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Search Results (271)

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Keywords = autoimmune demyelinating diseases

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10 pages, 477 KiB  
Article
Immunogenetics of Multiple Sclerosis in Romanian Patients: Preliminary Data
by Alexandra Elena Constantinescu, Ion Mărunțelu, Andreea Pleșa, Carmen Adella Sîrbu, Florentina Cristina Pleșa, Andreia Ioana Constantinescu and Ileana Constantinescu
Int. J. Mol. Sci. 2025, 26(15), 7628; https://doi.org/10.3390/ijms26157628 - 6 Aug 2025
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease characterized by the immune system attacking the central nervous system, leading to demyelination and neurodegeneration. This work investigates the relationship between specific human leukocyte antigen (HLA) polymorphisms and MS, aiming to reveal the immunogenetic background [...] Read more.
Multiple sclerosis (MS) is a chronic autoimmune disease characterized by the immune system attacking the central nervous system, leading to demyelination and neurodegeneration. This work investigates the relationship between specific human leukocyte antigen (HLA) polymorphisms and MS, aiming to reveal the immunogenetic background of this disease for more individualized management approaches. This study employed a case–control design, analyzing HLA allele frequencies in 179 MS patients and 200 control subjects using next-generation sequencing, The key findings indicate significant associations between several HLA Class I and II alleles and MS, including HLA-B*35:03:01:03, HLA-C*04:01:01:14, HLA-DRB1*15:01:01:26, and HLA-DQA1*05:05:01:02. These findings emphasize the critical role of HLA molecules in MS Romanian patients. Full article
(This article belongs to the Section Molecular Immunology)
8 pages, 1643 KiB  
Case Report
Neuromyelitis Optica Diagnosis in Two Elderly Patients with Systematic Lupus Erythematosus: A Case Series
by Kyriaki Astara, Maria Lypiridou, Konstantinos Kalafatakis, Georgios Nikolaou and Georgios Stouraitis
Reports 2025, 8(3), 110; https://doi.org/10.3390/reports8030110 - 16 Jul 2025
Viewed by 338
Abstract
Background and Clinical Significance: Neuromyelitis optica (NMO) is a chronic demyelinating inflammatory disease of the central nervous system (CNS), mediated by autoantibodies against aquaporin-4 (AQ4) receptors. In the spectrum of NMO, other autoimmune diseases also coexist, though their association with systemic lupus erythematosus [...] Read more.
Background and Clinical Significance: Neuromyelitis optica (NMO) is a chronic demyelinating inflammatory disease of the central nervous system (CNS), mediated by autoantibodies against aquaporin-4 (AQ4) receptors. In the spectrum of NMO, other autoimmune diseases also coexist, though their association with systemic lupus erythematosus (SLE) is rare. Case Presentation: We present two cases of patients in their 70s who were diagnosed with NMO in the context of SLE. The first case concerns a 78-year-old woman with drug-induced SLE and thoracic myelitis who developed T4-level incomplete paraplegia over three weeks. The second case involves a 71-year-old woman with a history of SLE and myasthenia gravis, presenting with cervical myelitis with progressive worsening of walking and C4-level paraparesis over two months. In both cases, elevated serum anti-AQ4 titers were detected, establishing the diagnosis of NMO and differentiation from an atypical manifestation of SLE-related myelitis. High doses of intravenous corticosteroids with gradual tapering, along with cyclophosphamide, followed by rituximab, were administered in both patients. The first patient showed a poor response, while the second showed improvement. Conclusions: The coexistence of NMO with SLE is rare, but the occurrence of myelitis in patients with connective tissue diseases should raise the suspicion of NMO, especially in elderly women and several years after the diagnosis of SLE. Time to treatment is critical, as delays in treating NMO can result in cumulative and disabling damage. Full article
(This article belongs to the Section Allergy/Immunology)
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23 pages, 741 KiB  
Review
Kynurenines and Mitochondrial Disturbances in Multiple Sclerosis
by Daniel Pukoli and László Vécsei
Int. J. Mol. Sci. 2025, 26(11), 5098; https://doi.org/10.3390/ijms26115098 - 26 May 2025
Cited by 1 | Viewed by 822
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease characterised by inflammation, demyelination, and neurodegeneration within the central nervous system. The pathogenesis of MS involves an immune-mediated attack on myelin and neurons, accompanied by blood–brain barrier dysfunction and chronic CNS inflammation. Central to MS [...] Read more.
