Systemic lupus erythematosus (SLE) is a complex autoimmune disease that continues to raise major questions regarding its origin and progression. In recent years, Epstein–Barr virus (EBV) has gained particular attention as a potential trigger and modulator of the immune response in these patients. This study aimed to better understand this relationship by exploring how viral infection and the immunological environment of SLE influence gene regulation and immune cell activity.

When comparing SLE patients with healthy controls, we found that most cases exhibited active disease, with a high frequency of renal involvement. In these patients, the expression of key genes such as TNF-α and IFN-γ was reduced, whereas that of IL-10 was increased and inversely correlated with TNF-α, indicating a disrupted balance in the inflammatory response. Moreover, most patients showed evidence of active EBV infection, associated with the overexpression of LMP1, a viral protein capable of promoting the survival of autoreactive B cells and altering critical immune signaling pathways.

Another relevant finding was the activation of endogenous retroviruses (HERV-E). In heterologous plasma assays, we also confirmed that the lupus environment can directly modify the behavior of healthy immunocompetent cells, particularly by promoting changes in IL-6. Finally, we identified cross-reactivity between EBNA1 and Ro60, supporting the hypothesis of molecular mimicry as one of the mechanisms underlying the loss of immune tolerance.

Taken together, this study provides an integrated view of the role of EBV, endogenous retroviruses, and immune dysregulation in the pathogenesis of SLE. Beyond expanding the biological understanding of the disease, these findings suggest potential biomarkers and therapeutic pathways that may contribute to more precise and personalized management of lupus in the future.