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: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to verify the expression of tumour necrosis factor (TNF)-alpha mRNA by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in unstimulated peripheral blood mononuclear cells (MNCs) of 15 relapsing-remitting multiple sclerosis (MS) patients who underwent treatment with IFN-beta 1a (6 millions of international units (MIU) i.m. once a week) and in 15 untreated MS patients matched for age and expanded disability status score (EDSS). At the same time the expression of TNF-alpha mRNA was assessed in 10 healthy age-matched control subjects. All MS patients were assessed at the basal time and after 6 months. At the basal time, the band of TNF-alpha mRNA was detectable in 12 out of the 15 untreated patients and in 13 out of the 15 patients who underwent IFN-beta 1a treatment. The higher TNF-alpha mRNA was evident in patients with gadolinium-enhancing lesions. At the 6-month follow-up, 13 out of the 15 untreated patients still had detectable values of TNF-alpha mRNA and no significant difference emerged when compared with basal time. On the contrary, the expression of TNF-alpha mRNA was absent at the same time in nine out of the 15 patients treated with IFN-beta 1a. A longitudinal analysis carried out monthly in eight MS patients (four untreated and four treated) revealed a transient increase in TNF-alpha mRNA expression in MNCs of all four treated patients in the first 3 months, supporting previous findings of an early immunoenhancing effect of IFN-beta 1a. This early activation is followed by an inhibitory effect of IFN-beta 1a on TNF-alpha mRNA expression in about 2/3 of treated MS patients when assessed at 6 months. Further long-term studies are needed to confirm this immunomodulatory effect of IFN-beta 1a not only on TNF-alpha but also on other cytokines of Th(1)and Th(2)types.
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PMID:Expression of TNF-alpha mRNA by peripheral blood mononuclear cells of multiple sclerosis patients treated with IFN-beta 1A. 1144 10

Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis in humans. EAE can be passively transferred into naive syngeneic animals by administration of MOG-specific T cell clones. Lymphocytes isolated from green fluorescent protein (GFP)-transgenic (Tg) mice can light up by emitting green fluorescence, thus making it feasible to use such animals in a passive transfer model for EAE. When MOG-sensitized splenic lymphocytes from GFP-Tg mice were adoptively transferred to irradiated, syngeneic C57BL/6 and RAG-1(-/-)mice, typical symptoms of EAE developed. Analysis of the reconstituted mice with EAE revealed prominent infiltration of fluorescing (GFP+), CD4+ T cells into the central nervous system (CNS). Real-time confocal imaging revealed these cells in the spinal cords and brains of recipient mice. This infiltration was also confirmed by anti-GFP monoclonal antibodies. Furthermore, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) evaluation indicated that the infiltrating GFP+, CD4+ T cells exclusively produced T helper type 1 (Th1) cytokines, especially interferon-gamma (IFN-gamma). These results clearly show that MOG-specific CD4+ T cells preferentially invade into the CNS and mediate the development of EAE by producing Th1-biased cytokines.
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PMID:Role of MOG-stimulated Th1 type "light up" (GFP+) CD4+ T cells for the development of experimental autoimmune encephalomyelitis (EAE). 1148 34

Human endogenous retroviruses (HERVs) have been implicated as causative agents in diseases characterized by inflammation and macrophage activation, such as multiple sclerosis. Because monocyte activation and differentiation influence retroviral transcription and replication, we investigated the contribution of these processes to the expression of four HERV families (HERV-W, HERV-K, HERV-E, and HERV-H) in human monocytes, and autopsied brain tissue from patients with brain diseases associated with increased macrophage activity. Reverse transcriptase-polymerase chain reaction analysis of primary macrophages and U937 monocytoid cells stimulated with phorbol-12-myristate-13-acetate or lipopolysaccharide revealed three- to ninefold increases in HERV-W, HERV-K, and HERV-H RNA levels. In addition, elevated reverse transcriptase activity and HERV RNA were detectable in supernatants from PMA-stimulated U937 cultures, properties that could be attenuated with the inhibitor of monocyte differentiation threonine-lysine-proline. In contrast, stimulation of monocytes decreased or had no effect on HERV-E expression. Compared with controls, HERV-W and HERV-K expression was increased in brain tissue from patients with multiple sclerosis or human immunodeficiency virus infection or AIDS, with concomitant elevated tumor necrosis factor-alpha levels. Similarly, elevated HERV-W levels were detected in patients with Alzheimer's dementia only when tumor necrosis factor-alpha expression was also evident (2 of 6 cases). The detection of several HERVs in inflammatory brain diseases and the capacity to augment HERV expression in monocytes with compounds that influence cellular activity suggest that increased expression of these viruses is a consequence of increased immune activity rather than causative of distinct diseases.
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PMID:Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases. 1160 92

