Immune dysregulation underlies SLE pathogenesis and EBV infection and abnormal latent protein expression are associated with SLE. EBNA-1 acts as a molecular mimic with SLE-autoantigens, while LMP1 acts a functional mimic of CD40 in an enhanced and dysregulated manner. Mice expressing a mCD40-LMP1 transgene (Tg) have autoantibodies by 2-3 months, but no overt autoimmune disease. This study evaluates the immune response to EBNA-1 in mCD40-LMP1 Tg mice and whether the addition of a molecular mimic accelerates lupus pathogenesis. Although anti-EBNA-1 levels are comparable in EBNA-1 immunized mCD40-LMP1Tg and mCD40 WT congenic mice (compared to adjuvant control and naïve mice), EBNA-1 specific proliferative and inflammatory cytokine responses, including IL-6, IL-17, IFN-γ, and TNF-α, are significantly enhanced (p < 0.0001) in mCD40-LMP1 Tg mice. mCD40-LMP1 Tg mice immunized with EBNA-1 exhibit enhanced cellular responses (p < 0.0001) to the EBNA-1 antigenic epitope PPPGRRP and the Sm B’ cross-reactive sequence PPPGMRPP. Enhanced cellular immune dysregulation with mCD40-LMP1 EBNA-1 immunization is accompanied by splenomegaly, increased serum BUN and creatinine levels, and elevated anti-dsDNA and ANA levels (p <0.0001 compared to mCD40 WT mice, p < 0.01 compared to adjuvant and naïve mCD40-LMP1 mice). These data suggest that expression of EBNA-1 and LMP1 may contribute to immune dysregulation that leads to pathogenic autoantigen-specific lupus inflammation.
- Copyright © 2013 by The American Association of Immunologists, Inc.