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

Front Immunol. 2021 Feb 3;11:606936. doi: 10.3389/fimmu.2020.606936. eCollection 2020.


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.

Keywords: EBNA-1; Epstein-Barr virus; LMP1; autoimmunity; functional mimicry; molecular mimicry; mouse; systemic lupus erythematosus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / blood
  • Autoantigens / administration & dosage
  • Autoantigens / immunology*
  • Autoimmunity*
  • CD40 Antigens / genetics
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • Cross Reactions
  • Epitopes
  • Epstein-Barr Virus Nuclear Antigens / administration & dosage
  • Epstein-Barr Virus Nuclear Antigens / immunology*
  • Immunity, Cellular*
  • Immunity, Humoral*
  • Immunization
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Mimicry*
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / immunology*
  • Viral Matrix Proteins / metabolism
  • snRNP Core Proteins / administration & dosage
  • snRNP Core Proteins / immunology*


  • Antibodies, Antinuclear
  • Autoantigens
  • CD40 Antigens
  • EBV-associated membrane antigen, Epstein-Barr virus
  • Epitopes
  • Epstein-Barr Virus Nuclear Antigens
  • Viral Matrix Proteins
  • snRNP Core Proteins
  • EBV-encoded nuclear antigen 1