Infection of mice by low-neurovirulence Theiler's murine encephalomyelitis virus (TMEV), such as BeAn and DA viruses, provides a relevant experimental animal model for multiple sclerosis (MS). As a step toward determining the kinetics of a persistent central nervous system (CNS) infection that leads to chronic demyelination, we adapted a rapid, accurate and highly specific real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay for detection and quantitation of BeAn virus RNA copy equivalents in mouse tissues. The assay enabled detection of as few as 20-30 copies of BeAn virus RNA per microg of total RNA from infected mouse tissues and results for spinal cord revealed the same high levels of BeAn RNA as detected by Northern hybridization during the first 4 months of the persistent infection, but also was able to detect virus RNA copies as late as 1 year post-infection. Real-time RT-PCR analysis of BeAn virus RNA copy equivalents in different parts of the CNS, analyses not possible by Northern hybridization, revealed the following cline of virus persistence: spinal cord>brainstem/cerebellum>cerebrospinal fluid (CSF)>cerebral hemispheres. Systemic organs, including heart, intestine and mesenteric lymph nodes of infected mice, showed no evidence of viral persistence at 4 months post-infection.
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PMID:Enhanced detection of Theiler's virus RNA copy equivalents in the mouse central nervous system by real-time RT-PCR. 1190 36

IL-15 is a proinflammatory cytokine which has recently been implicated in multiple sclerosis (MS) pathogenesis, where it may play a role in the initiation and/or progression of the disease. We have used reverse transcriptase-polymerase chain reaction (RT-PCR) to study IL-15 mRNA levels in peripheral blood mononuclear cells (PBMC) from healthy controls and relapsing-remitting MS (RRMS) patients in a stable phase of the disease and during a bout, both before and after corticosteroid treatment (CST). IL-15 mRNA expression was found to be similar in controls and stable patients. We have detected an increased level of IL-15 mRNA in PBMC of patients with a relapse, which was maintained after CST. We have also found an inverse correlation between PBMC IL-15 mRNA levels at the onset of the relapse and the time elapsed since the previous attack, as well as an absence of correlation between IL-15 mRNA levels and the patient demographic and clinical characteristics. Results in the present work further suggest a role for IL-15 in MS pathophysiology.
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PMID:Increased levels of IL-15 mRNA in relapsing--remitting multiple sclerosis attacks. 1209 15

The transmissibility of the human endogenous retrovirus HERV-H/RGH-2 was investigated by marker rescue: intraspecies transmission of HERV-H/RGH-2 retrovirus particles was attempted by cocultivation of virion-producing, long-term cell cultures spontaneously formed from peripheral blood mononuclear cells from several multiple sclerosis patient cultures with a retroviral vector construct-harboring cell line. Transmissibility was assessed by assays for productive infection (reverse transcriptase activity), and assays for rescue of the retroviral vector construct in indicator cells. Our studies show that the human endogenous retrovirus HERV-H/RGH-2 is transmissible, albeit at a very low level. The human endogenous retrovirus HERV-H/RGH-2 is associated with multiple sclerosis (MS). Previously, we demonstrated sequence variants of the human endogenous retrovirus HERV-H family in virion form, by applying RT-PCR to virion RNA from the supernatants of long-term MS cell cultures, and to the particulate fraction of a series of MS patient plasma samples.
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PMID:A transmissible human endogenous retrovirus. 1220 9

Acute hemorrhagic leukoencephalitis (AHL) is a rare and usually fatal disorder characterized clinically by an acute onset of neurologic abnormalities. It may occur in association with a viral illness or vaccination. Radiology and brain biopsy are essential for the diagnosis. The etiology of AHL is unclear. We postulated that viral/bacterial infection might be responsible, directly or through an immune-mediated mechanism, for this acute inflammatory myelinopathy. Fifteen cases of AHL were studied. Infectious agents, including varicella zoster virus (VZV), herpes simplex virus (HSV), human herpes virus-6 (HHV-6), cytomegalovirus, Epstein-Barr virus, and Mycoplasma, were investigated in brain specimens using the polymerase chain reaction (PCR), reverse transcriptase (RT)-PCR, and immunohistochemistry. Using PCR, HSV DNA was found in four cases, VZV DNA in two, and HHV-6 DNA in one. Among the control cases, two were HSV DNA positive. Further investigation to detect HSV RNA and antigens in HSV DNA-positive cases revealed that two cases with AHL were both HSV RNA and antigen positive. AHL is a hyperacute disease, which is considered the most acute form of acute disseminated encephalomyelitis (ADEM). Our findings suggests that a viral infection may be implicated in its pathogenesis, most likely through an indirect mechanism; however, as only a few cases of this rare disease were examined, statistical significance was not achieved. As a number of patients with disorders of the ADEM group may progress to develop multiple sclerosis (MS), we argue that an organism that has produced the former may remain in the brain tissue and be subsequently involved in the production of a self-sustained disorder such as MS.
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PMID:Detection of infectious agents in brain of patients with acute hemorrhagic leukoencephalitis. 1240 70