Multiple sclerosis (MS) is a chronic autoimmune disease characterised by inflammation, demyelination, and neurodegeneration within the central nervous system. The pathogenesis of MS involves an immune-mediated attack on myelin and neurons, accompanied by blood–brain barrier dysfunction and chronic CNS inflammation. Central to MS pathology is dysregulation of the kynurenine pathway, which metabolises tryptophan into neuroactive compounds. Kynurenine pathway (KP) activation, driven by inflammatory cytokines, leads to the production of both neuroprotective (e.g., kynurenic acid, KYNA) and neurotoxic (e.g., quinolinic acid, QUIN) metabolites. Imbalance between these metabolites, particularly increased QUIN production, exacerbates glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunction, contributing to neuronal and oligodendrocyte damage. Mitochondrial dysfunction plays a critical role in the pathophysiology of MS, exacerbating neurodegeneration through impaired energy metabolism and oxidative stress. This review integrates the current understanding of KP dysregulation in multiple sclerosis across disease stages. In RRMS, heightened KP activity correlates with inflammation and neuroprotection attempts through increased KYNA production. In contrast, SPMS and PPMS are associated with a shift towards a more neurotoxic KP profile, marked by elevated QUIN levels and reduced KYNA, exacerbating neurodegeneration and disability progression. Understanding these mechanisms offers insights into potential biomarkers and therapeutic targets for MS, emphasising the need for strategies to rebalance KP metabolism and mitigate neurotoxicity in progressive disease stages. Full article
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33 pages, 498 KiB  
Review
New Frontiers in Multiple Sclerosis Treatment: From Targeting Costimulatory Molecules to Bispecific Antibodies
by Megan Reidy, Meerah Khan, Elizabeth A. Mills, Qi Wu, Josh Garton, Dean E. Draayer, Insha Zahoor, Shailendra Giri, Robert C. Axtell and Yang Mao-Draayer
Int. J. Mol. Sci. 2025, 26(8), 3880; https://doi.org/10.3390/ijms26083880 - 19 Apr 2025
Cited by 1 | Viewed by 1482
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. The therapeutic landscape for MS has evolved significantly since the 1990s, with the development of more than 20 different disease-modifying therapies (DMTs). These therapies effectively manage relapses and inflammation, but [...] Read more.
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. The therapeutic landscape for MS has evolved significantly since the 1990s, with the development of more than 20 different disease-modifying therapies (DMTs). These therapies effectively manage relapses and inflammation, but most have failed to meaningfully prevent disease progression. While classically understood as a T cell-mediated condition, the most effective DMTs in slowing progression also target B cells. Novel classes of MS therapies in development, including anti-CD40L monoclonal antibodies, CD19 chimeric antigen receptor (CAR) T cells, and Bruton’s tyrosine kinase (BTK) inhibitors show greater capacity to target and eliminate B cells in the brain/CNS, as well as impacting T-cell and innate immune compartments. These approaches may help tackle the disease at its immunopathological core, addressing both peripheral and central immune responses that drive MS progression. Another emerging therapeutic strategy is to use bispecific antibodies, which have the potential for dual-targeting various disease aspects such as immune activation and neurodegeneration. As such, the next generation of MS therapies may be the first to reduce both inflammatory demyelination and disease progression in a clinically meaningful way. Their ability to target specific immune cell populations while minimizing broad immune suppression could also lead to better safety profiles. Here, we explore the biological rationale, advantages, limitations, and clinical progress of these emerging immunotherapies for relapsing–remitting and progressive forms of MS. Full article
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27 pages, 1441 KiB  
Review
Microbiota-Driven Mechanisms in Multiple Sclerosis: Pathogenesis, Therapeutic Strategies, and Biomarker Potential
by Mohammad Hosein Nemati, Esmaeil Yazdanpanah, Roya Kazemi, Niloufar Orooji, Sepehr Dadfar, Valentyn Oksenych and Dariush Haghmorad
Biology 2025, 14(4), 435; https://doi.org/10.3390/biology14040435 - 17 Apr 2025
Viewed by 1768
Abstract
Multiple sclerosis (MS) is a well-known, chronic autoimmune disorder of the central nervous system (CNS) involving demyelination and neurodegeneration. Research previously conducted in the area of the gut microbiome has highlighted it as a critical contributor to MS pathogenesis. Changes in the commensal [...] Read more.
