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Recent Progress in Multiple Sclerosis 2.0
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Recent Progress in Multiple Sclerosis 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (25 July 2023) | Viewed by 12521

Special Issue Editors

Prof. Dr. Arnon Karni

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Guest Editor
Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo 6423906, Israel
Interests: multiple sclerosis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Friedemann Paul

E-Mail Website
Guest Editor
Clinical and Experimental Multiple Sclerosis Research Center, Charité—Universitätsmedizin Berlin, D-10117 Berlin, Germany
Interests: multiple sclerosis and neuromyelitis optica; neuroimaging; retinal optical coherence tomography; neuroprotection; dietary modulation of neuroinflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multiple sclerosis is the most common disease that leads to neurological disability in young people. Despite the advances over the years in understanding the disease, more knowledge is needed about the specific mechanisms of the relapses versus progression independent of relapses, the immediate damage caused by the formation of a new lesion and the secondary damage induced over time due to the demyelination and axonal damage. Inflammatory activity is, on the one hand, harmful but may also be protective. The various approaches to inducing the repair of the damage caused and the development of various imaging and molecular paraclinical biomarkers that demonstrate different aspects of disease activity and progression and the degree of response to treatment are worthy of study. All of these and more represent a broad and intensive field of research that will expand our understanding of the disease and lead to exciting discoveries.

The objective of this Special Issue, “Recent Progress in Multiple Sclerosis”, is to describe and bring together the most recent research conducted in the fields of the pathophysiology, of various biomarkers, and the treatment and repair of multiple sclerosis.

Prof. Dr. Arnon Karni
Prof. Dr. Friedemann Paul 
Guest Editors

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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.

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Keywords

  • multiple sclerosis
  • immune pathophysiology
  • remyelination and repair
  • molecular biomarker
  • imaging
  • disease monitoring
  • modifiable environmental factors
  • neuroprotection

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Published Papers (6 papers)

