Seyhan Yazar, Nicholas Schwab, Nicholas D. Sanderson, Jennifer Massey
EBNA2-Mediated Host Enhancer Hijacking and B cell Reprogramming described by Younis et al.2 (a) Latent EBNA2 replicates within EBV-infected CD27+ CD21low memory B cells. (b) Acting as a powerful epigenetic remodeler, EBNA2 binds to the host cell enhancer regions and disrupts the natural B-cell identity to “hijack” the host genome. (c) This increases the antigen-presenting cell (APC) transcriptomic function, leading to a profound immunophenotypic shift marked by the upregulation of TBX21 (T-bet), ZEB2 and the machinery required for MHC class II antigen presentation. This reprogramming turns a dormant memory B cell into a hyper-efficient APC. For decades, the epidemiological association between Epstein–Barr virus (EBV) and autoimmune diseases like systemic lupus erythematous (SLE) and multiple sclerosis (MS) remained largely correlative. A seminal 2022 study demonstrated that EBV infection precedes MS onset with a 32-fold increase in disease risk.1 In 2025, research transitioned to causation, offering mechanistic insights into how this ubiquitous herpesvirus can reconfigure the host immune system, extending the EBV axis beyond traditional autoimmunity into organ-specific idiopathic diseases like primary sclerosing cholangitis (PSC). Younis et al.2 used a specialized single-cell RNA sequencing technique to reveal that EBV preferentially resides within CD27+CD21low memory B cells, a subset already known for its expansion in chronic inflammatory conditions. In these cells, the viral transcription factor EBNA2 acts as an epigenetic remodeler that hijacks host enhancer region, amplifying the antigen-presenting cell transcriptomic program characterized by the upregulation of TBX21, ZEB2 and MHC class II components (Figure 1). These EBV-reprogrammed B cells were 25-fold more frequent in individuals with SLE than healthy controls. They do more than secrete autoantibodies; they robustly activate T follicular helper (Tfh) and T peripheral helper (Tph) cells, creating a self-sustaining cycle of autoantigen presentation and B-cell affinity maturation. This cellular phenotype was independently validated in early MS by Sorella et al.,3 who identified a significant expansion of T-BET+ CD21low CXCR3+ B cells that directly correlated with gadolinium enhancing lesions and disease activity. Furthermore, this hijack principle extends to PSC. El Abd et al.4 analyzed large patient cohorts and found that the immune repertoire of PSC patients carries a significantly higher burden of anti-EBV responses than controls. They also identified a specific PSC-associated T cell clonotype that is restricted by known PSC HLA risk alleles and, crucially, target EBV epitopes. Collectively, these diverse examples across SLE, MS and now PSC confirm that EBV is a universal pathogenic thread, hijacking the B cell repertoire to drive diverse chronic inflammatory states. While these studies provide a compelling mechanistic link between EBV and autoimmune diseases, it is important to emphasize that the expansion of EBV+ B cells alone is insufficient to cause disease. Because most EBV-infected individuals do not develop these autoimmune diseases, additional genetic or environmental “second hits” must act in concert with viral activity. A recent study by Adhelhak et al.5 provided a refined understanding of the MS Prodrome, an early set of signs, symptoms and other findings that occur before the onset of typical symptoms of MS. Their analysis showed that the immune-mediated CNS injury begins nearly a decade before clinical presentation. Serum proteomics indicated that myelin injury (detected by markers such as MBP or MOG peptides) precedes axonal injury (reflected by elevated neurofilament light chain, NfL) by approximately 6 years. This prodromal phase is marked by significant upregulation of IL-3 and NF-kB associated pathways, consistent with a prolonged state of subclinical neuroinflammation. It is likely that this chronic dysregulation is driven by the EBV-conditioned B-cell dysregulation described by Younis et al. A major unresolved question concerns the anatomical origin of MS-related immune activation and how it transitions into CNS-resident pathology. Sarkkinen et al.6 identified the deep cervical lymph nodes (dCLNs) as the key site of early EBV-driven B-cell maturation in MS. MS patients showed an enrichment of double negative (CD27−IgD−) memory B cells in the dCLNs, carrying a transcriptional signature consistent with EBV lytic activity. The mechanism for how these cells migrate from the periphery into the CNS was elucidated by Läderach et al.7 Using a humanized mouse model of symptomatic EBV infection, they demonstrated that the virus imprints a specific T-BET+CXCR3+ CNS-homing phenotype, allowing B cells to cross the blood–brain barrier and seed leptomeningeal spaces. While Laderach et al. characterized this homing phenotype, it remains debated whether EBV is the primary driver of barrier transit or merely a passenger within infiltrating subsets. Once resident in the CNS niches, these EBV-infected B cells act as ‘inflammatory hubs.’ Their secretome (including CXCL9/10 and CCL3/4/5) actively recruits Th1 and CD8+ effector T cells, effectively orchestrating the local inflammatory environment. The organization of these recruited cells into functional units was clarified by Kolz et al.,8 who demonstrated that T–B cell cooperation propagates CNS autoimmunity through the formation of ectopic lymphoid follicles (ELFs). These follicles act as autonomous “factories” where T-BET+ B cells engage with T peripheral helper (Tph) cells via the ICOS-ICOSL pathway. This local interaction bypasses the need for peripheral immune involvement, driving B-cell maturation and antibody production directly within the meninges. This recruitment appears to culminate in the establishment of a permanent immune reservoir. Pignata et al.9 identified that these recruited cells differentiate into CD4+ tissue-resident memory T cells (Trm). These CD69+CD103+ cells lack egress receptors like S1PR1, effectively sequestering them within the brain parenchyma where they produce high levels of IFN-γ gamma and granzyme B. The pathogenicity of these resident cells perhaps explains why peripheral therapies often fail in progressive MS as Pignata et al.9 showed that even after blocking further recruitment, these preexisting Trm cells are sufficient to sustain chronic neuroinflammation. This is corroborated by Orr and Steinmann,10 who utilized CODEX imaging to locate EBNA1 and LMP1 within active lesions of patients with secondary progressive MS (SPMS) and primary progressive MS (PPMS). They also observed EBV+ cells in direct proximity to reactive astrocytes/microglia, suggesting that viral antigens may contribute to local glial activation and blood–brain-barrier disruptions through localized cytokine gradients. A recurring theme across 2025 research is that EBV infection alone is insufficient to trigger autoimmunity; clinical disease only emerges when viral factors intersect with host immunogenetic susceptibility. This “Second Hit” framework is best illustrated by the molecular mimicry hypothesis. Sattarnezhad et al.11 showed that antibodies targeting EBNA1 cross-react with the CNS protein GlialCAM. While this mimicry could serve as a primary driver of MS pathology, its impact is highly dependent on the host's HLA profile. Proving this, MS risk scaled exponentially when high anti-EBNA1/GlicalCAM antibody titers are combined with the HLA-DRB1*15:01 risk haplotype (Class II), an effect further amplified in individuals lacking the protective HLA-A*02:01 allele (Class I).11 This suggest that the clinical disease results a cumulative failure of the HLA system to effectively manage the cross-reactive B-cell repertoire. Beyond antigen presentation, the 2025 data highlights how viral genetics can mimic human risk alleles to disable B-cell checkpoints. While both EBNA1 and EBNA2 are components of the EBV latency program, they serve different roles in the immunological signature of MS. Elevated anti-EBNA1 IgG levels is the strongest and most consistent serological predictors of MS risk, while EBNA2 is associated with increased disease frequency and cellular transformation. Mechelli et al.12 identified EBNA2 1.2 variant specifically downregulated CD40 signaling, mimicking human CD40 risk allele effects. As CD40 is a critical co-stimulatory molecule for B-cell survival and selection, by downregulating this pathway, the virus may impair B-cell tolerance. In carriers of the HLA-DRB1*15:01 risk haplotype, this EBNA2-mediated CD40 suppression seems to allow autoreactive B-cell clones (such as those cross-reactive with GlialCAM described by Sattarnezhad et al.11) to escape both central and peripheral immune checkpoints. In carriers of HLA-DRB1*15:01 haplotype, this viral-mediated suppression of CD40 may provide a molecular storm, facilitating the survival of the hijacked APC-like B cells identified by Younis et al.2 Finally, the genetic filter extends to the innate immunity system's ability to control the primary infection. While MS genetics traditionally focussed on Class II allele, Nova et al.13 analyzed the UK Biobank data and found carriers of HLA-E*01:01 allele with a history of infectious mononucleosis (IM) have a significantly higher risk of developing MS, independent of the well-established interactions between IM and HLA-DRB1*15:01 or HLA-A*02:01alleles. The authors proposed that the HLA-E*01:01 variant provides suboptimal immune control over EBV by poorly modulating NK cell-mediated surveillance during the primary infection. This impaired early clearance not only increases the likelihood of symptomatic IM but also potentially facilitates the expansion of the pathogenic, autoreactive B-cell reservoirs that drive later autoimmunity. The 2025 research landscape has advanced the EBV-autoimmunity axis from a longstanding epidemiological association to a framework supported by structural and mechanistic evidence (Table 1). Across SLE, MS and PSC, converging evidence suggests EBV-driven B-cell dysregulation as a central driver of chronic inflammation, offering a crucial window for early intervention. However, as argued by Giovannoni et al.14 achieving true disease control may require moving beyond broad immunomodulation. They contend that current B-cell depletion therapies represent a “leaky” strategy that fails to clear the sequestered EBV reservoirs within the CNS and deep lymphoid tissues. Consequently, the shift from managing established damage to preventing the autoimmune cascade entirely has become a tangible goal. Future efforts must focus on decoupling this ubiquitous infection from its pathogenic consequences, whether through the use of EBV-specific antivirals like tenofovir to inhibit lytic replication, T-cell therapies to clear latent reservoirs, or preventative vaccines. By dismantling the viral mechanisms that drive B-cell autoreactivity, we may halt the autoimmune cascade at its source. The authors declare no conflict of interest. Nicholas S. R. Sanderson: Writing – review and editing. Seyhan Yazar: Writing – original draft; writing – review and editing; visualization; conceptualization. Nicholas Schwab: Writing – review and editing. Jennifer Massey: Writing – review and editing; writing – original draft.