Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0014070 (encephalomyelitis)
13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article reviews recent advances in understanding the role of myelin proteolipid protein (PLP) in autoimmune demyelination. It is drawn largely from work published within the last ten years and discusses the immunology of PLP in the historical context of what has been learned from extensive studies on the immune response to myelin basic protein (MBP). Despite the fact that PLP is the major protein constituent of mammalian myelin, its role in autoimmune demyelination has not been widely recognized. The lack of understanding about the immunology of PLP is a direct result of the biochemical characteristics of the protein. PLP is a highly hydrophobic membrane protein with limited aqueous solubility. The hydrophobicity of PLP has thwarted immunologic studies of the intact protein. Recent work has circumvented the technical obstacles of studying the intact protein by using soluble synthetic PLP peptides. This approach has rapidly resulted in a more definitive understanding of the immune response to PLP. Presently, the data indicate that: i) PLP is a major central nervous system (CNS) specific encephalitogen; ii) CD4+ T cell reactivity to discrete PLP peptide determinants can mediate the development of acute, chronic relapsing, and chronic progressive experimental autoimmune encephalomyelitis (EAE); and iii) T cell reactivity to multiple PLP determinants occurs in patients with multiple sclerosis (MS), the major human CNS demyelinating disease.
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PMID:Peptide determinants of myelin proteolipid protein (PLP) in autoimmune demyelinating disease: a review. 752 55

Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus which causes a biphasic central nervous system (CNS) disease in certain strains of mice. Lytic virus replication within the CNS causes acute damage at early times post-infection, with the surviving animals developing a chronic CNS demyelinating disease. This damage is thought to result both from direct viral damage and from an immunopathological CD4+ T-cell mediated delayed-type hypersensitivity response to virus. By contrast, CD4+ T cells have a vital protective role at early times post-infection, as mice specifically depleted of CD4+ T cells of this subset prior to infection with TMEV die within 3-5 weeks. In an investigation of how CD4+ T cells act to mediate protection in TMEV-infected mice, we show that CD4+ cell-depleted animals, which fail to make a significant antiviral antibody response, could be protected by passive transfer of neutralizing antibodies. However, surviving animals had high levels of persisting virus in the CNS and they developed very severe symptoms of chronic demyelinating disease. The appearance of infectious virus was not due to selection of neutralizing antibody-resistant viral variants. These results demonstrate that the key protective role of CD4+ T cells in TMEV-infected mice is to provide help for antibody production by B cells at early times post-infection, but that other CD4+ cell-dependent mechanisms must contribute to control of virus replication, and are of importance in determining the levels of virus subsequently persisting in the CNS, and hence the severity of the chronic demyelinating disease.
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PMID:Study of the mechanisms by which CD4+ T cells contribute to protection in Theiler's murine encephalomyelitis. 790 93

Susceptible strains of mice infected intracerebrally with Theiler's murine encephalomyelitis virus develop a chronic, progressive, immune-mediated CNS demyelinating disease similar both pathologically and clinically to multiple sclerosis. Previous reports indicated that polyclonal immunoglobulins from mice injected with homogenized spinal cord promote CNS remyelination when given to SJL/J mice chronically infected with Theiler's virus. To explore further both the mechanism(s) and potential therapeutic usefulness of antibodies in the treatment of CNS demyelinating diseases, we made a panel of monoclonal antibodies derived from splenocytes of SJL/J mice injected with homogenized spinal cord, and screened them for their autoantigen-binding capability. Monoclonal IgM autoantibodies from two clones, designated SCH94.03 and SCH94.32, promoted fourfold more CNS remyelination than controls when given to chronically infected SJL/J mice. CNS remyelination, assessed morphologically by the presence of abnormally thin myelin sheaths relative to axonal diameter, correlated with the absence of clinical disease progression. In titration experiments, treatment with SCH94.03 and remyelination had a positive dose-response relationship, and as little as 10 micrograms of antibody promoted remyelination. Both SCH94.03 and SCH94.32 showed multiorgan autoreactivity, and recognized both surface and cytoplasmic determinants on glial cells. We propose that this model provides a unique system to elucidate the mechanism(s) and test the reparative potential of autoantibodies in the treatment of CNS injury.
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PMID:Monoclonal autoantibodies promote central nervous system repair in an animal model of multiple sclerosis. 793 75

