BACKGROUND: Previous investigations into the causal relationship between infections and systemic lupus erythematosus (SLE) have yielded controversial results. This study delves into the bidirectional causal relationships between various infectious agents and SLE, employing two-sample Mendelian randomization (MR) from an immunological perspective. METHODS: Utilizing genome-wide association study (GWAS) data for 46 antibody-mediated immune responses (AMIRs) to 13 pathogens and three distinct SLE datasets, we employed Bayesian Weighted MR (BWMR) and inverse variance weighted (IVW) methods to ascertain causal links, supplemented by meta-analysis to resolve inconsistencies. Sensitivity was evaluated using complementary methodologies. Genes mapped by instrumental variables (IVs) of each significant phenotype were further analyzed using summary-data-based MR (SMR). RESULTS: Meta-analysis of forward MR results suggested a protective role of elevated antibody levels against Epstein-Barr virus (EBV) antigens EBNA-1 (IVW: OR = 0.70, 95 % CI = 0.60-0.83, p <
0.001) and ZEBRA (IVW: OR = 0.72, 95 % CI = 0.53-0.97, p <
0.05) in SLE. Conversely, reverse MR indicated positive correlations between SLE and antibodies to Chlamydia trachomatis pGP3 (IVW: OR = 1.03, 95 % CI = 1.01-1.06, p <
0.01) and human herpesvirus 7 (HHV-7) U14 (IVW: OR = 1.03, 95 % CI = 1.01-1.06, p <
0.05), along with negative correlations with antibodies to Helicobacter pylori GroEL (IVW: OR = 0.96, 95 % CI = 0.92-0.99, p <
0.05), varicella-zoster virus (VZV) glycoproteins E and I (IVW: OR = 0.98, 95 % CI = 0.98-0.99, p <
0.001), and polyomavirus BKV IgG (IVW: OR = 0.92, 95 % CI = 0.88-0.95, p <
0.001). Additionally, SLE-associated genes were enriched in pathways such as the response to muramyl dipeptide (MDP), with seven genes showing significant causal relationships with AMIRs according to SMR analysis. CONCLUSIONS: Our findings do not support that antibody response to infections increase the risk of SLE. Rather, SLE itself influences antibody response to infections. These insights provide a deeper understanding of the interplay between infectious pathogens and SLE and may guide future preventive and therapeutic strategies.