Multiple sclerosis (MS) is a well-known, chronic autoimmune disorder of the central nervous system (CNS) involving demyelination and neurodegeneration. Research previously conducted in the area of the gut microbiome has highlighted it as a critical contributor to MS pathogenesis. Changes in the commensal microbiota, or dysbiosis, have been shown to affect immune homeostasis, leading to elevated levels of pro-inflammatory cytokines and disruption of the gut–brain axis. In this review, we provide a comprehensive overview of interactions between the gut microbiota and MS, especially focusing on the immunomodulatory actions of microbiota, such as influencing T-cell balance and control of metabolites, e.g., short-chain fatty acids. Various microbial taxa (e.g., Prevotella and Faecalibacterium) were suggested to lay protective roles, whereas Akkermansia muciniphila was associated with disease aggravation. Interventions focusing on microbiota, including probiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary therapies to normalize gut microbial homeostasis, suppress inflammation and are proven to improve clinical benefits in MS patients. Alterations in gut microbiota represent opportunities for identifying biomarkers for early diagnosis, disease progression and treatment response monitoring. Further studies need to be conducted to potentially address the interplay between genetic predispositions, environmental cues, and microbiota composition to get the precise mechanisms of the gut–brain axis in MS. In conclusion, the gut microbiota plays a central role in MS pathogenesis and offers potential for novel therapeutic approaches, providing a promising avenue for improving clinical outcomes in MS management. Full article
(This article belongs to the Section Biochemistry and Molecular Biology)
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47 pages, 1310 KiB  
Review
Impact of High-Efficacy Therapies for Multiple Sclerosis on B Cells
by Federica Galota, Simone Marcheselli, Sara De Biasi, Lara Gibellini, Francesca Vitetta, Alessia Fiore, Krzysztof Smolik, Giulia De Napoli, Martina Cardi, Andrea Cossarizza and Diana Ferraro
Cells 2025, 14(8), 606; https://doi.org/10.3390/cells14080606 - 17 Apr 2025
Cited by 1 | Viewed by 2540
Abstract
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative autoimmune disorder of the central nervous system characterized by demyelination and neurodegeneration. Traditionally considered a T-cell-mediated disease, the crucial role of B lymphocytes in its pathogenesis, through different mechanisms contributing to inflammation and autoreactivity, [...] Read more.
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative autoimmune disorder of the central nervous system characterized by demyelination and neurodegeneration. Traditionally considered a T-cell-mediated disease, the crucial role of B lymphocytes in its pathogenesis, through different mechanisms contributing to inflammation and autoreactivity, is increasingly recognized. The risk of long-term disability in MS patients can be reduced by an early treatment initiation, in particular with high-efficacy therapies. The aim of this review is to provide an overview of the mechanisms of action of high-efficacy therapies for MS, with a focus on their impact on B cells and how this contributes to the drugs’ efficacy and safety profiles. Anti-CD20 monoclonal antibodies, Alemtuzumab, Cladribine and sequestering therapies encompassing Natalizumab and S1P receptors modulators will be discussed and emerging therapies, including Bruton’s Tyrosine Kinase inhibitors, will be presented. Full article
(This article belongs to the Special Issue Cell Biology: State of the Art and Perspectives in Italy 2025)
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21 pages, 1045 KiB  
Review
Microglia/Macrophages in Autoimmune Demyelinating Encephalomyelitis (Multiple Sclerosis/Neuromyelitis Optica)
by Ryo Yamasaki
Int. J. Mol. Sci. 2025, 26(8), 3585; https://doi.org/10.3390/ijms26083585 - 10 Apr 2025
Cited by 1 | Viewed by 1154
Abstract
Microglia and macrophages are critical mediators of immune responses in the central nervous system. Their roles range from homeostatic maintenance to the pathogenesis of autoimmune demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorder. This review explores the origins of microglia [...] Read more.