Experimental allergic encephalomyelitis (EAE) is a demyelinating autoimmune disorder that can be induced in susceptible mice by T lymphocytes sensitized to central nervous system (CNS) myelin components and is a prime animal model for the human CNS demyelinating disorder, multiple sclerosis (MS). Although CNS inflammation in which T lymphocytes and activated macrophages are the predominant cell types is observed in mice with EAE and in humans with MS, the exact mechanisms underlying the CNS damage and demyelination are not understood. Nitric oxide (NO), a gaseous free radical, has recently been shown to be a cytolytic product of activated macrophages. Using electron paramagnetic resonance spectroscopy, the nitric oxide free radical complexed with iron-sulfur proteins has been identified in affected spinal cords of mice with EAE, concurrent with the diminution of iron-sulfur proteins. These results indicate NO may play a role in the disease process of EAE, and perhaps MS.
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PMID:Nitric oxide localized to spinal cords of mice with experimental allergic encephalomyelitis: an electron paramagnetic resonance study. 839 79

We postulated that humoral autoimmunity can play a beneficial role in CNS demyelinating diseases such as multiple sclerosis. We previously demonstrated that monoclonal natural autoantibody SCH94.03 suppresses CNS inflammation and promotes remyelination in a virus-induced model of chronic progressive multiple sclerosis. To further investigate the relationship between natural autoimmunity and CNS demyelination, we examined the effect of SCH94.03 treatment on clinical relapses and pathological disease in SJL/J mice with established adoptive-transfer relapsing experimental autoimmune encephalomyelitis. Treatment with SCH94.03 after recovery from the initial episode of clinical disease reduced relapse rates by half, prolonged relapse onset by 6 days and reduced spinal cord demyelination and meningeal inflammation by 40%. These results are consistent with the hypothesized immunomodulatory function of natural autoantibodies, and are the first direct demonstration that natural humoral autoimmunity can be beneficial in an autoimmune T-cell-mediated CNS demyelinating disease.
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PMID:Successful treatment of established relapsing experimental autoimmune encephalomyelitis in mice with a monoclonal natural autoantibody. 914 56

Nitric oxide (.NO) and its reactive derivative peroxynitrite (ONOO-) have been implicated in the pathogenesis of multiple sclerosis (MS). They are cytotoxic to oligodendrocytes and neurones in culture by inhibiting the mitochondrial respiratory chain (complexes II/III and IV) and inhibiting certain key intracellular enzymes. Recently .NO has been implicated as a possible aetiological factor in reversible conduction block in demyelinated axons. Inducible nitric oxide synthase (iNOS) is upregulated in the central nervous system of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. In some EAE models inhibiting iNOS activity decreases disease severity whilst in other models disease activity is exacerbated. Raised levels of nitrate and nitrite, stable end-products of .NO/ONOO-, are found in the cerebrospinal fluid, serum and urine of patients with MS. CSF levels of nitrate and nitrite correlate with blood-brain-barrier dysfunction, which suggests that .NO may play a role in inflammatory blood-brain-barrier dysfunction. In a longitudinal study on 24 patients with relapsing remitting and secondary progressive MS, raised serum nitrate and nitrite levels correlated with a relapsing course and infrequent relapses. However, no correlation was found between raised serum levels of nitrate and nitrite and MRI activity, disease progression, or the development of cerebral atrophy. In autoimmune mediated CNS demyelinating disease .NO may be a double-edged sword, mediating tissue damage on the one hand and on the other hand modulating complex immunological functions which may be protective.
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PMID:The potential role of nitric oxide in multiple sclerosis. 976 76

Although the etiology of multiple sclerosis (MS) is not known, several factors play a role in this disease: genetic contributions, immunologic elements, and environmental factors. Viruses and virus infections have been associated with the initiation and/or enhancement of exacerbations in MS. Theiler's murine encephalomyelitis virus (TMEV) infection of mice is one of the animal models used to mimic MS. In other animal model systems, DNA vaccination has been used to protect animals against a variety of virus infections. To explore the utility of DNA vaccination, we have constructed eukaryotic expression vectors encoding the TMEV capsid proteins VP1, VP2, and VP3. SJL/J mice were vaccinated intramuscularly once, twice, or three times with the different capsid protein cDNAs. This was followed by intracerebral TMEV infection to determine the effects of DNA vaccination on the course of TMEV-induced central nervous system (CNS) demyelinating disease. We found that vaccination of mice three times with cDNA encoding VP2 led to partial protection of mice from CNS demyelinating disease as determined by a decrease in clinical symptoms and histopathology. Vaccination of mice with cDNA encoding VP3 also led to a decrease in clinical symptoms. In contrast, mice vaccinated with cDNA encoding VP1 experienced a more severe disease with an earlier onset of clinical signs and enhanced histopathology compared with control mice. There was no correlation between anti-TMEV antibody titers and disease course. These results indicate that DNA immunization can modify chronic virus-induced demyelinating disease and may eventually lead to potential treatments for illnesses such as MS.
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PMID:DNA vaccination against Theiler's murine encephalomyelitis virus leads to alterations in demyelinating disease. 988