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Research

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9 pages, 274 KiB  
Article
Genetic Variant HLA-DRB1*0403 and Therapeutic Response to Disease-Modifying Therapies in Multiple Sclerosis: A Case-Control Study
by Esteban Alejandro Gomez-Gaitan, Yessica Eleanet Garcia-Ortega, Ana Miriam Saldaña-Cruz, Betsabe Contreras-Haro, Jorge Ivan Gamez-Nava, Emilio Edsaul Perez-Guerrero, Cesar Arturo Nava-Valdivia, Sergio Gallardo-Moya, Alejandra Martinez-Hernandez, Laura Gonzalez Lopez, Blanca Esthela Rios-Gonzalez, Jazmin Marquez-Pedroza, Miriam Mendez-del Villar, Yussef Esparza-Guerrero, Alejandra Villagomez-Vega and Miguel Angel Macias Islas
Int. J. Mol. Sci. 2023, 24(19), 14594; https://doi.org/10.3390/ijms241914594 - 27 Sep 2023
Cited by 3 | Viewed by 1325
Abstract
Multiple sclerosis (MS) is a chronic and demyelinating disease with an autoimmune origin, which leads to neurodegeneration and progressive disability. Approximately 30 to 50% of patients do not respond optimally to disease-modifying therapies (DMTs), and therapeutic response may be influenced by genetic factors [...] Read more.
Multiple sclerosis (MS) is a chronic and demyelinating disease with an autoimmune origin, which leads to neurodegeneration and progressive disability. Approximately 30 to 50% of patients do not respond optimally to disease-modifying therapies (DMTs), and therapeutic response may be influenced by genetic factors such as genetic variants. Therefore, our study aimed to investigate the association of the HLA-DRB1*0403 genetic variant and therapeutic response to DMTs in MS. We included 105 patients with MS diagnosis. No evidence of disease activity based on the absence of clinical relapse, disability progression or radiological activity (NEDA-3) was used to classify the therapeutic response. Patients were classified as follows: (a) controls: patients who achieved NEDA-3; (b) cases: patients who did not achieve NEDA-3. DNA was extracted from peripheral blood leukocytes. HLA-DRB1*0403 genetic variant was analyzed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. NEDA-3 was achieved in 86.7% of MS patients treated with DMTs. Genotype frequencies were GG 50.5%, GA 34.3%, and AA 15.2%. No differences were observed in the genetic variant AA between patients who achieved NEDA-3 versus patients who did not achieve NEDA-3 (48.7% vs. 43.1%, p = 0.6). We concluded that in Mexican patients with MS, HLA-DRB1*0403 was not associated with the therapeutic response to DMTs. Full article
(This article belongs to the Special Issue Recent Progress in Multiple Sclerosis 2.0)
14 pages, 1097 KiB  
Article
Vitamin D Receptor Gene Polymorphism Predicts the Outcome of Multidisciplinary Rehabilitation in Multiple Sclerosis Patients
by Franca Rosa Guerini, Cristina Agliardi, Letizia Oreni, Elisabetta Groppo, Elisabetta Bolognesi, Milena Zanzottera, Domenico Caputo, Marco Rovaris and Mario Clerici
Int. J. Mol. Sci. 2023, 24(17), 13379; https://doi.org/10.3390/ijms241713379 - 29 Aug 2023
Cited by 4 | Viewed by 1332
Abstract
Better knowledge about the possible role of genetic factors in modulating the response to multiple sclerosis (MS) treatment, including rehabilitation, known to promote neural plasticity, could improve the standard of care for this disease. Vitamin D receptor (VDR) gene polymorphisms are [...] Read more.
Better knowledge about the possible role of genetic factors in modulating the response to multiple sclerosis (MS) treatment, including rehabilitation, known to promote neural plasticity, could improve the standard of care for this disease. Vitamin D receptor (VDR) gene polymorphisms are associated with MS risk, probably because of the role played by vitamin D in regulating inflammatory and reparative processes. The aim of this study was to evaluate the association of the most important functional VDR SNPs (TaqI (T/C), ApaI (A/C), and FokI (C/T)) with functional outcome in MS patients undergoing multidisciplinary inpatient rehabilitation (MDR) treatment, in order to determine whether genetic profiling might be useful to identify subjects with a higher chance of recovery. To this end, 249 MS inpatients with a diagnosis of either progressive (pMS; n = 155) or relapsing remitting (RRMS; n = 94) disease who underwent MDR treatment (average duration = 5.1 weeks) were genotyped for VDR SNPs by real-time allelic discrimination. The rehabilitation outcome was assessed using the modified Barthel Index (mBI), Expanded Disability Status Scale (EDSS), and pain numerical rating scores (NRS) at the beginning and the end of MDR treatment. A positive correlation was observed in RRMS patients between the VDR TaqI major allele (TT) and mBI increase (i.e., better functional recovery), as assessed by the linear and logistic regression analysis adjusted for gender, age, disease duration, time of hospitalization, HLA-DRB1*15.01 positivity, and number of rehabilitative interventions (Beta = 6.35; p = 0.0002). The VDR-1 TaqI, ApaI, FokI: TCC haplotype was also associated with mBI increase in RRMS patients (Beta = 3.24; p = 0.007), whereas the VDR-2: CAC haplotype was correlated with a lower mBI increase (Beta = −2.18 p = 0.04) compared with the other haplotypes. VDR TaqI major allele (TT), as well as the VDR-1 TaqI, ApaI, FokI: TCC haplotype could be associated with a better rehabilitation outcome in RRMS patients. Full article
(This article belongs to the Special Issue Recent Progress in Multiple Sclerosis 2.0)
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11 pages, 1053 KiB  
Article
Inner Retinal Layer Changes Reflect Changes in Ambulation Score in Patients with Primary Progressive Multiple Sclerosis
by Jonathan A. Gernert, Luise Böhm, Michaela Starck, Stefan Buchka, Tania Kümpfel, Ingo Kleiter and Joachim Havla
Int. J. Mol. Sci. 2023, 24(16), 12872; https://doi.org/10.3390/ijms241612872 - 17 Aug 2023
Cited by 3 | Viewed by 1272
Abstract
The establishment of surrogate markers to detect disability progression in persons with multiple sclerosis (PwMS) is important to improve monitoring of clinical deterioration. Optical coherence tomography (OCT) could be such a tool. However, sufficient longitudinal data of retinal neuroaxonal degeneration as a marker [...] Read more.
