Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since tropical spastic paraparesis in 1985 was found to be associated with HTLV-I infection, it has been suggested that a retrovirus might be involved in multiple sclerosis (MS). Our group has studied long-term cultures of cerebrospinal fluid cells and peripheral blood mononuclear cells from MS patients and controls with the purpose of elucidating the possible involvement of a retrovirus in MS. For an extended period electron microscopical analysis (EM) of T-cell lines, derived from MS patients and controls and cultured for 4 weeks was performed. In two cultures obtained 8 months apart from a patient with progressive MS, retrovirus-like particles were observed in 1-2% of the cells examined. Recently a B-lymphoblastoid cell line (LCL) producing retrovirus-like particles and EBV was established from a 30-year-old male patient with a chronic progressive myelopathy, clinically resembling multiple sclerosis. Similar cell lines have now been established from two MS patients. The retrovirus-like particles produced by the LCL have been purified by gradient ultracentrifugation. In the purified material reverse transcriptase assays are clearly positive in the gradients where EM shows retrovirus-like particles. Antigen characterization, nucleic acid sequence analysis and antibody studies are now being performed. The retrovirus found is definitively different from other known human retroviruses. It has previously been found that 100% of patients with MS have antibodies against EBV, in contrast to controls where only 86-95% have antibodies against this virus. Previous epidemiological studies have pointed toward a post-pubertal primary EBV infection as an important event in the induction of MS disease. These studies have now been substantiated by our group. Though it is still unknown whether EBV infection is a prerequisite for development of MS or whether the 100% EBV seropositivity is a consequence of the MS disease, we have put forward the hypothesis that the etiological agent for development of MS and MS-like diseases is a new hitherto uncharacterized retrovirus, whereas development of neurologic disease is related to or even dependent on a delayed infection with a virus from the herpes group, most likely EBV. This dual infection hypothesis has been analyzed and was found to be in accordance with the most consistent epidemiological characteristics of MS. We have previously, also from epidemiological data, negated retroviruses, behaving as the known human retroviruses, as an independent cause of MS.
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PMID:A putative new retrovirus associated with multiple sclerosis and the possible involvement of Epstein-Barr virus in this disease. 751 5

cDNAs prepared from total RNA extracted from plaques of multiple sclerosis were amplified by the polymerase chain reaction. The 11-bp degenerate primers used were derived from conserved sequences of reverse transcriptase. Amplified cDNAs were fractionated according to size by electrophoresis in polyacrylamide gels under denaturing conditions. cDNAs of the proper size were cloned, grouped according to the sequence of their insert by differential hybridization, and sequenced. Six cDNAs were isolated and found to belong to new members of two groups of human endogenous retroviruses: the group related to ERV9 and that related to HERVK10 and HUMMTV. These sequences were expressed in all human organs tested, including normal white matter of brain. The approach described in this article is a powerful tool with which to isolate new members of the reverse transcriptase gene family.
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PMID:Isolation from human brain of six previously unreported cDNAs related to the reverse transcriptase of human endogenous retroviruses. 753 72

A leptomeningeal cell line (LM7) harbouring an unknown retrovirus was recently isolated from the cerebrospinal fluid of a patient with multiple sclerosis. However, spontaneous expression of the LM7 retrovirus in this primary culture is quite low. We present results showing that in vitro infection of LM7 cells with herpes simplex virus type 1 (HSV-1), but not that of control cells, results in (i) potent stimulation of the specific reverse transcriptase (RT) activity detected in the culture supernatant and (ii) co-expression of both typical HSV-1 virions and abundant retrovirus-like particles. Transfection of LM7 cells with plasmids expressing HSV-1 immediate early (IE) ICP0 and ICP4 proteins produced a similar enhancement of RT activity in culture supernatants with retrovirus-like particles being identifiable by electron microscopy. These effects were not observed with a plasmid expressing ICP27 or with the parental plasmid in LM7 cells, nor with any of these four plasmids in control cells. These results show that HSV IE trans-activating proteins strongly enhance the expression of the latent retrovirus present in LM7 cells. The possible role in vivo of herpesviruses as 'triggering' cofactors in the retrovirus hypothesis for multiple sclerosis aetiology is also discussed.
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PMID:Herpes simplex virus ICP0 and ICP4 immediate early proteins strongly enhance expression of a retrovirus harboured by a leptomeningeal cell line from a patient with multiple sclerosis. 767 35

