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H Perron

Publications and source records attributed to H Perron.

At least 19 recordsLinked to original sources
PubMed2007

Reduced expression of human endogenous retrovirus (HERV)-W GAG protein in the cingulate gyrus and hippocampus in schizophrenia, bipolar disorder, and depression.

The human endogenous retrovirus (HERV)-W multicopy family was identified in human DNA from the previously characterized multiple sclerosis associated retroviral element (MSRV). Upregulation of the HERV-W POL has been reported in cerebrospinal fluid of patients with schizophrenia. The expression of capsid (GAG) protein of HERV-W was studied by immunohistochemistry and western blotting in postmortem brain tissue of the anterior cingulate cortex and hippocampal formation of normal controls and of patients with schizophrenia, bipolar disorder and major depression. A physiological expression of GAG protein was detected in neurons as well as astroglial cells in normal brain both in the anterior cingulate cortex and in the hippocampal formation. There was a statistically significant reduction of this expression in neurons and astroglial cells in brains from individuals with schizophrenia, major depression, and bipolar disorder. The results from the present study confirm that GAG protein encoded by the HERV-W multicopy gene family is expressed in cells of the central nervous system under normal conditions. Our findings of a cell type-, brain region- and disease-specific reduced expression in schizophrenia, major depression, and bipolar disorder are compatible with a pathophysiological role of HERVs in human brain disorders. The causes and biological consequences of this differential regulation will be the subject of further investigations.

Astrocytes↗
PubMed2003

Multiple sclerosis-associated retrovirus particles cause T lymphocyte-dependent death with brain hemorrhage in humanized SCID mice model.

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.

Animals↗
PubMed2001

Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vbeta16 T-lymphocyte activation.

A retroviral element (MSRV) defining a family of genetically inherited endogenous retroviruses (HERV-W) has recently been characterized in cell cultures from patients with multiple sclerosis (MS). To address the possible relationship with MS, direct detection of circulating virion RNA was proposed but revealed technically difficult to perform in standardized conditions, in the face of multiple endogenous HERV-W copies. A parallel approach has evaluated MSRV potential pathogenicity in relation to characteristic features of multiple sclerosis, in particular, T-lymphocyte-mediated immunopathology. We report here that MSRV particles induce T-lymphocyte response with a bias in the Vbeta16 chain usage in surface receptor, whatever the HLA DR of the donor. A recombinant MSRV envelope-but not core-protein reproduced similar nonconventional activation. Molecular analysis of Vbeta CDR3 showed that Vbeta16 expansions are polyclonal. Our results thus provide evidence that MSRV envelope protein can trigger an abnormal immune response with similar characteristics to that of superantigens.

Antigens, Viral↗
PubMed2001

Glial toxicity in urine and multiple sclerosis.

The biochemical and biological characterization of a cytotoxic activity targeting macroglial cells (oligodendrocytes and astrocytes), in moncyte cultures and in CSF of a patient with multiple sclerosis, has previously been described. In further studies, cell-based tests have shown a good correlation between this glial cytotoxic (gliotoxic) activity, in CSF or in urine, and MS. We now present results obtained with urine samples from 102 MS patients, 51 patients with other neurological disease and 35 healthy subjects using a bioassay set up for the detection of an apoptosis-like effect induced in a glial cell-line. Significant gliotoxicity was detected in urine from 74/102 MS patients while only 4/51 neurological controls (P>0.001) and never in healthy subjects (P>0.001). Given the statistical tendency provided by this bioassay and its technical limitations for routine testing, it is now used for monitoring the molecular characterization of this 'gliotoxic factor'. Its replacement by a specific immunoassay could provide more accurate routine techniques for the detection of this biological marker in MS.

Adult↗
PubMed2000

Infrequency of detection of particle-associated MSRV/HERV-W RNA in the synovial fluid of patients with rheumatoid arthritis.

OBJECTIVES: To determine whether the recently identified multiple sclerosis-associated retrovirus, MSRV, is detectable in the serum and synovial fluid of patients with rheumatoid arthritis (RA). METHODS: A reverse transcription-polymerase chain reaction (RT-PCR) assay was used to seek evidence of particle-associated MSRV/HERV-W RNA in the plasma and synovial fluid of patients with RA and controls. Stringent precautions were taken to avoid detection of contaminating human genomic DNA and cellular RNA sequences. RESULTS: Thirty-seven plasma samples were tested (20 from RA patients and 17 from controls) but none had detectable MSRV/HERV-W RNA. Synovial fluid samples were available from nine patients with RA and 10 controls. Particle-associated MSRV/HERV-W RNA was reproducibly detected in two of nine synovial fluid samples from RA patients and in one control sample. The identity of RT-PCR products was confirmed by sequencing. CONCLUSION: MSRV/HERV-W RNA sequences are detectable in the synovial fluid of a small proportion of RA patients, but this phenomenon may not be specific to RA.