The establishment of surrogate markers to detect disability progression in persons with multiple sclerosis (PwMS) is important to improve monitoring of clinical deterioration. Optical coherence tomography (OCT) could be such a tool. However, sufficient longitudinal data of retinal neuroaxonal degeneration as a marker of disease progression exist only for PwMS with a relapsing–remitting course (RRMS) so far. In contrast, longitudinal data of retinal layers in patients with primary-progressive MS (PPMS) are inconsistent, and the association of OCT parameters with ambulatory performance in PwMS has rarely been investigated. We aimed to investigate the relative annual rates of change in retinal layers in PwMS (RRMS and PPMS) compared with healthy controls (HC) using OCT and to evaluate their association with ambulatoryfunctionalscore (AS) worsening in PPMS. A retrospective analysis of a longitudinal OCT dataset of the retinal layers of PwMS and HC from two MS centers in Germany was performed. Walking ability was measured over a standardized distance of 500 m, and changes during the observation period were categorized using the AS and the expanded disability status scale (EDSS). 61 HC with 121 eyes and 119 PwMS (PPMS: 57 patients with 108 eyes; RRMS: 62 patients with 114 eyes) were included. The median follow-up time for PwMS was 3 years. The relative annual change of pRNFL (peripapillary retinal nerve fiber layer) and INL (inner nuclear layer) was significantly different in PwMS compared with HC. RRMS and PPMS subgroups did not differ in the annual atrophy rates. In patients with PPMS, worsening of the AS was significantly associated with increased thinning of the TMV (total macular volume), GCIP (ganglion cell and inner plexiform layer), and ONPL (outer nuclear and outer plexiform layer) (all p-value < 0.05, r > 0.30). For every −0.1% decrease in the TMV, GCIP, and ONPL, the risk of a deterioration in the AS increased by 31% (hazard ratio (HR): 1.309), 11% (HR: 1.112), and 16% (HR: 1.161), respectively. In addition, worsening EDSS in PPMS was significantly associated with the relative annual atrophy rates of pRNFL, TMV, and GCIP (all p-value < 0.05). Disability progression in PPMS can be measured using OCT, and increasing annual atrophy rates of the inner retinal layers are associated with worsening ambulation. OCT is a robust and side-effect-free imaging tool, making it suitable for routine monitoring of PwMS. Full article
(This article belongs to the Special Issue Recent Progress in Multiple Sclerosis 2.0)
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21 pages, 26127 KiB  
Article
Involvement of Degenerating 21.5 kDa Isoform of Myelin Basic Protein in the Pathogenesis of the Relapse in Murine Relapsing–Remitting Experimental Autoimmune Encephalomyelitis and MS Autopsied Brain
by Chie Takano, Takuma Takano, Makoto Masumura, Ryuichi Nakamura, Shuichi Koda, Hiroki Bochimoto, Shigetaka Yoshida and Yoshio Bando
Int. J. Mol. Sci. 2023, 24(9), 8160; https://doi.org/10.3390/ijms24098160 - 2 May 2023
Cited by 4 | Viewed by 2561
Abstract
Multiple sclerosis (MS) is the chronic inflammatory demyelinating disease of the CNS. Relapsing–remitting MS (RRMS) is the most common type of MS. However, the mechanisms of relapse and remission in MS have not been fully understood. While SJL mice immunized with proteolipid protein [...] Read more.
Multiple sclerosis (MS) is the chronic inflammatory demyelinating disease of the CNS. Relapsing–remitting MS (RRMS) is the most common type of MS. However, the mechanisms of relapse and remission in MS have not been fully understood. While SJL mice immunized with proteolipid protein (PLP) develop relapsing–remitting experimental autoimmune encephalomyelitis (RR-EAE), we have recently observed that some of these mice were resistant to the active induction of relapsing EAE after initial clinical and histological symptoms of EAE with a severity similar to the relapsing EAE mice. To clarify the mechanism of relapsing, we examined myelin morphology during PLP139–151-induced RR-EAE in the SJL mice. While RR-EAE mice showed an increased EAE severity (relapse) with CNS inflammation, demyelination with abnormal myelin morphology in the spinal cord, the resistant mice exhibited a milder EAE phenotype with diminished relapse. Compared with the RR-EAE mice, the resistant mice showed less CNS inflammation, demyelination, and abnormalities of the myelin structure. In addition, scanning electron microscopic (SEM) analysis with the osmium-maceration method displayed ultrastructural abnormalities of the myelin structure in the white matter of the RR-EAE spinal cord, but not in that of the resistant mice. While the intensity of myelin staining was reduced in the relapsing EAE spinal cord, immunohistochemistry and immunoblot analysis revealed that the 21.5 kDa isoform of degenerating myelin basic protein (MBP) was specifically induced in the relapsing EAE spinal cord. Taken together, the neuroinflammation-induced degenerating 21 kDa isoform of MBP sheds light on the development of abnormal myelin on the relapse of MS pathogenesis. Full article
(This article belongs to the Special Issue Recent Progress in Multiple Sclerosis 2.0)
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16 pages, 2397 KiB  
Article
1,25(OH)2D3 Differently Modulates the Secretory Activity of IFN-DC and IL4-DC: A Study in Cells from Healthy Donors and MS Patients
by Isabella Sanseverino, Arturo Ottavio Rinaldi, Cristina Purificato, Antonio Cortese, Enrico Millefiorini and Maria Cristina Gauzzi
Int. J. Mol. Sci. 2023, 24(7), 6717; https://doi.org/10.3390/ijms24076717 - 4 Apr 2023
Viewed by 1791
Abstract
Immune mechanisms play an essential role in driving multiple sclerosis (MS) and altered trafficking and/or activation of dendritic cells (DC) were observed in the central nervous system and cerebrospinal fluid of MS patients. Interferon β (IFNβ) has been used as a first-line therapy [...] Read more.
Immune mechanisms play an essential role in driving multiple sclerosis (MS) and altered trafficking and/or activation of dendritic cells (DC) were observed in the central nervous system and cerebrospinal fluid of MS patients. Interferon β (IFNβ) has been used as a first-line therapy in MS for almost three decades and vitamin D deficiency is a recognized environmental risk factor for MS. Both IFNβ and vitamin D modulate DC functions. Here, we studied the response to 1,25-dihydoxyvitamin D3 (1,25(OH)2D3) of DC obtained with IFNβ/GM-CSF (IFN-DC) compared to classically derived IL4-DC, in three donor groups: MS patients free of therapy, MS patients undergoing IFNβ therapy, and healthy donors. Except for a decreased CCL2 secretion by IL4-DC from the MS group, no major defects were observed in the 1,25(OH)2D3 response of either IFN-DC or IL4-DC from MS donors compared to healthy donors. However, the two cell models strongly differed for vitamin D receptor level of expression as well as for basal and 1,25(OH)2D3-induced cytokine/chemokine secretion. 1,25(OH)2D3 up-modulated IL6, its soluble receptor sIL6R, and CCL5 in IL4-DC, and down-modulated IL10 in IFN-DC. IFN-DC, but not IL4-DC, constitutively secreted high levels of IL8 and of matrix-metalloproteinase-9, both down-modulated by 1,25(OH)2D3. DC may contribute to MS pathogenesis, but also provide an avenue for therapeutic intervention. 1,25(OH)2D3-induced tolerogenic DC are in clinical trial for MS. We show that the protocol of in vitro DC differentiation qualitatively and quantitatively affects secretion of cytokines and chemokines deeply involved in MS pathogenesis. Full article
(This article belongs to the Special Issue Recent Progress in Multiple Sclerosis 2.0)
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Review