Microglia and macrophages are critical mediators of immune responses in the central nervous system. Their roles range from homeostatic maintenance to the pathogenesis of autoimmune demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorder. This review explores the origins of microglia and macrophages, as well as their mechanisms of activation, interactions with other neural cells, and contributions to disease progression and repair processes. It also highlights the translational relevance of insights gained from animal models and the therapeutic potential of targeting microglial and macrophage activity in multiple sclerosis and neuromyelitis optica spectrum disorder. Full article
(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)
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10 pages, 220 KiB  
Review
Multiple Sclerosis: A Comprehensive Spectrum of Symptoms Beyond Motor Dysfunction
by Majed Alluqmani
Clin. Transl. Neurosci. 2025, 9(1), 19; https://doi.org/10.3390/ctn9010019 - 17 Mar 2025
Cited by 1 | Viewed by 1038
Abstract
Multiple sclerosis (MS) is a chronic autoimmune-mediated neurodegenerative disease that affects young adults. The diagnosis of MS currently based on the McDonald criteria, which based on four core principles: the presence of a symptomatic demyelinating syndrome, an objective neurologic finding, the dissemination in [...] Read more.
Multiple sclerosis (MS) is a chronic autoimmune-mediated neurodegenerative disease that affects young adults. The diagnosis of MS currently based on the McDonald criteria, which based on four core principles: the presence of a symptomatic demyelinating syndrome, an objective neurologic finding, the dissemination in space (DIS), and the dissemination in time (DIT). In addition, the diagnosis of MS relies on the exclusion of any alternative diagnosis. This may implicate the absence of systemic non-neurological symptoms and signs, such as rheumatological, cutaneous, or ophthalmological findings. Nevertheless, the non-neurological symptoms are commonly observed in patients with MS either at the onset of MS, which therefore can delay the diagnosis and the incrementation of a disease-modifying therapy, or during the course of the disease progression. The purpose of our review is to highlight non-neurological symptoms of MS that frequently go undiagnosed or mistakenly linked to other conditions, aiming for the more accurate and earlier diagnosis of MS. Full article
(This article belongs to the Section Neuroscience/translational neurology)
9 pages, 1953 KiB  
Case Report
Chronic Central Nervous System Graft-Versus-Host Disease to Unravel Progressive Visual Loss and Ischemic Stroke Recurrence Post-Allogeneic Hematopoietic Stem Cell Transplant: A Case Report
by Francesco Crescenzo, Alessandra Danese, Francesco Dall’Ora and Michelangelo Turazzini
Int. J. Mol. Sci. 2025, 26(5), 2289; https://doi.org/10.3390/ijms26052289 - 4 Mar 2025
Cited by 1 | Viewed by 1159
Abstract
Chronic graft-versus-host disease (cGVHD) is a prognostically negative event following hematopoietic stem cell transplant (HSCT). While cGVHD mainly affects the muscles, skin, oral mucosa, eyes, lungs, gastrointestinal tract, and liver, central nervous system (CNS) involvement remains possible and, moreover, is rare when it [...] Read more.
Chronic graft-versus-host disease (cGVHD) is a prognostically negative event following hematopoietic stem cell transplant (HSCT). While cGVHD mainly affects the muscles, skin, oral mucosa, eyes, lungs, gastrointestinal tract, and liver, central nervous system (CNS) involvement remains possible and, moreover, is rare when it occurs isolated. CNS-cGVHD can manifest with a wide spectrum of CNS disorders, including cerebrovascular diseases, autoimmune demyelinating diseases, and immune-mediated encephalitis. We present a case of 65-year-old man previously treated with HSCT presenting with progressive cerebrovascular disorder and optic neuropathy without any clear alternative causal processes except for immune-mediated CNS microangiopathy in the context of possible CNS-cGVHD, along with suggestive imaging and instrumental and laboratory findings. Starting one year after HSCT for acute myeloid leukemia, when the first cerebral ischemic event occurred and was then associated with a reduction in visual acuity, an extensive diagnostic work-up had remained inconclusive over many years, leading us to the hypothesis of CNS-cGVHD and, therefore, to the start of immunosuppressive therapy. Our experience highlighted not ignoring the possibility of cGVHD as the underlying mechanism of CNS disorder, even in the absence of other systemic presentations, once more common etiologies of CNS pathological processes have been ruled out. Full article
(This article belongs to the Special Issue New Insights of Biomarkers in Neurodegenerative Diseases)
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18 pages, 5110 KiB  
Article
Yerba Mate (Ilex paraguariensis) Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating Regulatory T Cell Function
by Andrés A. Herrada, Francisca Rodríguez-Arriaza, Alexandra Olate-Briones, Sofía Albornoz-Muñoz, Jorge Y. Faúndez-Acuña, Victor Rojas-Henríquez, Ledaliz Retamal-Quinteros, Carolina Prado and Noelia Escobedo
Nutrients 2025, 17(5), 897; https://doi.org/10.3390/nu17050897 - 4 Mar 2025
Viewed by 2772
Abstract
Background/Objectives: In Latin America, yerba mate (YM) is a popular infusion processed from the leaves and stems of Ilex paraguariensis. YM has been shown to have anti-inflammatory properties in several studies, although the effect of YM on multiple sclerosis (MS) remains elusive. [...] Read more.
