How Epstein Barr virus shapes lupus autoimmunity: mechanistic insights and therapeutic perspectives

Systemic lupus erythematosus (SLE) is a chronic, complex autoimmune disease arising from the interaction of environmental triggers with a genetically susceptible host. Among environmental factors, infection with Epstein–Barr virus (EBV) has one of the strongest and most consistent epidemiological associations with SLE. Patients with SLE display higher EBV seropositivity rates, increased viral loads, and more frequent viral reactivations compared with healthy individuals. In genetically predisposed hosts, EBV can disturb immune homeostasis and contribute to the breakdown of self-tolerance, acting within a broader network of environmental influences that shape lupus pathogenesis. Despite this well-established association, the precise mechanisms linking EBV infection to lupus autoimmunity have remained incompletely understood. Recent single-cell RNA-sequencing revealed that EBV-infected B cells in SLE are transcriptionally distinct, with enhanced EBNA2-driven antigen presentation and ability to activate autoreactive CD4 + T cells, which positions EBV as an active driver rather than a passive trigger of autoimmunity. These findings also highlight the interconnections between EBV-related mechanisms and dominant lupus pathways. These important new insights may have significant therapeutic implications, with a focus on B-cell targeted therapies that may suppress EBV reservoirs, while T-cell approaches, vaccines, and therapies disrupting EBV latency programs emerge as possible new strategies. This Mini Review summarizes established and emerging mechanistic evidence connecting EBV to SLE, with particular emphasis on recent data identifying EBV-infected B cells as potentialdrivers of lupus pathogenesis, and discusses the therapeutic implications of these findings.