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Viral Immunology Aug 2013Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible SJL mice that has similarities to multiple sclerosis in humans. TMEV...
Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible SJL mice that has similarities to multiple sclerosis in humans. TMEV infection of susceptible mice leads to a persistent virus infection of the central nervous system (CNS), which promotes the development of demyelinating disease associated with an inflammatory immune response in the CNS. TMEV infection of resistant C57BL6 mice results in viral clearance without development of demyelinating disease. Interestingly, TMEV infection of resistant mice deficient in IFNγ leads to a persistent virus infection in the CNS and development of demyelinating disease. We have previously shown that the innate immune response affects development of TMEV- induced demyelinating disease, thus we wanted to determine the role of IFNγ during the innate immune response. TMEV-infected IFNγ-deficient mice had an altered innate immune response, including reduced expression of innate immune cytokines, especially type I interferons. Administration of type I interferons, IFNα and IFNß, to TMEV-infected IFNγ-deficient mice during the innate immune response restored the expression of innate immune cytokines. Most importantly, administration of type I interferons to IFNγ-deficient mice during the innate immune response decreased the virus load in the CNS and decreased development of demyelinating disease. Microglia are the CNS resident immune cells that express innate immune receptors. In TMEV-infected IFNγ-deficient mice, microglia had reduced expression of innate immune cytokines, and administration of type I interferons to these mice restored the innate immune response by microglia. In the absence of IFNγ, microglia from TMEV-infected mice had reduced expression of some innate immune receptors and signaling molecules, especially IRF1. These results suggest that IFNγ plays an important role in the innate immune response to TMEV by enhancing the expression of innate immune cytokines, especially type I interferons, which directly affects the development of demyelinating disease.
Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cardiovirus Infections; Central Nervous System; Cytokines; Demyelinating Diseases; Disease Models, Animal; Disease Susceptibility; Female; Immunity, Innate; Inflammation; Interferon Regulatory Factor-1; Interferon-alpha; Interferon-beta; Interferon-gamma; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Multiple Sclerosis; Theilovirus; Viral Load
PubMed: 23829778
DOI: 10.1089/vim.2013.0004 -
Brain Pathology (Zurich, Switzerland) Oct 1998Dys- and demyelination are the common endpoints of several inherited diseases of glial cells, which elaborate myelin and which maintain the myelin sheath very much like... (Review)
Review
Dys- and demyelination are the common endpoints of several inherited diseases of glial cells, which elaborate myelin and which maintain the myelin sheath very much like an "external" cellular organelle. Whereas some of the genes that are affected by mutations appear to be glial-specific, other genes are expressed in many cell types but their defect is restricted to oligodendrocytes or Schwann cells. Many of the disease genes and their encoded proteins have been studied with the help of mouse models, and a number of different molecular pathomechanisms have emerged which have been summarized in Figure 8. Some of the new concepts in the field, which have been addressed in this review, have only emerged because similar pathomechanisms were discovered for different myelin proteins. Mouse models have clearly helped to address both, the molecular pathology of myelin diseases and the normal function of myelin genes, but as discussed in this review, these questions turned out to be very different. Despite the progress in understanding the role of the abundant myelin proteins, there also remain a number of open questions that concern, among other things, the initial axon-glia recognition, the assembly process of the myelin sheath, and the long-term interaction of axons with their myelinating glia. Finally, animal models of human neurological diseases should not be restricted to the study of pathology, but they should also contribute to the development of experimental treatments. It is encouraging that a few attempts have been made.
