Gene profiling of Epstein-Barr Virus and human endogenous retrovirus in peripheral blood mononuclear cells of SLE patients: immune response implications

Abstract

Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by the convergence of genetic, immunological, and viral elements resulting in a complex interaction of both internal and external factors. The role of the Epstein-Barr virus (EBV) and human endogenous retroviruses (HERV-E) as triggers and maintenance elements in the pathogenesis of SLE has been widely recognized. Previous studies have independently evaluated the effects of EBV and HERV-E in this disease. In this work, for the first time, these viral factors are jointly investigated in SLE patients. This study aimed at assessing the differential expression of immune regulatory genes and the incidence of specific viral pathogens (EBV and HERV-E), alongside the detailed characterization of surface markers in T- and B-lymphocytes in patients with SLE and control participants. A comparative analysis between patients with SLE and control participants was performed, evaluating the expression of phenotypic markers and genes involved in the immune response (TNF-α, IL-2, IL-6, IL-10, IFNG, TLR3), as well as HERV-E _gag and EBV viral genes (LMP1 and BZLF1).A significant association between SLE and EBV was found in this study. A notable increase in EBV LMP1 gene expression was observed in patients with SLE . Also, a significant overexpression of HERV-E was observed, in addition to a considerable increase in the distribution of the cell surface marker CD27 + on T- and B-lymphocytes, observed in individuals with SLE compared to the control group. This study provides evidence regarding the role that EBV virus plays in lymphocytes in the context of SLE, highlighting how both the virus and the host gene expression may influence disease pathogenesis by altering immune regulatory pathways mediated by TNF-α, IFN-γ, and IL-10, as well as parallel overexpression of HERV-E gag. The decrease in TLR3 could indicate a compromised antiviral response, which could facilitate viral reactivation and contribute to disease activity.

Keywords: B lymphocytes; Epstein-Barr virus (EBV); Human endogenous retrovirus (HERV-E); Lupus; T lymphocytes.

Fig.1

Box-whisker plot of relative expression of genes (A) (TNFA; TLR3; IFNG; IL-06; IL-10) (HERV- E gag, LMP1, and BZLF1), (B) ratio of circulating plasma IgG EBNA1, and IgG EA in patients (SLE) and control subjects (NC). * p < 0.05, *** p < 0.001, **** p < 0.0001.

Fig.2

Distribution of cell populations and their surface markers CD20 + (B lymphocyte); CD4 + (T helper lymphocyte); CD3 + (T lymphocyte); CD27 + (tumor necrosis factor receptor; TNF). Box-whisker plot of percentage distribution (%) of cell surface markers in patients (SLE) and control subjects (CN): A: CD4 + T lymphocytes expressing CD27 + . CD20 + B lymphocytes expressing CD27 + . *** p < 0.001, **** p < 0.0001.

Fig.3

Outline of relative gene expression (TNFA; TLR3; IFNG; IL-10; HERV- E gag, LMP1; CD27) showing imbalance in the context of patients with Systemic Lupus Erythematosus (SLE). The potential effect of EBV on DNA methylation is suggested by the dashed line. The arrow and red bars represent the critical points of affectation in patients with SLE. Created with BioRender.com.