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The Possible Effect of B-Cell Epitopes of Epstein-Barr Virus Early Antigen, Membrane Antigen, Latent Membrane Protein-1, and -2A on Systemic Lupus Erythematosus.

ABSTRACT: This study was aimed to evaluate the role of B-cell epitopes of Epstein-Barr virus (EBV) Early antigen protein D (EA), envelope glycoprotein GP340/membrane antigen (MA), latent membrane protein (LMP)-1, and LMP-2A in systemic lupus erythematosus (SLE). B-cell epitopes were predicted by analyzing secondary structure, transmembrane domains, surface properties, and homological comparison. 60 female mice were randomized equally into 12 groups: 1-10 groups were immunized by epitope peptides (EPs) 1-10, respectively, while 11 and 12 groups were PBS and Keyhole limpet hemocyanin (KLH) control groups. Immunoglobulin G (IgG) and autoantibody to nuclear antigen (ANA) concentrations in mice serum were determined at week 8. Indirect levels of EP1-10 were further detected by enzyme-linked immuno sorbent assay (ELISA) in 119 SLE patients and 64 age- and gender-matched health controls (HCs). 10 probable EBV EA, MA, LMP-1, and LMP-2A B-cell epitopes related to SLE self-antigens were predicted and corresponding EP1-10 were synthesized. IgG concentrations at week 8 were increased in EP1-10 and KLH groups compared with PBS group in mice; while ANA levels were elevated in only EP1-4, EP6-7, and EP10 groups compared to KLH group by ELISA, and ANA-positive rates were increased in only EP1, EP2, EP4, EP6, and EP10 groups by indirect immunofluorescence assay. EP1-4, EP6, and EP10 indirect levels were increased in SLE patients than HCs, while EP1, EP3, EP6, and EP9 were correlated with SLE disease activity index score. In conclusion, EBV EA, MA, LMP-1, and LMP-2A B-cell EPs increased SLE-related autoantibodies in mice, and their indirect levels might be served as potential biomarkers for SLE diagnosis and disease severity.

SUBMITTER: Tu J

PROVIDER: S-EPMC5819577 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Possible Effect of B-Cell Epitopes of Epstein-Barr Virus Early Antigen, Membrane Antigen, Latent Membrane Protein-1, and -2A on Systemic Lupus Erythematosus.

Tu Jianxin J Wang Xiaobing X Geng Guannan G Xue Xiangyang X Lin Xiangyang X Zhu Xiaochun X Sun Li L

Frontiers in immunology 20180212

This study was aimed to evaluate the role of B-cell epitopes of Epstein-Barr virus (EBV) Early antigen protein D (EA), envelope glycoprotein GP340/membrane antigen (MA), latent membrane protein (LMP)-1, and LMP-2A in systemic lupus erythematosus (SLE). B-cell epitopes were predicted by analyzing secondary structure, transmembrane domains, surface properties, and homological comparison. 60 female mice were randomized equally into 12 groups: 1-10 groups were immunized by epitope peptides (EPs) 1-1 ...[more]

PMID: 29497417

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Project description: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.

Project description:The human herpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are associated with Hodgkin's lymphoma (HL) and Primary effusion lymphomas (PEL), respectively, which are B cell malignancies that originate from germinal center B cells. PEL cells but also a quarter of EBV-positive HL tumor cells do not express the genuine B cell receptor (BCR), a situation incompatible with survival of normal B cells. EBV encodes LMP2A, one of EBV's viral latent membrane proteins, which likely replaces the BCR's survival signaling in HL. Whether KSHV encodes a viral BCR mimic that contributes to oncogenesis is not known because an experimental model of KSHV-mediated B cell transformation is lacking. We addressed this uncertainty with mutant EBVs encoding the KSHV genes K1 or K15 in lieu of LMP2A and infected primary BCR-negative (BCR(-)) human B cells with them. We confirmed that the survival of BCR(-) B cells and their proliferation depended on an active LMP2A signal. Like LMP2A, the expression of K1 and K15 led to the survival of BCR(-) B cells prone to apoptosis, supported their proliferation, and regulated a similar set of cellular target genes. K1 and K15 encoded proteins appear to have noncomplementing, redundant functions in this model, but our findings suggest that both KSHV proteins can replace LMP2A's key activities contributing to the survival, activation and proliferation of BCR(-) PEL cells in vivo.Several herpesviruses encode oncogenes that are receptor-like proteins. Often, they are constitutively active providing important functions to the latently infected cells. LMP2A of Epstein-Barr virus (EBV) is such a receptor that mimics an activated B cell receptor, BCR. K1 and K15, related receptors of Kaposi's sarcoma-associated herpesvirus (KSHV) expressed in virus-associated tumors, have less obvious functions. We found in infection experiments that both viral receptors of KSHV can replace LMP2A and deliver functions similar to the endogenous BCR. K1, K15, and LMP2A also control the expression of a related set of cellular genes in primary human B cells, the target cells of EBV and KSHV. The observed phenotypes, as well as the known characteristics of these genes, argue for their contributions to cellular survival, B cell activation, and proliferation. Our findings provide one possible explanation for the tumorigenicity of KSHV, which poses a severe problem in immunocompromised patients.

Dataset Information

The Possible Effect of B-Cell Epitopes of Epstein-Barr Virus Early Antigen, Membrane Antigen, Latent Membrane Protein-1, and -2A on Systemic Lupus Erythematosus.

Publications

The Possible Effect of B-Cell Epitopes of Epstein-Barr Virus Early Antigen, Membrane Antigen, Latent Membrane Protein-1, and -2A on Systemic Lupus Erythematosus.

Similar Datasets

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