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International Journal of Molecular... Jan 2019The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual's risk of developing this central... (Review)
Review
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.
Topics: Animals; Central Nervous System Diseases; Demyelinating Diseases; Dietary Supplements; Humans; Hypercalcemia; Vitamin D
PubMed: 30626090
DOI: 10.3390/ijms20010218 -
Journal of Neurovirology Apr 2003A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent... (Review)
Review
A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent demyelinating diseases are progressive multifocal leukoencephalopathy, caused by JC papovirus destruction of oligodendrocytes, and subacute sclerosing panencephalitis, an invariably fatal childhood disease caused by persistent measles virus. The most common neurological disease of young adults in the developed world, multiple sclerosis, is also characterized by lesions of inflammatory demyelination; however, the etiology of this disease remains an enigma. A viral etiology is possible, because most demyelinating diseases of known etiology in both man and animals are viral. Understanding of the pathogenesis of virus-induced demyelination derives for the most part from the study of animal models. Studies with neurotropic strains of mouse hepatitis virus, Theiler's virus, and Semliki Forest virus have been at the forefront of this research. These models demonstrate how viruses enter the brain, spread, persist, and interact with immune responses. Common features are an ability to infect and persist in glial cells, generation of predominantly CD8(+) responses, which control and clear the early phase of virus replication but which fail to eradicate the infection, and lesions of inflammatory demyelination. In most cases demyelination is to a limited extent the result of direct virus destruction of oligodendrocytes, but for the most part is the consequence of immune and inflammatory responses. These models illustrate the roles of age and genetic susceptibility and establish the concept that persistent CNS infection can lead to the generation of CNS autoimmune responses.
Topics: Animals; Demyelinating Diseases; Humans; Multiple Sclerosis; Virus Diseases
PubMed: 12707846
DOI: 10.1080/13550280390194046 -
Journal of Neurochemistry Oct 2008Oligodendrocytes (OLs) are mature glial cells that myelinate axons in the brain and spinal cord. As such, they are integral to functional and efficient neuronal... (Review)
Review
Oligodendrocytes (OLs) are mature glial cells that myelinate axons in the brain and spinal cord. As such, they are integral to functional and efficient neuronal signaling. The embryonic lineage and postnatal development of OLs have been well-studied and many features of the process have been described, including the origin, migration, proliferation, and differentiation of precursor cells. Less clear is the extent to which OLs and damaged/dysfunctional myelin are replaced following injury to the adult CNS. OLs and their precursors are very vulnerable to conditions common to CNS injury and disease sites, such as inflammation, oxidative stress, and elevated glutamate levels leading to excitotoxicity. Thus, these cells become dysfunctional or die in multiple pathologies, including Alzheimer's disease, spinal cord injury, Parkinson's disease, ischemia, and hypoxia. However, studies of certain conditions to date have detected spontaneous OL replacement. This review will summarize current information on adult OL progenitors, mechanisms that contribute to OL death, the consequences of their loss and the pathological conditions in which spontaneous oligodendrogenesis from endogenous precursors has been observed in the adult CNS.
Topics: Animals; Cell Death; Central Nervous System; Demyelinating Diseases; Humans; Inflammation; Nerve Regeneration; Nervous System Diseases; Neurodegenerative Diseases; Oligodendroglia; Stem Cells
PubMed: 18643793
DOI: 10.1111/j.1471-4159.2008.05570.x -
Progress in Brain Research 2017Diseases of glia, including astrocytes and oligodendrocytes, are among the most prevalent and disabling, yet least appreciated, conditions in neurology. In recent years,...
