Epstein-Barr Virus (EBV) Encoded Dutpase Exacerbates the Immune pathology of Lupus Nephritis In Vivo

Epstein-Barr virus (EBV) is an environmental factor with strong links to systemic lupus erythematous (SLE) pathogenesis; however, the mechanism(s) remains unclear. The goal of this study was to determine whether the EBV protein "deoxyuridine triphosphate nucleotidohydrolase (dUTPase)", which can induce aberrant immune responses, contributes to the immunopathology of lupus nephritis (LN). Using the NZM2410/J SLE mouse model, we demonstrated that intramuscular injections of EBV-dUTPase protein (10 μg) significantly enhanced glomerulonephritis compared to PBS-injected controls. The inflammation was characterized by interstitial/tubular cellular infiltrates, as well as increased IgG complex formation and C3 deposition in glomeruli. Additional immunohistochemical analyses revealed that EBV-dUTPase strongly induced IL-17 in glomeruli and tubules. More importantly, examination of kidney biopsies from class III/IV LN patients demonstrated the presence of EBV-dUTPase in infiltrating plasma-cell aggregates near glomeruli, where neighboring cells with increased TLR-2 and IL-17 expression were observed, suggesting EBV-dUTPase may exacerbate the immunopathologies in some LN patients.