Background/Objectives: In Latin America, yerba mate (YM) is a popular infusion processed from the leaves and stems of Ilex paraguariensis. YM has been shown to have anti-inflammatory properties in several studies, although the effect of YM on multiple sclerosis (MS) remains elusive. The purpose of this study was to examine the effect of YM on the development of MS, by using the experimental autoimmune encephalomyelitis (EAE) mouse model while also evaluating its effect over infiltration of immune cells into the central nervous system (CNS) and regulatory T cell (Treg) function. Methods: YM or vehicle were administrated to mice daily by oral gavage for seven days prior to EAE induction and during the entire course of the disease. EAE score was recorded daily, and immune cell infiltration into the CNS was measured by flow cytometry and immunofluorescence. Results: Our results showed that YM administration decreases EAE symptoms and immune cell infiltration into the CNS, along with reducing demyelination, compared to the vehicle treatment. Moreover, an increase in the Treg population, immune cells capable of generating tolerance and decreased inflammation, was observed in mice receiving YM, together with improved Treg suppressive capabilities after YM treatment in vitro. Conclusions: In summary, we showed that YM promotes an immunosuppressive environment by modulating Treg function, reducing EAE symptoms and immune cell infiltration into the brain, and suggesting that YM consumption could be a good cost-effective treatment for MS. Full article
(This article belongs to the Special Issue Nutrition and Autoimmune Diseases)
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12 pages, 532 KiB  
Communication
CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review
by Edoardo Genio, Mauro Lecca, Rachele Ciccocioppo and Edoardo Errichiello
Genes 2025, 16(3), 306; https://doi.org/10.3390/genes16030306 - 3 Mar 2025
Viewed by 1256
Abstract
Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4), a member of the immunoglobulin superfamily, is an essential negative regulator of immune responses that is constitutively expressed on both regulatory (Treg) and activated T cells. To date, heterozygous germline variants in CTLA4, leading to haploinsufficiency, have been associated with [...] Read more.
Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4), a member of the immunoglobulin superfamily, is an essential negative regulator of immune responses that is constitutively expressed on both regulatory (Treg) and activated T cells. To date, heterozygous germline variants in CTLA4, leading to haploinsufficiency, have been associated with several immunological disorders, including hypogammaglobulinemia, multi-organ autoimmunity, lymphoproliferative disorders, and enlarged lymphoid organs. Indeed, CTLA4 carriers display highly heterogeneous clinical manifestations with a phenotypic spectrum ranging from asymptomatic carrier status to fatal autoimmunity. Here, we describe a family with autoimmune phenotypes (Hashimoto thyroiditis, psoriasiform dermatitis, celiac disease/inflammatory bowel disease, and rheumatoid arthritis), segregating across three different generations due to a recurrent missense variant [c.436G>A, p.(Gly146Arg)] in the CTLA4 gene. Interestingly, the proband showed prominent neurological manifestations, including seizures, hydrocephalus, and demyelination, which are less frequently reported in individuals with pathogenic variants in CTLA4. A detailed literature review of neurologic features that have been reported so far in CTLA4 carriers is also provided. Full article
(This article belongs to the Special Issue Genes and Variants in Human Rare Genetic Diseases)
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23 pages, 1993 KiB  
Review
Unveiling the Important Role of Gut Microbiota and Diet in Multiple Sclerosis
by Amina Džidić Krivić, Emir Begagić, Semir Hadžić, Amir Bećirović, Emir Bećirović, Harisa Hibić, Lejla Tandir Lihić, Samra Kadić Vukas, Hakija Bečulić, Tarik Kasapović and Mirza Pojskić
Brain Sci. 2025, 15(3), 253; https://doi.org/10.3390/brainsci15030253 - 27 Feb 2025
Cited by 1 | Viewed by 1789