Diseases of glia, including astrocytes and oligodendrocytes, are among the most prevalent and disabling, yet least appreciated, conditions in neurology. In recent years, it has become clear that besides the overtly glial disorders of oligodendrocyte loss and myelin failure, such as the leukodystrophies and inflammatory demyelinations, a number of neurodegenerative and psychiatric disorders may also be causally linked to glial dysfunction and derive from astrocytic as well as oligodendrocytic pathology. The relative contribution of glial dysfunction to many of these disorders may be so great as to allow their treatment by the delivery of allogeneic glial progenitor cells, the precursors to both astroglia and myelin-producing oligodendrocytes. Given the development of new methods for producing and isolating these cells from pluripotent stem cells, both the myelin disorders and appropriate glial-based neurodegenerative conditions may now be compelling targets for cell-based therapy. As such, glial cell-based therapies may offer potential benefit to a broader range of diseases than ever before contemplated, including disorders such as Huntington's disease and the motor neuron degeneration of amyotrophic lateral sclerosis, which have traditionally been considered neuronal in nature.
Topics: Demyelinating Diseases; Humans; Myelin Sheath; Neuroglia; Oligodendroglia; Pluripotent Stem Cells
PubMed: 28554396
DOI: 10.1016/bs.pbr.2017.02.010 -
Revista de Neurologia Sep 2010Neuromyelitis optica (NMO) or Devic's disease is an autoimmune, inflammatory and demyelinating central nervous system disorder that affects mainly to optic nerve and... (Review)
Review
INTRODUCTION
Neuromyelitis optica (NMO) or Devic's disease is an autoimmune, inflammatory and demyelinating central nervous system disorder that affects mainly to optic nerve and spinal cord. Recent advances have substantially permitted to expand the knowledge about this entity.
AIM
To present a clinical update on the current understanding of the nature, progression, diagnosis and treatment of NMO.
DEVELOPMENT
Due to its demyelinating nature and its recurrent behavior in most cases, NMO was first considered a form of multiple sclerosis (MS). However, recent findings have led to the conclusion that NMO is a distinct disorder, presenting important immunopathological, clinical, prognostic and therapeutic differences from MS. Fundamental in the under-standing of the disease was the recent discovery of antibodies directed against aquaporin-4 (anti-AQP4, also known as NMO-IgG), which are present in the majority of NMO cases clinically defined, and in a minority of patients with MS. Despite the knowledge on its immunopathogenesis and advances in diagnosis, the treatment of NMO is still challenging.
CONCLUSION
NMO is a demyelinating disease different from MS. Current diagnostic criteria have been enriched with the recent description of the humoral disorder underlying NMO. However, current treatment options for NMO are far from being ideal.
Topics: Aquaporin 4; Autoantibodies; Demyelinating Diseases; Diagnosis, Differential; Disease Progression; Humans; Multiple Sclerosis; Neuromyelitis Optica; Prognosis
PubMed: 20669128
DOI: No ID Found -
Clinical Microbiology Reviews Jul 2012Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for... (Review)
Review
Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.
Topics: Antibodies, Monoclonal, Humanized; Brain; Coinfection; Demyelinating Diseases; Gene Expression Regulation, Viral; Genome, Viral; HIV; HIV Infections; Humans; Immune Reconstitution Inflammatory Syndrome; JC Virus; Leukoencephalopathy, Progressive Multifocal; Risk Factors; Virus Replication
PubMed: 22763635
DOI: 10.1128/CMR.05031-11 -
Frontiers in Immunology 2023Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections in the central nervous system and induces chronic inflammatory demyelinating... (Review)
Review
Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections in the central nervous system and induces chronic inflammatory demyelinating disease in susceptible mice. TMEV infects dendritic cells, macrophages, B cells, and glial cells. The state of TLR activation in the host plays a critical role in initial viral replication and persistence. The further activation of TLRs enhances viral replication and persistence, leading to the pathogenicity of TMEV-induced demyelinating disease. Various cytokines are produced via TLRs, and MDA-5 signals linked with NF-κB activation following TMEV infection. In turn, these signals further amplify TMEV replication and the persistence of virus-infected cells. The signals further elevate cytokine production, promoting the development of Th17 responses and preventing cellular apoptosis, which enables viral persistence. Excessive levels of cytokines, particularly IL-6 and IL-1β, facilitate the generation of pathogenic Th17 immune responses to viral antigens and autoantigens, leading to TMEV-induced demyelinating disease. These cytokines, together with TLR2 may prematurely generate functionally deficient CD25-FoxP3+ CD4 T cells, which are subsequently converted to Th17 cells. Furthermore, IL-6 and IL-17 synergistically inhibit the apoptosis of virus-infected cells and the cytolytic function of CD8+ T lymphocytes, prolonging the survival of virus-infected cells. The inhibition of apoptosis leads to the persistent activation of NF-κB and TLRs, which continuously provides an environment of excessive cytokines and consequently promotes autoimmune responses. Persistent or repeated infections of other viruses such as COVID-19 may result in similar continuous TLR activation and cytokine production, leading to autoimmune diseases.
