title: Latent virus infection upregulates CD40 expression facilitating enhanced autoimmunity in a model of multiple sclerosis.
abstract: Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS) by multiple groups working worldwide. Previously, we reported that when experimental autoimmune encephalomyelitis (EAE) was induced in mice latently infected with murine γ-herpesvirus 68 (γHV-68), the murine homolog to EBV, a disease more reminiscent of MS developed. Specifically, MS-like lesions developed in the brain that included equal numbers of IFN-γ producing CD4(+) and CD8(+) T cells and demyelination, none of which is observed in MOG induced EAE. Herein, we demonstrate that this enhanced disease was dependent on the γHV-68 latent life cycle and was associated with STAT1 and CD40 upregulation on uninfected dendritic cells. Importantly, we also show that, during viral latency, the frequency of regulatory T cells is reduced via a CD40 dependent mechanism and this contributes towards a strong T helper 1 response that resolves in severe EAE disease pathology. Latent γ-herpesvirus infection established a long-lasting impact that enhances subsequent adaptive autoimmune responses.
authors.affiliation: Department of Microbiology and Immunology, The University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3.
authors.forename: Costanza
authors.initials: C
authors.lastname: Casiraghi
authors.affiliation: Department of Microbiology and Immunology, The University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3.
authors.forename: Ana Citlali
authors.initials: AC
authors.lastname: Márquez
authors.affiliation: Department of Microbiology and Immunology, The University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3.
authors.forename: Iryna
authors.initials: I
authors.lastname: Shanina
authors.affiliation: Department of Microbiology and Immunology, The University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3.
authors.forename: Marc Steven
authors.initials: MS
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics*; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D019013:CD40 Antigens / Q000235:genetics*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental; D015870:Gene Expression; D006566:Herpesviridae Infections / Q000150:complications / Q000821:virology; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D009103:Multiple Sclerosis / Q000209:etiology* / Q000473:pathology; D010641:Phenotype; D018144:Rhadinovirus / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D017735:Virus Latency
chemical_list: D019013:CD40 Antigens; D050794:STAT1 Transcription Factor