Corinne Bernard

GeNeuro, Genève, Geneva, Switzerland

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Publications (10)43.89 Total impact

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    ABSTRACT: Objective Differentiation of oligodendroglial precursor cells is crucial for central nervous system remyelination and is influenced by both extrinsic and intrinsic factors. Recent studies showed that human endogenous retrovirus type W (HERV-W) contributes significantly to brain damage. In particular, its envelope protein ENV can mediate injury to specific cell types of the brain and immune system. Here, we investigated whether ENV protein affects oligodendroglial differentiation. Methods Immunostaining and gene expression analyses were performed to establish the expression and regulation of the known ENV receptor, Toll-like receptor 4 (TLR4), on oligodendroglial precursor cells in human brain tissue and in culture. Cultured primary oligodendroglial precursor cells were stimulated with ENV protein to determine the effects of this ligand/receptor interaction. ResultsWe demonstrated that the ENV protein is present in close proximity to TLR4-expressing oligodendroglial precursor cells adjacent to multiple sclerosis lesions. Human and rat oligodendroglial precursor cells expressed TLR4, and the ENV-mediated activation of TLR4 led to the induction of proinflammatory cytokines and inducible nitric oxide synthase as well as the formation of nitrotyrosine groups and a subsequent reduction in myelin protein expression. InterpretationOur findings suggest that ENV-mediated induction of nitrosative stress via activation of TLR4 results in an overall reduction of the oligodendroglial differentiation capacity, thereby contributing to remyelination failure. Therefore, pharmacological or antibody-mediated inhibition of ENV may prevent the blockade of myelin repair in the diseased or injured central nervous system. Ann Neurol 2013;74:721–732
    Annals of Neurology 11/2013; 74(5). · 11.19 Impact Factor
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    ABSTRACT: Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type ‘W’ family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10–4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.
    Translational psychiatry. 01/2013; 3:e224.
  • Translational psychiatry. 01/2013; 3:e226.
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    ABSTRACT: BACKGROUND: The envelope protein from multiple sclerosis (MS) associated retroviral element (MSRV), a member of the Human Endogenous Retroviral family 'W' (HERV-W), induces dysimmunity and inflammation. OBJECTIVE: The objective of this study was to confirm and specify the association between HERV-W/MSRV envelope (Env) expression and MS. METHODS: 103 MS, 199 healthy controls (HC) and controls with other neurological diseases (28), chronic infections (30) or autoimmunity (30) were analysed with an immunoassay detecting Env in serum. Env RNA or DNA copy numbers in peripheral blood mononuclear cells (PBMC) were determined by a quantitative polymerase chain reaction (PCR). Env was detected by immunohistology in the brains of patients with MS with three specific monoclonals. RESULTS: Env antigen was detected in a serum of 73% of patients with MS with similar prevalence in all clinical forms, and not in chronic infection, systemic lupus, most other neurological diseases and healthy donors (p<0.01). Cases with chronic inflammatory demyelinating polyneuropathy (5/8) and rare HC (4/103) were positive. RNA expression in PBMC and DNA copy numbers were significantly elevated in patients with MS versus HC (p<0.001). In patients with MS, DNA copy numbers were significantly increased in chronic progressive MS (secondary progressive MS vs relapsing-remitting MS (RRMS) p<0.001; primary progressive MS vs RRMS -<0.02). Env protein was evidenced in macrophages within MS brain lesions with particular concentrations around vascular elements. CONCLUSION: The association between MS disease and the MSRV-type HERV-W element now appears quite strong, as evidenced ex-vivo from serum and PBMC with post-mortem confirmation in brain lesions. Chronic progressive MS, RRMS and clinically isolated syndrome show different ELISA (Enzyme-Linked Immunosorbent Assay) and/or PCR profiles suggestive of an increase with disease evolution, and amplicon sequencing confirms the association with particular HERV-W elements.
    Multiple Sclerosis 03/2012; · 4.47 Impact Factor
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    ABSTRACT: Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.
    Translational psychiatry. 01/2012; 2:e201.
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    ABSTRACT: Unexpected findings on endogenous retroviral elements expressed in cells from patients with Multiple Sclerosis appear to open a new avenue of research, after years of research dedicated to the understanding of their biological significance in human health and disease. Human endogenous retroviral family W (HERV-W) RNA present in circulating viral particles (Multiple Sclerosis associated RetroViral element, MSRV) has been associated with the evolution and prognosis of Multiple Sclerosis. HERV-W elements encode a powerful immunopathogenic envelope protein (ENV) that activates a pro-inflammatory and autoimmune cascade through interaction with Toll-Like Receptor 4 (TLR4) on antigen-presenting cells, and triggers superantigen-like dysregulation of T-lymphocytes. HERV-W/ENV antigen has further been shown to be an upstream inducer of immunopathogenicity like that in MS and has repeatedly been detected in association with MS lesions in post-mortem brain studies. ENV protein now represents a novel target in MS, in our ongoing development of a neutralising therapeutic antibody. We here review the pieces of a puzzle, which now offer a consistent picture for Multiple Sclerosis aetiopathogenesis. Interestingly, at the gene-environment interface, this picture also includes gender-related specificities through the potential interplay with endogenous retrovirus type W copies present on the X chromosome.
    Journal of the neurological sciences 06/2009; 286(1-2):65-72. · 2.32 Impact Factor
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    Retrovirology 01/2009; · 5.66 Impact Factor
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    Retrovirology 01/2009; · 5.66 Impact Factor
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    Retrovirology 01/2009; · 5.66 Impact Factor
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    ABSTRACT: Recent and independent molecular studies have shown an association between human endogenous retroviruses type "W" family (HERV-W) and schizophrenia, mostly by polymerase chain reaction studies, but none has yet addressed specific antigen detection in living patients. Forty-nine schizophrenic patients and an equivalent number of healthy control subjects were included in the present exploratory study. The HERV-W GAG and envelope (ENV) proteins were quantified in the serum with a dedicated immunoassay set-up with specific monoclonal antibodies to either antigen. In schizophrenic patients, positive antigenemia for ENV was found in 23 of 49 (47%) and for GAG in 24 of 49 (49%). Only 1 of 30 (3%) for ENV and 2 of 49 (4%) for GAG were positive in blood donors (p < .01 for ENV; p < .001 for GAG). Interestingly, bioclinical data analyses revealed significant correlation between GAG or ENV antigenemia (a protein causing dysimmune inflammatory effects) and C-reactive protein (CRP) levels (a systemic inflammation biomarker). Frequently elevated CRP has previously been described in schizophrenic patients and has been shown to match with an evolution toward cognitive deficit and neuronal loss. Elsewhere viruses such as influenza, long-associated with risk for schizophrenia through perinatal infections, have been shown to activate HERV-W elements in human cells. We therefore discuss a relationship between environment factors long-associated with early risk, genetic factors represented by this endogenous family, the production of its pro-inflammatory ENV protein and known "inflammation-mediated" neurotoxicity, as a possible hypothesis for a pathogenic cascade in association with HERV-W. Our present results thus confirm that HERV-W studies have opened a novel avenue of research in schizophrenia.
    Biological psychiatry 09/2008; 64(12):1019-23. · 8.93 Impact Factor