Journal article
Epstein-Barr Functional Mimicry: Pathogenicity of Oncogenic Latent Membrane Protein-1 in Systemic Lupus Erythematosus and Autoimmunity
Frontiers in immunology, Vol.11, pp.606936-606936
02/03/2021
DOI: 10.3389/fimmu.2020.606936
PMCID: PMC7886997
PMID: 33613527
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.
Details
- Title: Subtitle
- Epstein-Barr Functional Mimicry: Pathogenicity of Oncogenic Latent Membrane Protein-1 in Systemic Lupus Erythematosus and Autoimmunity
- Creators
- Melissa E. Munroe - Oklahoma Medical Research FoundationJourdan R. Anderson - Oklahoma Medical Research FoundationTimothy F. Gross - Oklahoma Medical Research FoundationLaura L. Stunz - University of IowaGail A. Bishop - University of IowaJudith A. James - Oklahoma Medical Research Foundation
- Resource Type
- Journal article
- Publication Details
- Frontiers in immunology, Vol.11, pp.606936-606936
- DOI
- 10.3389/fimmu.2020.606936
- PMID
- 33613527
- PMCID
- PMC7886997
- NLM abbreviation
- Front Immunol
- ISSN
- 1664-3224
- eISSN
- 1664-3224
- Publisher
- Frontiers Media S.A
- Grant note
- National Institute of Allergy and Infectious Diseases National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute of General Medical Sciences
- Language
- English
- Date published
- 02/03/2021
- Academic Unit
- Microbiology and Immunology; President; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984297435702771
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