Arthritis, Rheumatoid↗
PubMed2000

Particle-associated retroviral RNA and tandem RGH/HERV-W copies on human chromosome 7q: possible components of a 'chain-reaction' triggered by infectious agents in multiple sclerosis?

Different groups have observed retrovirus particle (RVP) production in cell cultures from patients with multiple sclerosis (MS). This in vitro production appeared relatively specific for MS versus healthy controls, but was likely to be enhanced or activated by infectious triggers such as Herpesviruses (e.g. HSV, EBV). Independent molecular analysis of retroviral RNA associated with RVP revealed two different genetic families of endogenous retroviral elements (HERV): MSRV/HERV-W and RGH/HERV-H. Interestingly, these sequences were detected by mutually exclusive primers in RT - PCR amplifications. Surprisingly, these two HERV families both contain an ancestral proviral copy inserted in chromosome 7q21-22 region at about 1 kb of distance of each other. Another HERV-W proviral sequence is located within a T-cell alpha-delta receptor (TCR) gene in chromosome 14q11.2 region. Interestingly, these two regions correspond to genetic loci previously identified as potentially associated with 'multigenic' susceptibility to MS and TCR alpha chain genetic determinants have been reported to be statistically associated with MS. A plausible role for infectious agents triggering a co-activation of the chromosome 7q HERV tandem (replicative retrovirus and/or other virus and/or intracellular bacteria) and, eventually, other HERV copies, is discussed. The role of particular HERV polymorphism and the production of pathogenic molecules (gliotoxin and superantigen) possibly associated with retroviral expression are also evoked. An integrative concept of pathogenic 'chain-reaction' in MS involving several step-specific pathogenic 'agents' and 'products' somewhat interacting with particular genetic elements would federate most partial data obtained on MS, including retroviral expression.

Chromosomes, Human, Pair 7↗
PubMed1999

Phylogeny of a novel family of human endogenous retrovirus sequences, HERV-W, in humans and other primates.

A novel human endogenous retrovirus, HERV-W, has been characterized on the basis of multiple sclerosis-associated retrovirus (MSRV) probes. We have analyzed the phylogenetic distribution of HERV-W in humans and other primate species. As HERV-W presents a C/D chimeric nature and is largely composed of deleted elements, Southern blots were performed using gag, pol, env, and LTR probes. The relative complexities observed for gag, pol, env, and LTR regions were similar in humans, apes, and Old World monkeys, the minimal number of bands observed after Southern blot analysis being 25, 50, 10, and at least 100, respectively. The HERV-W family entered the genome of catarrhines more than 25 million years ago.

Animals↗
PubMed1999

Molecular cloning and characterization of MSRV-related sequences associated with retrovirus-like particles.

New sequences have been obtained by successive overlapping RT-PCR extensions from the pol region of a retroviral RNA (multiple sclerosis-associated retroviral element, MSRV) amplified in retrovirus-like particles from patients with multiple sclerosis. gag and pol sequences are related to type C oncoviruses, whereas the env sequence is closer to type D. A tryptophan-like (W) tRNA primer-binding site was identified downstream of the RU5 region in the 5'LTR, and the U3R region cloned in the 3'LTR exhibited potent promoter activity. MSRV clones define a novel family of endogenous elements, HERV-W. From our data, HERV-W RNAs are copackaged in extracellular particles which might be produced by replication-competent or transcomplemented HERV-W copies or by an exogenous member of the HERV-W family.

Amino Acid Sequence↗
PubMed1999

Specificities of multiple sclerosis cerebrospinal fluid and serum antibodies against mimotopes.

In order to characterize antigenic epitopes specifically targeted by the immune response of patients with multiple sclerosis (MS), the antibody specificities of cerebrospinal fluids (CSF) and sera from the same MS patients have been analyzed using a random pentadecapeptide library displayed on phage. The 3 peptides (mimotopes) selected with MS sera were not disease-specific. In contrast, the combination of 4 MS CSF selected mimotopes, allowed the detection of specific antibodies in 21 of 60 MS CSF whereas only 2 of 27 CSF from patients with other neurological diseases equally recognized the 4 mimotopes. Some amino acid similarities were found between two MS CSF selected mimotopes and two envelope regions (319-329 and 433-443, respectively) of MSRV (multiple-sclerosis-associated retrovirus) and the related endogenous retrovirus HERV-W.

Amino Acid Sequence↗
PubMed1999

Human retroviral sequences associated with extracellular particles in autoimmune diseases: epiphenomenon or possible role in aetiopathogenesis?