The inflammatory cytokines IFN-gamma and TNF-alpha have been demonstrated in various autoimmune diseases, and are thought to participate in the induction and pathogenesis of disease. TFN-alpha is a cytopathic cytokine that is cytotoxic for oligodendrocytes in vitro and has been implicated in the pathology of multiple sclerosis and its animal model experimental allergic encephalomyelitis (EAE). We used reverse transcriptase (RT)-PCR to study the kinetics, cellular source, and regulation of cytokine gene expression in the central nervous system (CNS) of SJL/J mice with myelin basic protein-induced EAE at different stages of the disease. The expression of CD3, IL-2, IFN-gamma, and TNF-alpha mRNA was barely detectable in the CNS of unmanipulated mice or mice that were immunized with adjuvant but showed no symptoms. These mRNAs were readily detectable in the CNS of mice during peak disease, then coordinately dropped to background levels during remission. Analysis of cells isolated from the CNS of mice with acute EAE showed that the Th1 cytokines, IL-2 and IFN-gamma, were produced by infiltrating CD4+ T cells. In contrast, TNF-alpha was predominantly transcribed by non-T mononuclear CNS cells, the majority of which were identified as microglia and macrophages by their Mac-1 phenotype. Microglia could be discriminated by their low expression of CD45. Incubation of freshly derived, adult microglia from normal, uninfiltrated, CNS with activated Th1 supernatant induced the production of TNF-alpha mRNA. Therefore, TNF-alpha is made by both CNS-resident microglia and infiltrating macrophages during EAE, and this production is tightly controlled by cytokines secreted by infiltrating CD4+ T cells.
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PMID:TNF-alpha expression by resident microglia and infiltrating leukocytes in the central nervous system of mice with experimental allergic encephalomyelitis. Regulation by Th1 cytokines. 781 94

Successful transfer of multiple sclerosis (MS) into severe combined immunodeficient (SCID) mice by intracisternal injection of cerebrospinal fluid (CSF) cells from six of 15 patients at exacerbation has been reported. The relative expression of mRNA for cytokines in demyelinated lesions from SCID-hu-MS by a semiquantitative reverse transcriptase-polymerase chain reaction analysis revealed marked increase in expression of mRNAs for TNF-alpha and IL-6. This result raised the possibility that these cytokines played an important role in the demyelinating process in SCID-hu-MS. To test whether or not an antibody (Ab) to murine TNF-alpha has a preventive effect on transfer of MS into SCID mice, intracisternal injection of CSF cells from two patients at exacerbation together with anti-murine TNF-alpha Ab was performed, and we observed effective prevention of transfer. In addition, we also found an Ab to human CD3 (OKT3) to have a preventive effect. The former result suggests that control of TNF-alpha may be effective in treatment of MS and the latter suggests that MS is a T cell-mediated disease.
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PMID:[Transfer of multiple sclerosis into SCID mice]. 799 92

Nitric oxide (NO) has been implicated as a pathogenic mediator in a variety of central nervous system (CNS) disease states, including the animal model of multiple sclerosis (MS) and experimental allergic encephalomyelitis. We have examined post-mortem brain tissues collected from patients previously diagnosed with MS, as well as tissues collected from the brains of patients dying without neuropathies. Both Northern blot analysis and reverse transcriptase (RT)-driven in situ PCR (RT-in situ PCR) studies demonstrated that inducible NO synthase (iNOS) mRNA was present in the brain tissues from MS patients but was absent in equivalent tissues from normal controls. We have also performed experiments identifying the cell type responsible for iNOS expression by RT-in situ PCR in combination with immunohistochemistry. Concomitantly, we analyzed the tissues for the presence of the NO reaction product nitrotyrosine to demonstrate the presence of a protein nitrosylation adduct. We report here that iNOS mRNA was detectable in the brains of 100% of the CNS tissues from seven MS patients examined but in none of the three normal brains. RT-in situ PCR experiments also demonstrated the presence of iNOS mRNA in the cytoplasm of cells that also expressed the ligand recognized by the Ricinus communis agglutinin 1 (RCA-1), a monocyte/macrophage lineage marker. Additionally, specific labeling of cells was observed when brain tissues from MS patients were exposed to antisera reactive with nitrotyrosine residues but was significantly less plentiful in brain tissue from patients without CNS disease. These results demonstrate that iNOS, one of the enzymes responsible for the production of NO, is expressed at significant levels in the brains of patients with MS and may contribute to the pathology associated with the disease.
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PMID:Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. 861 40

Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in an immune-mediated demyelinating disease (TMEV-IDD) similar to human multiple sclerosis (MS). Although the etiology of MS remains unknown, a role of an infectious agent has been implicated in its onset. Previously we have shown the ability of bacterial lipopolysaccharide (LPS) to alter susceptibility to TMEV-IDD in genetically resistant C57BL/6 mice. In this study, the potential of LPS to alter pathogenicity of a low/non-pathogenic variant of TMEV was investigated. After intraperitoneal treatment of genetically susceptible SJL/J mice with LPS before and during viral infection, 80-100% of the mice developed clinical symptoms, while without LPS treatment none of the mice were affected. However, clinical severity in these LPS-treated mice was much milder than the level induced by the wild type pathogenic virus. Increased susceptibility to the disease after LPS treatment did not correlate with splenic T cell proliferative responses against viral antigens. However, by reverse transcriptase polymerase chain reaction (RT-PCR) analyses, an early increase in the production of Th1-type proinflammatory cytokine messages (e.g., interferon-gamma [IFN-gamma] and enhancement of viral persistence was observed in the CNS of LPS-treated, virus-infected animals as compared to mice infected with the variant virus alone. These results indicate that environmental factors such as a bacterial infection (e.g., LPS) promoting proinflammatory cytokine production can significantly enhance the pathogenicity of demyelination induced by a normally non-pathogenic virus.
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PMID:Treatment with lipopolysaccharide enhances the pathogenicity of a low-pathogenic variant of Theiler's murine encephalomyelitis virus. 889 89

The effect of pentoxifylline (PTX) on experimental allergic encephalomyelitis (EAE) in mice, a known animal model of multiple sclerosis (MS), was investigated. PTX was orally administrated at 10, 40 and 100 mg/kg/day, respectively. Although oral PTX at these doses had no significant effect on the incidence and severity of EAE, oral PTX (40 mg/kg/day) alone produced a significant delay in the onset of EAE. Semiquantitative reverse transcriptase-polymerase chain reaction analysis revealed that PTX at this dose reduced the mRNA levels for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6 in peripheral blood mononuclear cells (PBMC) of mice with EAE. A histopathological study showed that PTX treatment delayed infiltration of inflammatory cells in the central nervous system (CNS) of mice with EAE. These results indicated that the tolerable dose of PTX had a suppressive effect on the induction phase of EAE by modulating cytokine production in PBMC but had no effect on the severity of EAE. The findings in the present study with animals suggested that a tolerable dose of PTX might prolong the intervals between relapses in MS, but might not improve the clinical sign and symptoms of MS.
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PMID:Pentoxifylline delays the onset of experimental allergic encephalomyelitis in mice by modulating cytokine production in peripheral blood mononuclear cells. 895 77

Multiple sclerosis (MS) patient samples were screened for known or novel retroviruses using an ultrasensitive technique, IMx PERT, that detects the presence of reverse transcriptase (RT). This procedure has 10(5)- to 10(7)-fold greater sensitivity than conventional RT assays and is capable of detecting 10 to 50 virions. Moreover, IMx PERT is at least as sensitive as polymerase chain reaction, and requires no previous knowledge of viral nucleotide sequence. The MS specimens analyzed in this study included 136 sera from 79 patients and 128 cerebrospinal fluid samples from 53 patients with relapsing or chronic progressive disease. In addition, peripheral blood mononuclear cells from 19 MS patients were cultured in an attempt to amplify or induce expression of low-copy number or cell-associated retrovirus. No evidence of retrovirus was found in any of the specimens obtained from MS patients.
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PMID:Search for retrovirus in patients with multiple sclerosis. 895 25

Recent evidence indicates that membrane-bound costimulatory molecules of the B7 family are important for T-cell activation and are upregulated in IFN gamma-stimulated human microglia and in multiple sclerosis active lesions. In this study we have performed a detailed analysis of B7-1 and B7-2 expression and regulation in cultured mouse glial cells using immunocytochemical and semi-quantitative reverse transcriptase-polymerase chain reaction techniques. In an immortalized mouse microglial cell line (BV-2), expression of B7-1 and B7-2 was enhanced by interferon-gamma (IFN gamma). IFN gamma was a weak inducer of B7-2 mRNA and immunoreactivity in microglia primary cultures obtained from the neonatal mouse brain, whereas lipopolysaccharide, tumour necrosis factor-alpha, colony-stimulating factors and interleukin-1 beta did not affect microglial B7-2 expression. Combined IFN gamma and lipopolysaccharide treatment very effectively upregulated the B7-2 gene expression and immunoreactivity in microglia, but not in astrocytes. In both glial cell types, expression of B7-1 was not induced by any of the above agents. Among known microglia/macrophage deactivators, interleukin-10, prostaglandin E2 and cAMP-elevating agents, but not transforming growth factor-beta 1 and interleukin-4, inhibited B7-2 transcripts and immunoreactivity in IFN gamma/LPS-stimulated microglia, thus suggesting possible paracrine and autocrine mechanisms for regulating the expression of this important T-cell costimulatory signal in the brain.
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PMID:Analysis of B7-1 and B7-2 costimulatory ligands in cultured mouse microglia: upregulation by interferon-gamma and lipopolysaccharide and downregulation by interleukin-10, prostaglandin E2 and cyclic AMP-elevating agents. 900 48


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