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Cells
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Molecular Basis of Multiple Sclerosis Development and Treatment
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Molecular Basis of Multiple Sclerosis Development and Treatment

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

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 10032

Special Issue Editors

Prof. Dr. Christoph Kleinschnitz

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Guest Editor
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
Prof. Dr. Refik Pul

E-Mail Website
Guest Editor
Neurology Department, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Universitätsklinikum Essen, Hufelandstr. 55, 45147 Essen, Germany
Interests: neuroimmunology; multiple sclerosis (clinical/experimental); animal models; glial cells; biomarkers in MS; neuroprotection; neuroimaging
Special Issues, Collections and Topics in MDPI journals
Dr. Jelena Skuljec

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Guest Editor
Neurology Department, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Universitätsklinikum Essen, Hufelandstr. 55, 45147 Essen, Germany
Interests: neuroimmunology; multiple sclerosis (clinical/experimental); animal models; glial cells; immune tolerance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Multiple sclerosis (MS) is the most common neurological disease in young adults. Around 2.8 million people are estimated to live with MS worldwide, and the prevalence is increasing globally. Variations in disease courses and unpredictable clinical manifestations make this disease challenging to diagnose and treat.

MS is thought to arise as the result of environmental exposure in genetically susceptible individuals. However, many questions remain unanswered in this respect, including the exact cause(s), cell type(s), and molecular pathways involved in driving the MS risk and pathology. An inconsistent clinical course and wide range of affected central nervous system (CNS) areas between patients argue against a single specific antigen driving the disease. It also remains elusive whether the progressive MS and a highly active course with tumefactive lesions represent distinct disease entities. Significant progress has been made using the genome-wide association approach when identifying genetic variants that might contribute to MS susceptibility. These variants are distributed across the cells of both the adaptive and the innate immune system arms, suggesting that key disease processes appear to be more widespread than the formerly implied central role of dysregulated CD4+ T cells. B cells, microglia, dendritic cells, and NK cells have emerged as new disease-associated immune cell populations, although their spatial and temporal disease-specific context remains to be discovered. Besides high-risk, protective genotypes have also been identified and might help us to develop safe and effective new treatments for MS. Modern techniques such as single-cell or other high-resolution immune profiling may reveal how environmental context influences the phenotype and detrimental role of causal cells and, importantly, how to reverse their pathogenic state through different therapies.

The progress that has been made in developing new immune-modifying therapies for MS in recent years is fascinating. Nevertheless, all current drugs fail to prevent neurodegeneration. Moreover, not only are the molecular and cellular mechanisms underlying their effects not completely characterized, but the specificity also needs to be improved in order to spare the protective cellular subtypes.

Recent studies have suggested that the events leading to plaque formation and neuronal decline are present much earlier than clinical symptoms occur. Thus, one of the future research goals should be early neuroprotective and remyelinating treatments that target CNS-resident cells. The inclusion of the oligoclonal bands in the new 2017 revised McDonald criteria supports the concept of early diagnosis and treatment but also underlines the need for reliable prognostic biomarkers reflecting both inflammatory and neurodegenerative aspects.

This Special Issue aims to compile original research, reviews, mini-reviews, and opinion articles addressing the molecular and cellular events underlying the onset and progression of MS, including novel aspects of current therapeutic interventions and the discovery of advanced strategies to prevent or treat this complex disease. We welcome the submission of articles covering but not limited to the following subtopics:

  • Epidemiology and risk factors related to MS;
  • Genetic factors of MS susceptibility;
  • The role of inflammation/immune cells in MS pathology;
  • Molecular and cellular mechanisms of demyelination;
  • Molecular and cellular mechanisms of remyelination;
  • Molecular and cellular mechanisms of neurodegeneration;
  • Novel biomarkers for the diagnosis of MS;
  • Mode of action of MS drugs.

Prof. Dr. Christoph Kleinschnitz
Prof. Dr. Refik Pul
Dr. Jelena Skuljec
Guest Editors

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. Cells is an international peer-reviewed open access semimonthly 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 2700 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

  • multiple sclerosis
  • demyelination
  • remyelination
  • inflammation
  • neurodegeneration
  • biomarker
  • disease mechanism
  • mode of action of MS drugs

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Published Papers (4 papers)