Fibronectin (FN), a large family of plasma and extracellular matrix (ECM) glycoproteins, plays an important role in leukocyte migration. In normal central nervous system (CNS), a fine and delicate mesh of FN is virtually restricted to the basal membrane of cerebral blood vessels and to the glial limitans externa. Experimental autoimmune encephalomyelitis (EAE), an inflammatory CNS demyelinating disease, was induced in Lewis rats with a spinal cord homogenate. During the preclinical phase and the onset of the disease, marked immunolabelling was observed on the endothelial luminal surface and basal lamina of spinal cord and brainstem microvasculature. In the paralytic phase, a discrete labelling was evident in blood vessels of spinal cord and brainstem associated or not with an inflammatory infiltrate. Conversely, intense immunolabelling was present in cerebral and cerebellar blood vessels, which were still free from inflammatory cuffs. Shortly after clinical recovery minimal labelling was observed in a few blood vessels. Brainstem and spinal cord returned to normal, but numerous inflammatory foci and demyelination were still evident near the ventricle walls, in the cerebral cortex and in the cerebellum. Intense expression of FN in brain vessels ascending from the spinal cord towards the encephalon preceded the appearance of inflammatory cells but faded away after the establishment of the inflammatory cuff. These results indicate an important role for FN in the pathogenesis of CNS inflammatory demyelinating events occurring during EAF.
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PMID:Modulation of fibronectin expression in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis. 1041 70

Chemokines are low molecular weight chemotactic peptides that bind seven transmembrane-spanning, G protein-coupled receptors and deliver signals leading to T cell costimulation, hematopoeisis, cytokine expression, T cell differentiation, and integrin activation. Experimental autoimmune encephalomyelitis (EAE) is a CD4+ Th1-mediated demyelinating disease of the central nervous system (CNS) that serves as a model for multiple sclerosis (MS). A hallmark in the pathogenesis of this CNS demyelinating disease is the emigration of T cells and monocytes from the blood to the CNS. There are several considerations that suggest a role for chemokines in the influx of inflammatory cells and the resulting disease process including a tight temporal expression pattern with relationship to disease activity and prevention of disease development by in vivo neutralization. We review the evidence that temporal and spatial expressions of chemokines are crucial factors, complementing adhesion molecule upregulation, that regulate EAE and potentially MS disease activity as well as the functions of chemokines in Th1 and Th2 biology.
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PMID:Role of chemokines in the regulation of Th1/Th2 and autoimmune encephalomyelitis. 1053 3

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a chronic-progressive, immune-mediated CNS demyelinating disease and a relevant model of multiple sclerosis. Myelin destruction is initiated by TMEV-specific CD4(+) T cells targeting persistently infected CNS-resident APCs leading to activation of myelin epitope-specific CD4(+) T cells via epitope spreading. We examined the temporal development of virus- and myelin-specific T cell responses and acquisition of virus and myelin epitopes by CNS-resident APCs during the chronic disease course. CD4(+) T cell responses to virus epitopes arise within 1 wk after infection and persist over a >300-day period. In contrast, myelin-specific T cell responses are first apparent approximately 50-60 days postinfection, appear in an ordered progression associated with their relative encephalitogenic dominance, and also persist. Consistent with disease initiation by virus-specific CD4(+) T cells, CNS mononuclear cells from TMEV-infected SJL mice endogenously process and present virus epitopes throughout the disease course, while myelin epitopes are presented only after initiation of myelin damage (>50-60 days postinfection). Activated F4/80(+) APCs expressing high levels of MHC class II and B7 costimulatory molecules and ingested myelin debris chronically accumulate in the CNS. These results suggest a process of autoimmune induction in which virus-specific T cell-mediated bystander myelin destruction leads to the recruitment and activation of infiltrating and CNS-resident APCs that process and present endogenous myelin epitopes to autoreactive T cells in a hierarchical order.
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PMID:Temporal development of autoreactive Th1 responses and endogenous presentation of self myelin epitopes by central nervous system-resident APCs in Theiler's virus-infected mice. 1104 65


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