Topics: Animals; Demyelinating Diseases; Humans; Mice; Mice, Transgenic; Mutation; Myelin Sheath
PubMed: 9804383
DOI: 10.1111/j.1750-3639.1998.tb00200.x -
Clinical & Developmental Immunology 2013The central nervous system (CNS) is immune privileged with access to leukocytes being limited. In several neurological diseases, however, infiltration of immune cells... (Review)
Review
The central nervous system (CNS) is immune privileged with access to leukocytes being limited. In several neurological diseases, however, infiltration of immune cells from the periphery into the CNS is largely observed and accounts for the increased representation of macrophages within the CNS. In addition to extensive leukocyte infiltration, the activation of microglia is frequently observed. The functions of activated macrophages/microglia within the CNS are complex. In three animal models of multiple sclerosis (MS), namely, experimental autoimmune encephalomyelitis (EAE) and cuprizone- and lysolecithin-induced demyelination, there have been many reported detrimental roles associated with the involvement of macrophages and microglia. Such detriments include toxicity to neurons and oligodendrocyte precursor cells, release of proteases, release of inflammatory cytokines and free radicals, and recruitment and reactivation of T lymphocytes in the CNS. Many studies, however, have also reported beneficial roles of macrophages/microglia, including axon regenerative roles, assistance in promoting remyelination, clearance of inhibitory myelin debris, and the release of neurotrophic factors. This review will discuss the evidence supporting the detrimental and beneficial aspects of macrophages/microglia in models of MS, provide a discussion of the mechanisms underlying the dichotomous roles, and describe a few therapies in clinical use in MS that impinge on the activity of macrophages/microglia.
Topics: Animals; Cell Movement; Central Nervous System; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Immunologic Factors; Lysophosphatidylcholines; Macrophages; Microglia; Multiple Sclerosis; Neurons; Oligodendroglia; T-Lymphocytes
PubMed: 23840244
DOI: 10.1155/2013/948976 -
Multiple Sclerosis and Related Disorders Dec 2022Since the start of COVID-19 vaccination worldwide, there have been several reports of inflammatory demyelinating diseases of the central nervous system (CNS-IDDs)...
BACKGROUND
Since the start of COVID-19 vaccination worldwide, there have been several reports of inflammatory demyelinating diseases of the central nervous system (CNS-IDDs) following vaccination.
METHODS
We prospectively collected cases of new-onset CNS-IDDs with a temporal relationship between disease onset and COVID-19 vaccination and investigated their proportion among newly registered cases of CNS-IDD over the past year.
RESULTS
Among 117 cases, 10 (8.5%) had their first disease manifestation within one month following COVID-19 vaccination: 2 multiple sclerosis, 2 neuromyelitis optica spectrum disorder, 3 MOG antibody-associated disease, and 3 unclassified CNS-IDDs.
CONCLUSION
This observation suggests that COVID-19 vaccination may trigger the onset of various CNS-IDDs in susceptible individuals.
Topics: Humans; Autoantibodies; Central Nervous System; Central Nervous System Diseases; COVID-19; COVID-19 Vaccines; Demyelinating Autoimmune Diseases, CNS; Neuromyelitis Optica
PubMed: 36037757
DOI: 10.1016/j.msard.2022.104141 -
Journal of Neuroinflammation Sep 2012Theiler's virus infection induces chronic demyelinating disease in mice and has been investigated as an infectious model for multiple sclerosis (MS). IL-1 plays an...
BACKGROUND
Theiler's virus infection induces chronic demyelinating disease in mice and has been investigated as an infectious model for multiple sclerosis (MS). IL-1 plays an important role in the pathogenesis of both the autoimmune disease model (EAE) and this viral model for MS. However, IL-1 is known to play an important protective role against certain viral infections. Therefore, it is unclear whether IL-1-mediated signaling plays a protective or pathogenic role in the development of TMEV-induced demyelinating disease.
METHODS
Female C57BL/6 mice and B6.129S7-Il1r1tm1Imx/J mice (IL-1R KO) were infected with Theiler's murine encephalomyelitis virus (1 x 106 PFU). Differences in the development of demyelinating disease and changes in the histopathology were compared. Viral persistence, cytokine production, and immune responses in the CNS of infected mice were analyzed using quantitative PCR, ELISA, and flow cytometry.
RESULTS
Administration of IL-1β, thereby rending resistant B6 mice susceptible to TMEV-induced demyelinating disease, induced a high level of Th17 response. Interestingly, infection of TMEV into IL-1R-deficient resistant C57BL/6 (B6) mice also induced TMEV-induced demyelinating disease. High viral persistence was found in the late stage of viral infection in IL-1R-deficient mice, although there were few differences in the initial anti-viral immune responses and viral persistent levels between the WT B6 and IL-1R-deficiecent mice. The initial type I IFN responses and the expression of PDL-1 and Tim-3 were higher in the CNS of TMEV-infected IL-1R-deficient mice, leading to deficiencies in T cell function that permit viral persistence.