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Research

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14 pages, 988 KiB  
Article
Immune Response to Seasonal Influenza Vaccination in Multiple Sclerosis Patients Receiving Cladribine
by Leoni Rolfes, Steffen Pfeuffer, Jelena Skuljec, Xia He, Chuanxin Su, Sinem-Hilal Oezalp, Marc Pawlitzki, Tobias Ruck, Melanie Korsen, Konstanze Kleinschnitz, Derya Aslan, Tim Hagenacker, Christoph Kleinschnitz, Sven G. Meuth and Refik Pul
Cells 2023, 12(9), 1243; https://doi.org/10.3390/cells12091243 - 25 Apr 2023
Cited by 4 | Viewed by 2560
Abstract
Cladribine has been approved for the treatment of multiple sclerosis (MS) and its administration results in a long-lasting depletion of lymphocytes. As lymphopenia is known to hamper immune responses to vaccination, we evaluated the immunogenicity of the influenza vaccine in patients undergoing cladribine [...] Read more.
Cladribine has been approved for the treatment of multiple sclerosis (MS) and its administration results in a long-lasting depletion of lymphocytes. As lymphopenia is known to hamper immune responses to vaccination, we evaluated the immunogenicity of the influenza vaccine in patients undergoing cladribine treatment at different stages vs. controls. The antibody response in 90 cladribine-treated MS patients was prospectively compared with 10 control subjects receiving platform immunotherapy (NCT05019248). Serum samples were collected before and six months after vaccination. Response to vaccination was determined by the hemagglutination-inhibition test. Postvaccination seroprotection rates against influenza A were comparable in cladribine-treated patients and controls (H1N1: 94.4% vs. 100%; H3N2: 92.2% vs. 90.0%). Influenza B response was lower in the cladribine cohort (61.1% vs. 80%). The increase in geometric mean titers was lower in the cladribine group vs. controls (H1N1: +98.5 vs. +188.1; H3N2: +225.3 vs. +300.0; influenza B: +40.0 vs. +78.4); however, titers increased in both groups for all strains. Seroprotection was achieved irrespective of vaccination timing and lymphocyte subset counts at the time of vaccination in the cladribine cohort. To conclude, cladribine-treated MS patients can mount an adequate immune response to influenza independently of treatment duration and time interval to the last cladribine administration. Full article
(This article belongs to the Special Issue Molecular Basis of Multiple Sclerosis Development and Treatment)
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20 pages, 7373 KiB  
Article
Rat Ovarian Function Is Impaired during Experimental Autoimmune Encephalomyelitis
by Ana Milosevic, Irena Lavrnja, Danijela Savic, Katarina Milosevic, Jelena Skuljec, Ivana Bjelobaba and Marija M. Janjic
Cells 2023, 12(7), 1045; https://doi.org/10.3390/cells12071045 - 30 Mar 2023
Cited by 1 | Viewed by 1861
Abstract
Multiple sclerosis (MS) is an autoimmune disease affecting the CNS and occurring far more prevalently in women than in men. In both MS and its animal models, sex hormones play important immunomodulatory roles. We have previously shown that experimental autoimmune encephalomyelitis (EAE) affects [...] Read more.
Multiple sclerosis (MS) is an autoimmune disease affecting the CNS and occurring far more prevalently in women than in men. In both MS and its animal models, sex hormones play important immunomodulatory roles. We have previously shown that experimental autoimmune encephalomyelitis (EAE) affects the hypothalamic–pituitary–gonadal axis in rats of both sexes and induces an arrest in the estrous cycle in females. To investigate the gonadal status in female rats with EAE, we explored ovarian morphometric parameters, circulating and intraovarian sex steroid levels, and the expression of steroidogenic machinery components in the ovarian tissue. A prolonged state of diestrus was recorded during the peak of EAE, with maintenance of the corpora lutea, elevated intraovarian progesterone levels, and increased gene and protein expression of StAR, similar to the state of pseudopregnancy. The decrease in CYP17A1 protein expression was followed by a decrease in ovarian testosterone and estradiol levels. On the contrary, serum testosterone levels were slightly increased. With unchanged serum estradiol levels, these results point at extra-gonadal sites of sex steroid biosynthesis and catabolism as important regulators of their circulating levels. Our study suggests alterations in the function of the female reproductive system during central autoimmunity and highlights the bidirectional relationships between hormonal status and EAE. Full article
(This article belongs to the Special Issue Molecular Basis of Multiple Sclerosis Development and Treatment)
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12 pages, 2076 KiB  
Article
Prophylactic Glatiramer Acetate Treatment Positively Attenuates Spontaneous Opticospinal Encephalomyelitis
by Ümmügülsüm Koc, Steffen Haupeltshofer, Katharina Klöster, Seray Demir, Ralf Gold and Simon Faissner
Cells 2023, 12(4), 542; https://doi.org/10.3390/cells12040542 - 8 Feb 2023
Viewed by 1755
Abstract
Background: Glatiramer acetate (GA) is a well-established treatment option for patients with clinically isolated syndrome and relapsing–remitting multiple sclerosis (MS) with few side effects. The double transgenic mouse model spontaneous opticospinal encephalomyelitis (OSE), based on recombinant myelin oligodendrocyte glycoprotein35-55 reactive T and [...] Read more.
Background: Glatiramer acetate (GA) is a well-established treatment option for patients with clinically isolated syndrome and relapsing–remitting multiple sclerosis (MS) with few side effects. The double transgenic mouse model spontaneous opticospinal encephalomyelitis (OSE), based on recombinant myelin oligodendrocyte glycoprotein35-55 reactive T and B cells, mimicks features of chronic inflammation and degeneration in MS and related disorders. Here, we investigated the effects of prophylactic GA treatment on the clinical course, histological alterations and peripheral immune cells in OSE. Objective: To investigate the effects of prophylactic glatiramer acetate (GA) treatment in a mouse model of spontaneous opticospinal encephalomyelitis (OSE). Methods: OSE mice with a postnatal age of 21 to 28 days without signs of encephalomyelitis were treated once daily either with 150 µg GA or vehicle intraperitoneally (i. p.). The animals were scored daily regarding clinical signs and weight. The animals were sacrificed after 30 days of treatment or after having reached a score of 7.0 due to animal care guidelines. We performed immunohistochemistry of spinal cord sections and flow cytometry analysis of immune cells. Results: Preventive treatment with 150 µg GA i. p. once daily significantly reduced clinical disease progression with a mean score of 3.9 ± 1.0 compared to 6.2 ± 0.7 in control animals (p < 0.01) after 30 d in accordance with positive effects on weight (p < 0.001). The immunohistochemistry showed that general inflammation, demyelination or CD11c+ dendritic cell infiltration did not differ. There was, however, a modest reduction of the Iba1+ area (p < 0.05) and F4/80+ area upon GA treatment (p < 0.05). The immune cell composition of secondary lymphoid organs showed a trend towards an upregulation of regulatory T cells, which lacked significance. Conclusions: Preventive treatment with GA reduces disease progression in OSE in line with modest effects on microglia/macrophages. Due to the lack of established prophylactic treatment options for chronic autoimmune diseases with a high risk of disability, our study could provide valuable indications for translational medicine. Full article
(This article belongs to the Special Issue Molecular Basis of Multiple Sclerosis Development and Treatment)
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Review