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14 pages, 880 KiB  
Review
Role of Microglial Cells in the Pathophysiology of MS: Synergistic or Antagonistic?
by Hubert Mado, Monika Adamczyk-Sowa and Paweł Sowa
Int. J. Mol. Sci. 2023, 24(3), 1861; https://doi.org/10.3390/ijms24031861 - 17 Jan 2023
Cited by 11 | Viewed by 3272
Abstract
Many studies indicate an important role of microglia and their cytokines in the pathophysiology of multiple sclerosis (MS). Microglia are the macrophages of the central nervous system (CNS). They have many functions, such as being “controllers” of the CNS homeostasis in pathological and [...] Read more.
Many studies indicate an important role of microglia and their cytokines in the pathophysiology of multiple sclerosis (MS). Microglia are the macrophages of the central nervous system (CNS). They have many functions, such as being “controllers” of the CNS homeostasis in pathological and healthy conditions, playing a key role in the active immune defense of the CNS. Macroglia exhibit a dual role, depending on the phenotype they adopt. First, they can exhibit neurotoxic effects, which are harmful in the case of MS. However, they also show neuroprotective and regenerative effects in this disease. Many of the effects of microglia are mediated through the cytokines they secrete, which have either positive or negative properties. Neurotoxic and pro-inflammatory effects can be mediated by microglia via lipopolysaccharide and gamma interferon. On the other hand, the mediators of anti-inflammatory and protective effects secreted by microglia can be, for example, interleukin-4 and -13. Further investigation into the role of microglia in MS pathophysiology may perhaps lead to the discovery of new therapies for MS, as recent research in this area has been very promising. Full article
(This article belongs to the Special Issue Recent Progress in Multiple Sclerosis 2.0)
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