Bidirectional causal relationships between antibody-mediated immune responses and autoimmune diseases: Insights from Mendelian randomization analysis

Autoimmune diseases like systemic lupus erythematosus (SLE) and multiple sclerosis (MS) involve intricate interactions between immune responses and genetic factors, and this study aimed to explore the causal and bidirectional relationships between antibody-mediated immune responses and these diseases to deepen understanding of their mechanisms. A bidirectional 2-sample Mendelian randomization (MR) approach was used, with genetic variants as instrumental variables; antibody data were obtained from the UK Biobank, and autoimmune disease data from the FinnGen database. Generalized summary data-based MR and complementary MR methods were applied to ensure robust results, and Bonferroni-adjusted thresholds were used to address multiple testing. The results showed that elevated levels of Epstein-Barr virus EBNA-1 and ZEBRA antibodies were associated with a reduced risk of SLE, while higher human herpesvirus 7 U14 antibody levels increased SLE risk; for MS, higher Epstein-Barr virus EBNA-1 antibody levels were linked to an increased risk. Bidirectional analyses revealed that autoimmune diseases such as SLE and MS also affect antibody levels, indicating a complex 2-way interaction. This study identifies the bidirectional relationships between antibody-mediated immune responses and autoimmune diseases, notes that pathogen-specific antibody levels can act as protective or risk factors depending on the disease, and provides new insights into the immunopathogenesis of SLE and MS as well as potential directions for therapeutic intervention.