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by neurodegeneration, axonal damage, demyelination, and inflammation. Recently, gut dysbiosis has been linked to MS and other autoimmune conditions. Namely, gut microbiota has a vital role in regulating [...] Read more.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by neurodegeneration, axonal damage, demyelination, and inflammation. Recently, gut dysbiosis has been linked to MS and other autoimmune conditions. Namely, gut microbiota has a vital role in regulating immune function by influencing immune cell development, cytokine production, and intestinal barrier integrity. While balanced microbiota fosters immune tolerance, dysbiosis disrupts immune regulation, damages intestinal permeability, and heightens the risk of autoimmune diseases. The critical factor in shaping the gut microbiota and modulating immune response is diet. Research shows that high-fat diets rich in saturated fats are associated with disease progression. Conversely, diets rich in fruits, yogurt, and legumes may lower the risk of MS onset and progression. Specific dietary interventions, such as the Mediterranean diet (MD) and ketogenic diet, have shown potential to reduce inflammation, support neuroprotection, and promote CNS repair. Probiotics, by restoring microbial balance, may also help mitigate immune dysfunction noted in MS. Personalized dietary strategies targeting the gut microbiota hold promise for managing MS by modulating immune responses and slowing disease progression. Optimizing nutrient intake and adopting anti-inflammatory diets could improve disease control and quality of life. Understanding gut-immune interactions is essential for developing tailored nutritional therapies for MS patients. Full article
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19 pages, 1021 KiB  
Review
Hypoxic Neuroinflammation in the Pathogenesis of Multiple Sclerosis
by Bethany Y. A. Hollingworth, Patrick N. Pallier, Stuart I. Jenkins and Ruoli Chen
Brain Sci. 2025, 15(3), 248; https://doi.org/10.3390/brainsci15030248 - 26 Feb 2025
Cited by 1 | Viewed by 1749
Abstract
Multiple sclerosis (MS) is an autoimmune disease that damages the myelin sheath around the central nervous system axons, leading to neurological dysfunction. Although the initial damage is driven by inflammation, hypoxia has been reported in several brain regions of MS patients, but the [...] Read more.
Multiple sclerosis (MS) is an autoimmune disease that damages the myelin sheath around the central nervous system axons, leading to neurological dysfunction. Although the initial damage is driven by inflammation, hypoxia has been reported in several brain regions of MS patients, but the significance of this for prognosis and treatment remains unclear. Neuroinflammation can induce hypoxia, and hypoxia can induce and exacerbate neuroinflammation, forming a vicious cycle. Within MS lesions, demyelination is often followed by remyelination, which may restore neurological function. However, demyelinated axons are vulnerable to damage, which leads to the accumulation of the permanent neurological dysfunction typical in MS, with this vulnerability heightened during hypoxia. Clinically approved therapies for MS are immunomodulatory, which can reduce relapse frequency/severity, but there is a lack of pro-regenerative therapies for MS, for example promoting remyelination. All tissues have protective responses to hypoxia, which may be relevant to MS lesions, especially during remyelinating episodes. When oxygen levels are reduced in the brain, constitutively expressed hypoxia-inducible factors (HIF) are stabilised, upregulating hundreds of genes, including neuroprotective factors. Furthermore, astrocytes upregulate heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) in the early stage of MS. HB-EGF promotes protective mechanisms and induces oligodendrocyte and neuron differentiation and survival. This review article outlines the neuroinflammation and hypoxia cycle in MS pathology and identifies potential therapeutic targets to limit neurodegeneration and/or promote regeneration. Both HIF and HB-EGF signalling pathways induce endogenous protection mechanisms in the CNS, promoting neuroprotection and remyelination directly, but also indirectly by modulating the immune response in MS. Promoting such endogenous protective signalling pathways could be an effective therapy for MS patients. Full article
(This article belongs to the Special Issue New Advances in Neuroimmunology and Neuroinflammation)
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25 pages, 1205 KiB  
Review
Clinical Management in Multiple Sclerosis
by Ana Victoria Arredondo-Robles, Karen Paola Rodríguez-López and Rodolfo Daniel Ávila-Avilés
Neuroglia 2025, 6(1), 6; https://doi.org/10.3390/neuroglia6010006 - 5 Feb 2025
Viewed by 3430
Abstract
This review aims to provide a comprehensive overview of the main types, subtypes, clinical manifestations, and current therapeutic strategies for multiple sclerosis, emphasizing recent advancements and clinical challenges. Multiple Sclerosis (MS) is a demyelinating, chronic, autoimmune, and inflammatory disease that affects the Central [...] Read more.
