Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently identified the inducible isoform of nitric oxide synthase (iNOS) in inflammatory lesions of the central nervous system (CNS) in mice with experimental allergic encephalomyelitis (EAE), a known animal model of multiple sclerosis (MS). In the present study, the role of excessive nitric oxide (NO) production via iNOS was investigated in mice with EAE using immunohistochemistry with antibodies to nitrotyrosine and iNOS, NADPH-diaphorase histochemistry, and the in situ terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) method to detect cell death, presumably through an apoptotic mechanism. NADPH-diaphorase histochemistry and immunohistochemistry for iNOS revealed an elevation of nitric oxide synthase (NOS) activity during the course of EAE, which came from iNOS. Nitrotyrosine was detected in infiltrated cells and some glial cells in the spinal cord lesions, where iNOS-positive inflammatory cells were present at the peak of EAE. The findings implied the generation of NO and peroxynitrite in the EAE lesions, which might damage structural and functional proteins. The TUNEL positive cells were mainly inflammatory ones, and most of them were located in close proximity to iNOS-positive cells, while some of them were iNOS-positive themselves. These results suggested that excessive NO via iNOS played an important role to eliminate inflammatory cells in the CNS of mice with EAE, possibly through an apoptotic mechanism.
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PMID:Nitric oxide via an inducible isoform of nitric oxide synthase is a possible factor to eliminate inflammatory cells from the central nervous system of mice with experimental allergic encephalomyelitis. 905 66

Mice develop a fatal encephalomyelitis after infection with the Trinidad donkey strain of Venezuelan equine encephalitis (VEE) virus. Adult mice were inoculated intraperitoneally with VEE virus and the brains were examined at different time points. Morphological changes were assessed by histological staining. VEE virus antigen was detected with immunoperoxidase staining, and DNA fragmentation was evaluated in situ using the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) method. VEE antigen was found in many areas of the brain and it was prominent in neurons. There were mild associated inflammatory changes. DNA fragmentation was demonstrated in many of these areas using TUNEL. In areas with TUNEL staining, morphological neuronal changes ranged from nuclear chromatin condensations to nuclear and cellular fragmentation, which are characteristic of apoptosis. There is strong morphological and biochemical evidence of apoptotic cell death in this experimental model of VEE virus infection.
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PMID:Apoptotic cell death is an important cause of neuronal injury in experimental Venezuelan equine encephalitis virus infection of mice. 911

The etiology of hydrocephalus is never established in the majority of clinical cases, while various agents, nutritional deficiencies, and genetic factors have been shown to play a role. Viral infection has been recognized as one of the causative factors in the development of hydrocephalus. The wild-type DA strain of Theiler's murine encephalomyelitis virus (TMEV), which belongs to the family Picornaviridae, causes a chronic demyelinating disease in mice with viral persistence that resembles multiple sclerosis. We found that a DA virus variant, hydrocephalus 101 virus (H101 virus), caused hydrocephalus in mice, a condition previously never described for TMEV. To clarify the relationship between DA virus infection and hydrocephalus, we compared H101 virus and wild-type DA virus infection in mice. Using immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL), we found that during the acute phase of infection, H101 virus caused macrocephaly and meningitis with the presence of apoptosis, while parenchymal involvement was not evident. In contrast, wild-type DA virus caused an acute polioencephalomyelitis with parenchymal infection and apoptosis. During the chronic phase, H101 virus infection caused communicating hydrocephalus without viral persistence. No demyelination and little or no anti-TMEV antibodies were observed in H101 virus-infected mice. Sequence analysis revealed that H101 virus had mutations in the 5'UTR and capsid protein coding region. Characterization of this new hydrocephalus model gives insight into the possible viral involvement in human hydrocephalus cases of obscure etiology.
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PMID:Hydrocephalus in mice infected with a Theiler's murine encephalomyelitis virus variant. 941 79

