Epstein-Barr virus shapes intrathecal Th1/Th17 immunity and parenchymal involvement in neuro-Behçet's disease

Human herpesviruses (HHVs) are implicated in neuro-inflammatory diseases due to their ability to establish persistent latency and reactivate in the context of immune dysregulation. Whilst Epstein -Barr virus (EBV) is recognized as a key factor in multiple sclerosis (MS), its role in neuro-Behçet's disease (NBD) remains poorly understood.

Serum and paired CSF samples were obtained from treatment-naïve patients with NBD and MS. Neurotropic viral DNA in CSF was screened by multiplex PCR. Virus-specific IgG antibodies against HSV-1 and EBV antigens (VCA and EBNA1) were measured by ELISA in serum and CSF. Real-time PCR was used to assess the expression of EBV latent genes (LMP1 and EBNA1), as well as cytokines and transcription factors, in CSF samples from NBD patients.

In this study, we demonstrate a high prevalence of EBV DNA in the cerebrospinal fluid (CSF) of patients with NBD (71.43%), significantly higher than that observed in MS (35.29%), whereas other neurotropic herpesviruses are rarely detected. Notably, the presence of EBV in the CSF is not associated with a specific intrathecal humoral response, suggesting predominantly latent viral persistence and cell-mediated immune control. The concurrent expression of the latent proteins LMP1 and EBNA1 indicates a type II latency program, capable of activating interferon pathways. EBV-positive patients exhibit an immune signature characterized by significantly elevated levels of IFN-γ and IFN-α, associated with Th1/Th17 polarization and reduced FOXP3 expression, reflecting a Th17/Treg imbalance. Furthermore, EBV status is associated with distinct clinical phenotypes, with parenchymal forms being observed exclusively in EBV-positive patients.

This suggests that EBV may contribute to the pathophysiology of NBD by promoting a pro-inflammatory intrathecal microenvironment. It also positions EBV as a potential biomarker and therapeutic target in this condition.