CONCLUSIONS
These results suggest that the presence of high IL-1 level exerts the pathogenic role by elevating pathogenic Th17 responses, whereas the lack of IL-1 signals promotes viral persistence in the spinal cord due to insufficient T cell activation by elevating the production of inhibitory cytokines and regulatory molecules. Therefore, the balance of IL-1 signaling appears to be extremely important for the protection from TMEV-induced demyelinating disease, and either too much or too little signaling promotes the development of disease.
Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Female; Interleukin-1beta; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Multiple Sclerosis; Poliomyelitis; Signal Transduction; Theilovirus
PubMed: 22985464
DOI: 10.1186/1742-2094-9-217 -
Journal of Neuroimmunology Jul 2017Neurotropic viruses are important causes of morbidity and mortality in human populations. Some of these viruses preferentially infect oligodendrocytes in the white... (Review)
Review
Neurotropic viruses are important causes of morbidity and mortality in human populations. Some of these viruses preferentially infect oligodendrocytes in the white matter, causing either direct lysis of infected cells, or more commonly myelin damage as a consequence of the host immune response to the virus. Virus-induced demyelination has similarities to the human disease multiple sclerosis. To study this disease process in experimental animals, mice are infected, most commonly, with neurotropic strains of mouse hepatitis virus, a coronavirus or Theiler's murine encephalomyelitis, a picornavirus. While the diseases caused by these two viruses differ in some aspects, in both cases demyelination is a major consequence of the infection. As in autoimmune disease, therapeutic interventions that diminish an overactive immune response would be useful. However, unlike autoimmune disease, complete suppression would result in unchecked virus replication, generally leading to more severe disease. Here we discuss two approaches that dampen but do not fully suppress the host immune response. Regulatory T cells, especially those that are specific for antigens recognized by pathogenic T cells, and IL-10 are two anti-inflammatory/pro-resolution factors that demonstrate efficacy in experimental models of virus-induced demyelination and may be useful in patients infected with viruses that cause demyelination.
Topics: Animals; Demyelinating Diseases; Humans; Interleukin-10; T-Lymphocytes, Regulatory; Virus Diseases
PubMed: 28065579
DOI: 10.1016/j.jneuroim.2017.01.001 -
Brain Pathology (Zurich, Switzerland) Jan 1999This review summarises the role that reactive oxygen and nitrogen species play in demyelination, such as that occurring in the inflammatory demyelinating disorders... (Review)
Review
This review summarises the role that reactive oxygen and nitrogen species play in demyelination, such as that occurring in the inflammatory demyelinating disorders multiple sclerosis and Guillain-Barré syndrome. The concentrations of reactive oxygen and nitrogen species (e.g. superoxide, nitric oxide and peroxynitrite) can increase dramatically under conditions such as inflammation, and this can overwhelm the inherent antioxidant defences within lesions. Such oxidative and/or nitrative stress can damage the lipids, proteins and nucleic acids of cells and mitochondria, potentially causing cell death. Oligodendrocytes are more sensitive to oxidative and nitrative stress in vitro than are astrocytes and microglia, seemingly due to a diminished capacity for antioxidant defence, and the presence of raised risk factors, including a high iron content. Oxidative and nitrative stress might therefore result in vivo in selective oligodendrocyte death, and thereby demyelination. The reactive species may also damage the myelin sheath, promoting its attack by macrophages. Damage can occur directly by lipid peroxidation, and indirectly by the activation of proteases and phospholipase A2. Evidence for the existence of oxidative and nitrative stress within inflammatory demyelinating lesions includes the presence of both lipid and protein peroxides, and nitrotyrosine (a marker for peroxynitrite formation). The neurological deficit resulting from experimental autoimmune demyelinating disease has generally been reduced by trial therapies intended to diminish the concentration of reactive oxygen species. However, therapies aimed at diminishing reactive nitrogen species have had a more variable outcome, sometimes exacerbating disease.