To elucidate the role of brain cells in the immune regulation in the central nervous system (CNS), acute and chronic relapsing experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats and the location of apoptotic inflammatory cells and their interaction with astrocytes and microglia was investigated at various stages of the disease. Apoptotic cells detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) were few in number at day 10-12 post-immunization (PI), increased and peaked at day 13 PI. Then, these cells decreased gradually by day 21 PI. The most characteristic finding was that apoptotic cells were mainly distributed in the CNS parenchyma with only a few cells present in perivascular cuffs. Double staining by the TUNEL method and immunocytochemistry for astrocytes and microglia revealed that astrocytes were more closely associated with apoptotic cells than microglia. Apoptotic cell death may be one mechanism by which T cells are eliminated from the CNS. Furthermore, the present study suggests that astrocytes, rather than microglia, induce programmed cell death of infiltrating inflammatory cells.
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PMID:Interaction between apoptotic cells and reactive brain cells in the central nervous system of rats with autoimmune encephalomyelitis. 958 13

Increasing evidence suggests that macrophages (M(phi)s) are necessary for persistence of Theiler's murine encephalomyelitis virus (TMEV) in the mouse central nervous system. Analysis of BeAn virus infection in the Mphi cell lines P388D1, J774A.1 and PU5-1.8, which are intermediate in their state of differentiation and resemble multifunctional resident M(phi)s, revealed restricted TMEV growth. As a result of the restricted infection, these Mphi cell lines were induced to undergo apoptosis as demonstrated by cellular morphology, DNA fragmentation, caspase protease activity, and in individual cells, by terminal deoxytransferase dUTP nick-end labelling (TUNEL).
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PMID:Restricted Theiler's murine encephalomyelitis virus infection in murine macrophages induces apoptosis. 1042 38

Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated disorder characterized by infiltration of the central nervous system (CNS) by mononuclear cells and macrophages, and serves as a model for multiple sclerosis. In acute monophasic and relapsing remitting forms of EAE, the CNS inflammatory infiltrates are cleared within a few days and, simultaneously, animals recover from their clinical disability. The mechanisms for rapid disappearance of the inflammatory cells are not fully understood. Fas and Fas-ligand (Fas-L) molecules are thought to play an important role in the deletion of autoimmune reactive T cells through apoptosis. However, recent observations in transgenic lpr and gld mice show that mutations inactivating Fas and Fas-L respectively ameliorate signs of EAE despite persistence of immune cell infiltrates into the CNS. In the current study, the expression of Fas and Fas-L was investigated by immunochemistry and in situ hybridization during the course of EAE in DA rats that were actively immunized with syngenic spinal cord homogenate. CNS apoptotic cells were simultaneously examined using terminal transferase dUTP nick end-labeling techniques. During the acute phase of the disease, a significant proportion of CNS CD4+ cells (80%) and macrophages (50%) expressed Fas and Fas-L (80 and 60%, respectively). Simultaneously, about 20% of CD4+ cells and 30% of macrophages were found to be apoptotic. Some astrocytes and neurons also expressed Fas and Fas-L, although they did not appear to be apoptotic. These results further support a role for Fas-mediated lymphocyte and macrophage apoptosis in this model of CNS autoimmune disease but they also suggest a more complex role for Fas/Fas-L interactions in CNS autoimmunity, including resident cells.
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PMID:Fas system up-regulation in experimental autoimmune encephalomyelitis. 1056 24

PLP139-51-induced experimental autoimmune encephalomyelitis (R-EAE) displays a relapsing-remitting paralytic course in female SJL mice. We investigated the role of apoptosis/activation-induced cell death (AICD) in the spontaneous recovery from acute disease. Clinical EAE was significantly enhanced in Fas (CD95/APO-1)-deficient SJL lpr/lpr mice, which displayed significantly increased mean peak clinical scores, reduced remission rates, and increased mortality when compared with their SJL +/lpr littermates. PLP139-151-specific proliferative responses were fairly equivalent in the 2 groups, but draining lymph node T cells from SJL lpr/lpr mice produced dramatically increased levels of IFN-gamma. Central nervous system (CNS) Fas and FasL mRNA levels in wild-type SJL (H-2(s)) mice peaked just before spontaneous disease remission and gradually declined as disease remitted. We applied the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay to detect apoptosis in situ in spinal cords of mice at various clinical stages of EAE. Most TUNEL(+) cells were found during active periods of inflammation: the acute, peak, and relapse time points. Significantly fewer apoptotic cells were observed at preclinical and remission time points. Collectively, these findings indicate that Fas-mediated apoptosis/AICD plays a major role in the spontaneous remission after the initial acute inflammatory episode and represents an important intrinsic mechanism in regulation of autoimmune responses.
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PMID:Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis. 1064 1