Topics: Mice; Animals; Theilovirus; Interleukin-6; Demyelinating Diseases; NF-kappa B; Virulence; COVID-19; Cytokines; Virus Replication
PubMed: 37153539
DOI: 10.3389/fimmu.2023.1167972 -
Neurobiology of Disease Jan 2023Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination...
Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut-microbiota-brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve.
Topics: Animals; Mice; Brain; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice, Inbred C57BL; Microbiota; Microglia; Multiple Sclerosis; Vagus Nerve
PubMed: 36493975
DOI: 10.1016/j.nbd.2022.105951 -
Neuropathology and Applied Neurobiology Dec 2008Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Recent evidence suggests that dysfunction of surviving demyelinated axons... (Review)
Review
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Recent evidence suggests that dysfunction of surviving demyelinated axons and axonal degeneration contribute to the progression of MS. We review the evidence for and potential mechanisms of degeneration as well as dysfunction of chronically demyelinated axons in MS with particular reference to mitochondria, the main source of adenosine-5'-triphosphate in axons. Besides adenosine-5'-triphosphate production, mitochondria play an important role in calcium handling and produce reactive oxygen species. The mitochondrial changes in axons lacking healthy myelin sheaths as well as redistribution of sodium channels suggest that demyelinated axons would be more vulnerable to energy deficit than myelinated axons. A dysfunction of mitochondria in lesions as well as in the normal-appearing white and grey matter is increasingly recognized in MS and could be an important determinant of axonal dysfunction and degeneration. Mitochondria are a potential therapeutic target in MS.
Topics: Adenosine Triphosphate; Animals; Axons; Demyelinating Diseases; Disease Progression; Energy Metabolism; Humans; Mitochondria; Multiple Sclerosis; Myelin Sheath; Nerve Degeneration
PubMed: 19076696
DOI: 10.1111/j.1365-2990.2008.00987.x -
NeuroImage Nov 2018MRI is a valuable tool to assess myelin during development and demyelinating disease processes. While multiexponential T and quantitative magnetization transfer measures...
MRI is a valuable tool to assess myelin during development and demyelinating disease processes. While multiexponential T and quantitative magnetization transfer measures correlate with myelin content, neither provides the total myelin volume fraction. In many cases correlative measures are adequate; but to assess microstructure of myelin, (e.g. calculate the g-ratio using MRI), an accurate measure of myelin volume fraction is imperative. Using a volumetric model of white matter, we relate MRI measures of myelin to absolute measures of myelin volume fraction and compare them to quantitative histology. We assess our approach in control mice along with two models of hypomyelination and one model of hypermyelination and find strong agreement between MRI and histology amongst models. This work investigates the sensitivities of MRI myelin measures to changes in axon geometry and displays promise for estimating g-ratio from MRI.
Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Magnetic Resonance Imaging; Mice; Mice, Knockout; Models, Theoretical; Myelin Sheath; Neuroimaging; Sensitivity and Specificity; White Matter
PubMed: 28025129
DOI: 10.1016/j.neuroimage.2016.12.067