This review aims to provide a comprehensive overview of the main types, subtypes, clinical manifestations, and current therapeutic strategies for multiple sclerosis, emphasizing recent advancements and clinical challenges. Multiple Sclerosis (MS) is a demyelinating, chronic, autoimmune, and inflammatory disease that affects the Central Nervous System (CNS). Its classification has the following subtypes: Relapsing-Remitting (RRMS), Secondary-Progressive (SPMS), and Primary-Progressive (PPMS), including rarer subtypes such as Clinically Isolated Syndrome (CIS), Radiologically Isolated Syndrome (RIS), Balo’s Concentric Sclerosis (BCS), Schilder’s Disease (SD), and Progressive-Relapsing MS (PRMS). This article divides the various treatments for MS into the following three categories: acute relapse management, symptomatic treatments, and Disease-Modifying Treatments (DMTs). The latter represents revolutionary research in MS, since they are the drugs considered as the best treatment alternatives for this disease. Full article
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13 pages, 2361 KiB  
Article
Mitochondrial Uncoupler, 2,4-Dinitrophenol, Reduces Spinal Cord Paralysis and Retinal Ganglion Cell Loss in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis
by Nuala O’Neill, Reas S. Khan, Suad Abd Alhadi, Kimberly E. Dine, John G. Geisler, Brahim Chaqour, Ahmara G. Ross and Kenneth S. Shindler
Biomolecules 2025, 15(2), 189; https://doi.org/10.3390/biom15020189 - 28 Jan 2025
Viewed by 1387
Abstract
Optic neuritis is an inflammatory demyelinating disease of the optic nerve that often occurs in multiple sclerosis (MS) patients. Sixty percent of patients develop some level of permanent visual loss due to retinal ganglion cell (RGC) damage following optic neuritis, with no known [...] Read more.
Optic neuritis is an inflammatory demyelinating disease of the optic nerve that often occurs in multiple sclerosis (MS) patients. Sixty percent of patients develop some level of permanent visual loss due to retinal ganglion cell (RGC) damage following optic neuritis, with no known treatment to prevent this loss. Prior studies showed that MP201, a prodrug of 2,4-dinitrophenol (DNP) administered in the experimental autoimmune encephalitis (EAE) mouse model of MS attenuated optic neuritis with preserved vision, increased retinal ganglion cell (RGC) survival, decreased axon loss, and reduced demyelination. Oral administration of MP201, which converts to active form DNP after entry in the portal vein, decreases mitochondrial-derived reactive oxygen species (ROS) and restores calcium homeostasis, which are both implicated in many neurodegenerative diseases. Due to the established therapeutic benefits of prodrug MP201 in EAE mice, we hypothesized that administration of DNP itself may also have significant potential for therapeutic effects. Here, effects of varying doses of DNP treatment in EAE mice were assessed by the extent of spinal cord paralysis, optokinetic response (OKR), RGC survival, and optic nerve demyelination and inflammation. Results show that daily oral doses of 5-10 mg/kg DNP initiated after onset of EAE can significantly reduce spinal cord paralysis, a marker of the EAE MS-like disease, by day 42 after disease induction. DNP treatment significantly reduces RGC loss induced by optic neuritis in EAE mice; however, effects of DNP do not significantly improve visual function, or optic nerve demyelination and inflammation. Current studies show DNP treatment promotes increased RGC survival, but continued inflammation and demyelination likely reduce visual function, suggesting future studies examining combination therapy of DNP with anti-inflammatory agents may be warranted. Full article
(This article belongs to the Section Molecular Medicine)
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