The precise role of tumour necrosis factor alpha (TNFalpha) in multiple sclerosis (MS) is still controversial. Most findings from the animal model experimental allergic encephalomyelitis have yet to be confirmed in multiple sclerosis. The aim of this study was to define the significance of TNFalpha with respect to the hallmark of MS, that is demyelination. Therefore, 78 lesion areas from diagnostic brain biopsies of 32 patients were analysed. Lesion demyelinating activity was classified by the presence of myelin degradation products in macrophages and macrophage activation markers. Non-radioactive in situ hybridisation was carried out to detect TNFalpha mRNA expressing cells. DNA fragmentation was visualised by TdT-mediated X-dUTP nick end labeling. A significantly higher number of cells expressed TNFalpha mRNA in active demyelinating lesions than in inactive or remyelinating lesions irrespective of the extent of the inflammatory infiltrate. TNFalpha mRNA expression correlated with the appearance of DNA fragmentation in T lymphocytes and oligodendrocytes within the lesions. In the periplaque white matter, expression of TNFalpha mRNA negatively correlated with oligodendrocyte numbers. These data support previous findings from animal models and in vitro experiments. Although not proving, the current study strongly suggests a pathogenic role of TNFalpha in demyelination in human multiple sclerosis and gives further support for TNFalpha-directed therapeutic strategies.
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PMID:Tumour necrosis factor alpha mRNA expression in early multiple sclerosis lesions: correlation with demyelinating activity and oligodendrocyte pathology. 1065 46

The expression of pro-apoptotic molecules p53 and Bax in the spinal cord of rats with experimental autoimmune encephalomyelitis (EAE) was examined. Apoptosis was confirmed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method. TUNEL (+) apoptotic cells were mainly either ED1 (+) macrophages or T-cells in the parenchyma of EAE. Western blot analysis showed that both p53 and Bax expression significantly (P<0. 01) increased in the spinal cords of EAE rats at the peak stage, and thereafter declined. An immunohistochemical study showed that inflammatory cells (notably T cells) in the parenchyma express p53 and Bax, while brain cells, including neurons and glia, were devoid of nuclear staining for these molecules. The nuclear expression of p53 largely matches apoptotic cells in the parenchyma of EAE. These findings suggest that the pro-apoptotic molecules p53 and Bax may play an important role in eliminating T cells in the parenchyma in EAE.
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PMID:Increased expression of p53 and Bax in the spinal cords of rats with experimental autoimmune encephalomyelitis. 1089 4

Apoptosis is usually associated with genomic DNA fragmentation which can be detected in situ by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) assay. We describe a combined TUNEL and double immunofluorescent labeling technique to determine the fate of inflammatory infiltrates and resident glial cells in the central nervous system following the onset of an autoimmune demyelinating disease such as experimental allergic encephalomyelitis (EAE) in rats. Anti-digoxigenin (anti-DIG) antibody conjugated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA) emitting blue fluorescence was used to detect apoptotic cell DNA, which was already labeled by modified TUNEL using alkali-stable DIG-11-dUTP. Anti-mouse IgG secondary antibody conjugated with Texas Red emitting red fluorescence was used to detect anti-rat CD11b primary antibody (clone OX-42) directed to the surface antigen of mononuclear phagocytes including microglia. Using this technique, we detected apoptotic mononuclear phagocytes (co-labeled with blue and red fluorescences) in the spinal cord sections of rats with EAE.
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PMID:Combined TUNEL and double immunofluorescent labeling for detection of apoptotic mononuclear phagocytes in autoimmune demyelinating disease. 1090 97


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