of MS. Moreover, we will discuss how these cells are thought to act and contribute to MS histopathology, also addressing their promising role as promoters of successful remyelination within the CNS. Finally, we will analyze how understanding these protective mechanisms may be crucial in the search for potential therapies for MS. Full article
(This article belongs to the Special Issue New Advances and Challenges in Multiple Sclerosis: Pathophysiology and Therapeutic Strategies)
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Other

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32 pages, 1571 KiB  
Systematic Review
Neurological Benefits, Clinical Challenges, and Neuropathologic Promise of Medical Marijuana: A Systematic Review of Cannabinoid Effects in Multiple Sclerosis and Experimental Models of Demyelination
by Victor Longoria, Hannah Parcel, Bameelia Toma, Annu Minhas and Rana Zeine
Biomedicines 2022, 10(3), 539; https://doi.org/10.3390/biomedicines10030539 - 24 Feb 2022
Cited by 18 | Viewed by 12629
Abstract
Despite current therapeutic strategies for immunomodulation and relief of symptoms in multiple sclerosis (MS), remyelination falls short due to dynamic neuropathologic deterioration and relapses, leading to accrual of disability and associated patient dissatisfaction. The potential of cannabinoids includes add-on immunosuppressive, analgesic, neuroprotective, and [...] Read more.
Despite current therapeutic strategies for immunomodulation and relief of symptoms in multiple sclerosis (MS), remyelination falls short due to dynamic neuropathologic deterioration and relapses, leading to accrual of disability and associated patient dissatisfaction. The potential of cannabinoids includes add-on immunosuppressive, analgesic, neuroprotective, and remyelinative effects. This study evaluates the efficacy of medical marijuana in MS and its experimental animal models. A systematic review was conducted by a literature search through PubMed, ProQuest, and EBSCO electronic databases for studies reported since 2007 on the use of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) in MS and in experimental autoimmune encephalomyelitis (EAE), Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), and toxin-induced demyelination models. Study selection and data extraction were performed by 3 reviewers, and 28 studies were selected for inclusion. The certainty of evidence was appraised using the Cochrane GRADE approach. In clinical studies, there was low- and moderate-quality evidence that treatment with ~1:1 CBD/THC mixtures as a nabiximols (Sativex®) oromucosal spray reduced numerical rating scale (NRS) scores for spasticity, pain, and sleep disturbance, diminished bladder overactivity, and decreased proinflammatory cytokine and transcription factor expression levels. Preclinical studies demonstrated decreases in disease severity, hindlimb stiffness, motor function, neuroinflammation, and demyelination. Other experimental systems showed the capacity of cannabinoids to promote remyelination in vitro and by electron microscopy. Modest short-term benefits were realized in MS responders to adjunctive therapy with CBD/THC mixtures. Future studies are recommended to investigate the cellular and molecular mechanisms of cannabinoid effects on MS lesions and to evaluate whether medical marijuana can accelerate remyelination and retard the accrual of disability over the long term. Full article
(This article belongs to the Special Issue New Advances and Challenges in Multiple Sclerosis: Pathophysiology and Therapeutic Strategies)
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