Publications describing retroviral sequences associated with extracellular particles in Sjögren's syndrome or systemic lupus erythematosus, multiple sclerosis, and type I diabetes present novel arguments and raise complex questions about eventual relationships between retroviruses and autoimmunity. They are presented and discussed in the present review, preceded by an overview of the biology of retroviral elements.

Animals↗
PubMed1999

Molecular characterization and placental expression of HERV-W, a new human endogenous retrovirus family.

The multiple sclerosis-associated retrovirus (MSRV) isolated from plasma of MS patients was found to be phylogenetically and experimentally related to human endogenous retroviruses (HERVs). To characterize the MSRV-related HERV family and to test the hypothesis of a replication-competent HERV, we have investigated the expression of MSRV-related sequences in healthy tissues. The expression of MSRV-related transcripts restricted to the placenta led to the isolation of overlapping cDNA clones from a cDNA library. These cDNAs spanned a 7.6-kb region containing gag, pol, and env genes; RU5 and U3R flanking sequences; a polypurine tract; and a primer binding site (PBS). As this PBS showed similarity to avian retrovirus PBSs used by tRNATrp, this new HERV family was named HERV-W. Several genomic elements were identified, one of them containing a complete HERV-W unit, spanning all cDNA clones. Elements of this multicopy family were not replication competent, as gag and pol open reading frames (ORFs) were interrupted by frameshifts and stop codons. A complete ORF putatively coding for an envelope protein was found both on the HERV-W DNA prototype and within an RU5-env-U3R polyadenylated cDNA clone. Placental expression of 8-, 3.1-, and 1.3-kb transcripts was observed, and a putative splicing strategy was described. The apparently tissue-restricted HERV-W long terminal repeat expression is discussed with respect to physiological and pathological contexts.

Amino Acid Sequence↗
PubMed1998

Detection of a gliotoxic activity in the cerebrospinal fluid from multiple sclerosis patients.

We recently showed that peripheral blood cell supernatants from multiple sclerosis (MS) patients, containing reverse transcriptase activity and retroviral RNA from the newly human identified multiple sclerosis retrovirus (MSRV), also secrete a cytotoxin which induces death of primary mouse cortical glial cells. We have hypothesized that macrophages could release this cytotoxin in the cerebrospinal fluid. The cerebrospinal fluid cytotoxicity from 166 patients with various neurological diseases (including MS patients) was tested on glial cells in vitro. Our bioassay shows that a glial cytotoxic activity is significantly present in cerebrospinal fluid from patients with relapsing-remitting MS at relapse. Since this cytotoxic activity seems to correlate with active cases of MS, it may represent a critical pathogenic factor in the neuropathology of MS.

Adult↗
PubMed1998

A gliotoxic factor and multiple sclerosis.

The pathogenesis of multiple sclerosis (MS) is unknown. Searching for possible toxic factors, it was found that 3-day exposure to heat-treated cerebrospinal fluid (CSF) from MS patients caused apoptotic death of astrocytes and oligodendrocytes, but not fibroblasts, myoblasts, Schwann cells, endothelial cells and neurons, in vitro. CSFs from other inflammatory or non-inflammatory neurological diseases showed no toxicity. Exposure of these glial cells to partially purified MS CSF produced DNA fragmentation, apoptotic bodies, chromatin condensation, cell shrinkage, and changes in the levels of known cytokines. A cytotoxic factor, called gliotoxin, was characterized chromatographically as a stable 17-kDa glycoprotein. Since this protein is highly cytotoxic for astrocytes and oligodendrocytes, it may represent an initial pathogenic factor, leading to the neuropathological features of MS, such as blood-brain barrier involvement and demyelination.

Animals↗
PubMed1998

Case report: DNA fragmentation in glial cells in a cerebral biopsy from a multiple sclerosis patient.

Multiple sclerosis is characterized by myelin destruction and oligodendrocyte loss. The neuropathological hallmark of the disease is the presence of demyelinated plaques in the central nervous system. We have recently found a gliotoxic factor in MS cerebrospinal fluid which induces programmed cell death in vitro, in glial cells. Here we show DNA fragmentation and glial cell death in biopsy samples, obtained from a patient who underwent surgery with suspicion of tumor, and whose disease record, including brain autopsy, demonstrated an active multiple sclerosis. We used the in situ TUNEL technique, a method which sensitively detects the DNA fragmentation accompanying programmed cell death in tissue sections, and compatible with classical fixation techniques. We found intense DNA fragmentation in nuclei of glial cells at-or very near-to the site of demyelination. A double labeling technique showed that glial fibrillary associated protein positive astrocytes may undergo programmed cell death in multiple sclerosis.

Astrocytes↗