title: Modulation of B-cell tolerance by murine gammaherpesvirus 68 infection: requirement for Orf73 viral gene expression and follicular helper T cells.
abstract: Viruses such as Epstein-Barr virus (EBV) have been linked to mechanisms that support autoantibody production in diseases such as systemic lupus erythematosus. However, the mechanisms by which viruses contribute to autoantibody production remain poorly defined. This stems in part, from the high level of seropositivity for EBV (> 95%) and the exquisite species specificity of EBV. In this study we overcame these problems by using murine gammaherpesvirus 68 (MHV68), a virus genetically and biologically related to EBV. We first showed that MHV68 drives autoantibody production by promoting a loss of B-cell anergy. We next showed that MHV68 infection resulted in the expansion of follicular helper T (Tfh) cells in vivo, and that these Tfh cells supported autoantibody production and a loss of B-cell anergy. Finally, we showed that the expansion of Tfh cells and autoantibody production was dependent on the establishment of viral latency and expression of a functional viral gene called Orf73. Collectively, our studies highlighted an unexpected role for viral latency in the development of autoantibodies following MHV68 infection and suggest that virus-induced expansion of Tfh cells probably plays a key role in the loss of B-cell anergy.
authors: Medical College of Wisconsin, Division of Allergy/Immunology, Department of Pediatrics, The Children's Research Institute, Milwaukee, WI, USA. sgauld@mcw.edu
authors: Stephen B
authors: SB
authors: Gauld
authors: Jessica L
authors: JL
authors: De Santis
authors: Joseph M
authors: JM
authors: Kulinski
authors: Jennifer A
authors: JA
authors: McGraw
authors: Steven M
authors: SM
authors: Leonardo
authors: Elizabeth A
authors: EA
authors: Ruder
authors: Weston
authors: W
authors: Maier
authors: Vera L
authors: VL
authors: Tarakanova
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D018144:Rhadinovirus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000821:virology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017735:Virus Latency / Q000235:genetics / Q000276:immunology
chemical_list: D001323:Autoantibodies; C581957:Orf73 protein, Murid herpesvirus 4; D014764:Viral Proteins