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13 pages, 2167 KiB  
Review
Linking Mechanisms of Vitamin D Signaling with Multiple Sclerosis
by Carsten Carlberg and Marcin P. Mycko
Cells 2023, 12(19), 2391; https://doi.org/10.3390/cells12192391 - 30 Sep 2023
Cited by 2 | Viewed by 2424
Abstract
Environmental triggers often work via signal transduction cascades that modulate the epigenome and transcriptome of cell types involved in the disease process. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system being characterized by a combination of recurring inflammation, demyelination [...] Read more.
Environmental triggers often work via signal transduction cascades that modulate the epigenome and transcriptome of cell types involved in the disease process. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system being characterized by a combination of recurring inflammation, demyelination and progressive loss of axons. The mechanisms of MS onset are not fully understood and genetic variants may explain only some 20% of the disease susceptibility. From the environmental factors being involved in disease development low vitamin D levels have been shown to significantly contribute to MS susceptibility. The pro-hormone vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) as a high affinity ligand to the transcription factor VDR (vitamin D receptor) and is a potent modulator of the epigenome at thousands of genomic regions and the transcriptome of hundreds of genes. A major target tissue of the effects of 1,25(OH)2D3 and VDR are cells of innate and adaptive immunity, such as monocytes, dendritic cells as well as B and T cells. Vitamin D induces immunological tolerance in T cells and reduces inflammatory reactions of various types of immune cells, all of which are implicated in MS pathogenesis. The immunomodulatory effects of 1,25(OH)2D3 contribute to the prevention of MS. However, the strength of the responses to vitamin D3 supplementation is highly variegated between individuals. This review will relate mechanisms of individual’s vitamin D responsiveness to MS susceptibility and discuss the prospect of vitamin D3 supplementation as a way to extinguish the autoimmunity in MS. Full article
(This article belongs to the Special Issue Molecular Basis of Multiple Sclerosis Development and Treatment)
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