T cells recognizing self or microbial antigens may trigger or reactivate immune-mediated diseases. Monitoring the frequency of specific T cell clonotypes to assess a possible link with the course of disease has been a difficult task with currently available technology. Our goal was to track individual candidate pathogenic T cell clones, selected on the basis of previous extensive studies from patients with immune-mediated disorders of the CNS, including multiple sclerosis, HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) and chronic Lyme neuroborreliosis. We developed and applied a highly specific and sensitive technique to track single CD4(+) and CD8(+) T cell clones through the detection and quantification of T cell receptor (TCR) alpha or beta chain complementarity-determining region 3 transcripts by real-time reverse transcriptase (RT)-PCR. We examined the frequency of the candidate pathogenic T cell clones in the peripheral blood and CSF during the course of neurological disease. Using this approach, we detected variations of clonal frequencies that appeared to be related to clinical course, significant enrichment in the CSF, or both. By integrating clonotype tracking with direct visualization of antigen-specific staining, we showed that a single T cell clone contributed substantially to the overall recognition of the viral peptide/MHC complex in a patient with HAM/TSP. T cell clonotype tracking is a powerful new technology enabling further elucidation of the dynamics of expansion of autoreactive or pathogen-specific T cells that mediate pathological or protective immune responses in neurological disorders.
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PMID:Molecular tracking of antigen-specific T cell clones in neurological immune-mediated disorders. 1247 92

A retroviral element (multiple sclerosis-associated retrovirus, MSRV) defining a family of genetically inherited endogenous retroviruses (human endogenous retrovirus type W, HERV-W) has been characterized in cell cultures from patients with multiple sclerosis. Recently, MSRV retroviral particles or the envelope recombinant protein were shown to display superantigen activity in vitro, but no animal model has yet been set up for studying the pathogenicity of this retrovirus. In the present study, the pathogenicity of different sources of MSRV retroviral particles has been evaluated in a hybrid animal model: severe combined immunodeficiency (SCID) mice grafted with human lymphocytes and injected intraperitoneally with MSRV virion or mock controls. MSRV-injected mice presented with acute neurological symptoms and died within 5 to 10 days post injection. Necropsy revealed disseminated and major brain hemorrhages, whereas control animals did not show abnormalities (P <.001). In ill animals, reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed circulating MSRV RNA in serum, whereas overexpression of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma was evidenced in spleen RNA. Neuropathological examination confirmed that hemorrhages occurred prior to death in multifocal areas of brain parenchyma and meninges. Further series addressed the question of immune-mediated pathogenicity, by inoculating virion to SCID mice grafted with total and T lymphocyte-depleted cells in parallel: dramatic and statistically significant reduction in the number of affected mice was observed in T-depleted series (P <.001). This in vivo study suggests that MSRV retroviral particles from MS cultures have potent immunopathogenic properties mediated by T cells compatible with the previously reported superantigen activity in vitro, which appear to be mediated by an overexpression of proinflammatory cytokines.
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PMID:Multiple sclerosis-associated retrovirus particles cause T lymphocyte-dependent death with brain hemorrhage in humanized SCID mice model. 1258 71

In the etiopathogenesis of multiple sclerosis (MS), both genetic and environmental factors play an important role. Among environmental factors, viral infections are most likely connected with the etiology of MS. There are many evidence suggesting possible involvement of retroviruses in the development of autoimmune diseases including MS. Multiple sclerosis-associated retrovirus (MSRV) seems to be the important candidate for viral etiology of MS. The aim of the study was to analyze MSRV pol sequences in patients with MS. As control, groups of myasthenia gravis, Parkinson's disease, and migraine patients, and healthy individuals have been studied. The MSRV pol sequences have been analyzed in RNA isolated from the serum and in DNA and RNA of peripheral blood lymphocytes from untreated MS patients and control groups. The MSRV pol sequences have been detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and PCR technique, using specific oligonucleotide primers. In the serum RNA (cDNA), MSRV pol sequences have been identified in 31/32 MS patients. MSRV pol sequences were detected in serum cDNA of 9/17 myasthenia gravis patients, 7/16 Parkinson's disease patients, 10/21 migraine patients, and 13/27 healthy individuals. MSRV pol sequences were observed also in RNA from lymphocytes of all MS patients, 12/17 myasthenia gravis patients, 9/16 Parkinson's disease patients, 14/21 migraine patients, and 18/27 healthy donors. In the DNA from peripheral blood lymphocytes of all studied patients and healthy individuals, MSRV pol sequences have been found. The observed pattern of fiber-fluorescence in situ hybridization (FISH) signals suggests the presence of multiple copies of MSRV pol sequences, most likely tandemly dispersed in the genome. It can be concluded that MSRV pol sequences are endogenous, widespread in lymphocytes DNA, and transcribed into RNA of MS patients as well as of other studied patients and healthy individuals. However, more frequent expression of MSRV sequences detected in lymphocytes RNA (cDNA), as well as their presence in higher frequency in the serum of MS patients, may suggest the involvement of MSRV in the etiopathogenesis on MS.
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PMID:Multiple sclerosis-associated virus-related pol sequences found both in multiple sclerosis and healthy donors are more frequently expressed in multiple sclerosis patients. 1258 74


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