Multi-omics profiling uncovers paradoxical Epstein-Barr virus involvement in autoimmune liver disease pathogenesis

Autoimmune liver disease (AILD) is a group of immune-mediated chronic liver injury diseases of unknown etiology. The pathogenesis of AILD is not clear, and it poses a serious threat to human life and health for a long time. Several case reports and observational studies have shown that the Epstein-Barr virus (EBV) is directly associated with AILD.However, the causal nature of the intrinsic association remains uncertain.In this study, we investigated the potential association between Epstein-Barr virus and AILDs using a two-sample Mendelian randomization analysis and generalized summary-data-based MR (GSMR) by integrating a genome-wide association study (GWAS) of five antibodies against EBV with the latest GWAS summary statistics for AILDs derived from the FinnGen database. Using summary data-based Mendelian randomization (SMR), we identified AILD-associated candidate genes linked to EBV-related single nucleotide polymorphisms (SNPs). Subsequent transcriptomic and single-cell RNA sequencing analyses were performed to elucidate their functional roles in disease pathogenesis and their interactions with immune cell populations. We found that Epstein-Barr nuclear antigen 1 (EBNA-1) may be a protective factor in autoimmune hepatitis (AIH), while our reverse MR analysis similarly found that autoimmune hepatitis may decrease the levels of EBNA-1 antibodies. More importantly, we found a positive correlation between ZEBRA antibodies and primary biliary cholangitis (PBC). In addition, according to post-GWAS analysis, five genes showed significant causal relationships with AIH and four genes with PBC, of which AIF1-positive B cells may play an important role in AIH, and M1 macrophages may play an important role in PBC progression.Our findings suggest a complex role for EBV in AILD pathogenesis, potentially acting as a double-edged sword. This study represents the first lines of genetic evidence linking EBV and AILDs, opening new avenues for understanding the etiology and potential therapeutic targets in these chronic liver conditions.