Abstract
Systemic lupus erythematosus (SLE) and other autoimmune diseases are propelled by immune dysregulation and pathogenic, disease-specific autoantibodies. Autoimmunity against the lupus autoantigen Sm is associated with cross-reactivity to Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1). Additionally, EBV latent membrane protein-1 (LMP1), initially noted for its oncogenic activity, is an aberrantly active functional mimic of the B cell co-stimulatory molecule CD40. Mice expressing a transgene (Tg) for the mCD40-LMP1 hybrid molecule (containing the cytoplasmic tail of LMP1) have mild autoantibody production and other features of immune dysregulation by 2–3 months of age, but no overt autoimmune disease. This study evaluates whether exposure to the EBV molecular mimic, EBNA-1, stimulates antigen-specific and concurrently-reactive humoral and cellular immunity, as well as lupus-like features. After immunization with EBNA-1, mCD40-LMP1 Tg mice exhibited enhanced, antigen-specific, cellular and humoral responses compared to immunized WT congenic mice. EBNA-1 specific proliferative and inflammatory cytokine responses, including IL-17 and IFN-γ, were significantly increased (p<0.0001) in mCD40-LMP1 Tg mice, as well as antibody responses to amino- and carboxy-domains of EBNA-1. Of particular interest was the ability of mCD40-LMP1 to drive EBNA-1 associated molecular mimicry with the lupus-associated autoantigen, Sm. EBNA-1 immunized mCD40-LMP1 Tg mice exhibited enhanced proliferative and cytokine cellular responses (p<0.0001) to the EBNA-1 homologous epitope PPPGRRP and the Sm B/B’ cross-reactive sequence PPPGMRPP. When immunized with the SLE autoantigen Sm, mCD40-LMP1 Tg mice again exhibited enhanced cellular and humoral immune responses to both Sm and EBNA-1. Cellular immune dysregulation with EBNA-1 immunization in mCD40-LMP1 Tg mice was accompanied by enhanced splenomegaly, increased serum blood urea nitrogen (BUN) and creatinine levels, and elevated anti-dsDNA and antinuclear antibody (ANA) levels (p<0.0001 compared to mCD40 WT mice). However, no evidence of immune-complex glomerulonephritis pathology was noted, suggesting that a combination of EBV and genetic factors may be required to drive lupus-associated renal disease. These data support that the expression of LMP1 in the context of EBNA-1 may interact to increase immune dysregulation that leads to pathogenic, autoantigen-specific lupus inflammation.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease driven by dysregulated cellular and humoral immunity [1,2,3,4]
We have previously demonstrated that mCD40-latent membrane protein-1 (LMP1) Tg mice exhibit mild autoimmunity, marked by lymphadenopathy, splenomegaly, enhanced cytokine secretion, and autoantibody production [71]
To compare the cellular immune response to EBV nuclear antigen-1 (EBNA-1) and its antigenic epitope PPPGRRP, homologous to a comparable sequence in the lupus autoantigen Sm, draining lymph node cells from EBNA-1-immunized mCD40-LMP1 Tg, congenic WT, or CD40-deficient mice were cultured in the presence or absence of antigen (Figure 3 and Supplementary Figure 1)
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease driven by dysregulated cellular and humoral immunity [1,2,3,4]. Increased immune dysregulation is associated with increased clinical disease activity and flare [5,6,7] and places patients at risk of permanent end-organ damage, SLEassociated morbidity, and early mortality [8]. Such immune dysregulation begins years before clinical disease onset and amplifies through a feed-forward aggregation of altered innate and adaptive immune pathways as patients progress to SLE classification. Despite improved disease management and treatment approaches to suppress and circumvent dysregulated immunity, patients with SLE exhibit persistent and waxing/waning dysregulation of innate and adaptive immune pathways
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