Epstein-Barr Functional Mimicry: Pathogenicity of Oncogenic Latent Membrane Protein-1 in Systemic Lupus Erythematosus and Autoimmunity

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.

A High Prevalence of Anti-EBNA1 Heteroantibodies in Systemic Lupus Erythematosus (SLE) Supports Anti-EBNA1 as an Origin for SLE Autoantibodies

“…There are other suggestive results increasing the circumstantial evidence that EBV infection contributes to the propensity for autoimmunity, especially with the latency expression programs of EBV infection. For example, the CD40-imitating capacity of LMP1 (latent membrane protein 1), an EBV gene product expressed in latency, appears to lower the threshold for humoral autoimmunity ( 38 ). However, when these observations are combined with the immunochemistry and epidemiological observations concerning autoantibody origin, the association of SLE with EBV infection, and the added risk from anti-EBNA1, the accumulated EBV-related evidence begins to nominate possible molecular components of mechanism and to provide a plausible outline of a mechanistic scenario for EBV action starting with EBV infection and progressing to the clinical manifestations of SLE ( Figure 1 ).…”

Blood transcriptome analysis in a buck-ewe hybrid points towards an Nuclear Factor-kappa B lymphoproliferative autoimmune disorder

“…Symptomatic resemblance to systemic lupus in mice was described over 50 years ago in the F1 hybrids of New Zealand black (NZB) and New Zealand white (NZW) mice 29 . CD28 was connected to systemic lupus by three studies [30][31][32] and FASLG 30,32 as well as TRAF5 31,32 by two studies. While these lines of evidence put CD28, FASLG, and BCL2 into the main focus of an autoimmune phenotype in mammal hybrids, our data suggest that UBE2N plays a major role in regulation of the syndrome.…”

Human genetic and immunological determinants of SARS‐CoV‐2 and Epstein–Barr virus diseases in childhood: Insightful contrasts

“…At the population level, about 200,000 new cancer cases and approximately 200,000 cancer deaths worldwide can be attributed to EBV infection, accounting for 1.3%-1.9% of the global cancer burden [17][18][19]. EBV infection may also contribute to the development of certain autoimmune disorders, such as rheumatoid arthritis [20] and systemic lupus erythematosus [21]. In a recent study based on longitudinal analysis on a cohort of more than 10 million young adults, EBV was further suggested to be necessary for the development of multiple sclerosis [22].…”