Topics: Animals; Antioxidants; Demyelinating Diseases; Humans; Inflammation; Lipid Peroxidation; Nervous System; Nitrates; Nitric Oxide; Oxidants; Oxidative Stress; Reactive Oxygen Species
PubMed: 9989453
DOI: 10.1111/j.1750-3639.1999.tb00212.x -
Journal of Neurochemistry Feb 2021Multiple sclerosis (MS) represents the most common demyelinating disease affecting the central nervous system (CNS) in adults as well as in children. Furthermore, in... (Review)
Review
Multiple sclerosis (MS) represents the most common demyelinating disease affecting the central nervous system (CNS) in adults as well as in children. Furthermore, in children, in addition to acquired diseases such as MS, genetically inherited diseases significantly contribute to the incidence of demyelinating disorders. Some genetic defects lead to sphingolipid alterations that are able to elicit neurological symptoms. Sphingolipids are essential for brain development, and their aberrant functionality may thus contribute to demyelinating diseases such as MS. In particular, sphingolipidoses caused by deficits of sphingolipid-metabolizing enzymes, are often associated with demyelination. Sphingolipids are not only structural molecules but also bioactive molecules involved in the regulation of cellular events such as development of the nervous system, myelination and maintenance of myelin stability. Changes in the sphingolipid metabolism deeply affect plasma membrane organization. Thus, changes in myelin sphingolipid composition might crucially contribute to the phenotype of diseases characterized by demyelinalization. Here, we review key features of several sphingolipids such as ceramide/dihydroceramide, sphingosine/dihydrosphingosine, glucosylceramide and, galactosylceramide which act in myelin formation during rat brain development and in human brain demyelination during the pathogenesis of MS, suggesting that this knowledge could be useful in identifying targets for possible therapies.
Topics: Adult; Animals; Child; Demyelinating Diseases; Humans; Myelin Sheath; Nerve Fibers, Myelinated; Sphingolipids
PubMed: 33448358
DOI: 10.1111/jnc.15133 -
Journal of Neuroimmunology Jul 2010Persistent infection of the central nervous system (CNS) of mice with the neuroadapted JHM strain of mouse hepatitis (MHV) is characterized by ongoing demyelination... (Review)
Review
Persistent infection of the central nervous system (CNS) of mice with the neuroadapted JHM strain of mouse hepatitis (MHV) is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Although extensive demyelination occurs in mice persistently infected with MHV there is only limited remyelination. Therefore, the MHV model of demyelination is a relevant model for studying disease and evaluating therapeutic approaches to protect cells of the oligodendrocyte lineage and promote remyelination. This concept is further highlighted as the etiology of MS remains enigmatic, but viruses have long been considered as potential triggering agents in initiating and/or maintaining MS symptoms. As such, understanding mechanisms associated with promoting repair within the CNS in the context of a persistent viral infection is critical given the possible viral etiology of MS. This review focuses on recent studies using either mouse neural stem cells (NSCs) or human oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem cell (hESC) to promote remyelination in mice persistently infected with MHV. In addition, the potential role for chemokines in positional migration of transplanted cells is addressed.
Topics: Animals; Cell Lineage; Coronavirus Infections; Demyelinating Diseases; Disease Models, Animal; Encephalitis, Viral; Humans; Mice; Murine hepatitis virus; Nerve Fibers, Myelinated; Nerve Regeneration; Stem Cell Transplantation
PubMed: 20627412
DOI: 10.1016/j.jneuroim.2010.05.013 -
Seminars in Cell & Developmental Biology Aug 2021Demyelinating disorders of the central white matter are among the most prevalent and disabling conditions in neurology. Since myelin-producing oligodendrocytes comprise... (Review)
Review
Demyelinating disorders of the central white matter are among the most prevalent and disabling conditions in neurology. Since myelin-producing oligodendrocytes comprise the principal cell type deficient or lost in these conditions, their replacement by new cells generated from transplanted bipotential oligodendrocyte-astrocyte progenitor cells has emerged as a therapeutic strategy for a variety of primary dysmyelinating diseases. In this review, we summarize the research and clinical considerations supporting current efforts to bring this treatment approach to patients.
Topics: Animals; Cell Differentiation; Demyelinating Diseases; Humans; Neuroglia; Stem Cells
PubMed: 33414060
DOI: 10.1016/j.semcdb.2020.12.004