title: Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis.
abstract: BACKGROUND
  Proposed co-factors triggering the pathogenesis of multiple sclerosis (MS) are the Epstein Barr virus (EBV), and the potentially neuropathogenic MSRV (MS-associated retrovirus) and syncytin-1, of the W family of human endogenous retroviruses.
  
  
  RESULTS
  In search of links, the expression of HERV-W/MSRV/syncytin-1, with/without exposure to EBV or to EBV glycoprotein350 (EBVgp350), was studied on peripheral blood mononuclear cells (PBMC) from healthy volunteers and MS patients, and on astrocytes, by discriminatory env-specific RT-PCR assays, and by flow cytometry. Basal expression of HERV-W/MSRV/syncytin-1 occurs in astrocytes and in monocytes, NK, and B, but not in T cells. This uneven expression is amplified in untreated MS patients, and dramatically reduced during therapy. In astrocytes, EBVgp350 stimulates the expression of HERV-W/MSRV/syncytin-1, with requirement of the NF-κB pathway. In EBVgp350-treated PBMC, MSRVenv and syncytin-1 transcription is activated in B cells and monocytes, but not in T cells, nor in the highly expressing NK cells. The latter cells, but not the T cells, are activated by proinflammatory cytokines.
  
  
  CONCLUSIONS
  In vitro EBV activates the potentially immunopathogenic and neuropathogenic HERV-W/MSRV/syncytin-1, in cells deriving from blood and brain. In vivo, pathogenic outcomes would depend on abnormal situations, as in late EBV primary infection, that is often symptomatic, or/and in the presence of particular host genetic backgrounds. In the blood, HERV-Wenv activation might induce immunopathogenic phenomena linked to its superantigenic properties. In the brain, toxic mechanisms against oligodendrocytes could be established, inducing inflammation, demyelination and axonal damage. Local stimulation by proinflammatory cytokines and other factors might activate further HERV-Ws, contributing to the neuropathogenity. In MS pathogenesis, a possible model could include EBV as initial trigger of future MS, years later, and HERV-W/MSRV/syncytin-1 as actual contributor to MS pathogenicity, in striking parallelism with disease behaviour.
authors.affiliation: Department of Biomedical Sciences and Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari, Sassari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mameli
authors.forename: Luciana
authors.initials: L
authors.lastname: Poddighe
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mei
authors.forename: Elena
authors.initials: E
authors.lastname: Uleri
authors.forename: Stefano
authors.initials: S
authors.lastname: Sotgiu
authors.forename: Caterina
authors.initials: C
authors.lastname: Serra
authors.forename: Roberto
authors.initials: R
authors.lastname: Manetti
authors.forename: Antonina
authors.initials: A
authors.lastname: Dolei
mesh_terms: D000328:Adult; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D001483:Base Sequence; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000235:genetics; D019295:Computational Biology; D016207:Cytokines / Q000494:pharmacology; D004247:DNA / Q000235:genetics; D020077:Endogenous Retroviruses / Q000187:drug effects / Q000502:physiology*; D005260:Female; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D015752:Genes, env; D056426:Genetic Loci / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood* / Q000821:virology*; D016254:Mutagenesis, Insertional / Q000235:genetics; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics; D014775:Virus Activation / Q000187:drug effects; D055815:Young Adult
chemical_list: D016207:Cytokines; D015686:Gene Products, env; D011257:Pregnancy Proteins; C405335:syncytin; D012313:RNA; D004247:DNA