Abstract: Background　Idiopathic sudden sensorineural hearing loss (ISSNHL) is a type of sensorineural hearing impairment that occurs abruptly and whose etiology remains unclear. Although various exposure factors have been identified as potentially playing important roles in the pathophysiology of ISSNHL, their causal associations with ISSNHL are still not well understood. Objective　To explore the role of immune cell traits in mediating the association between immune-related/inflammatory diseases and ISSNHL. Methods　Publicly available genome-wide association study (GWAS) data for 12 immune-related and inflammatory diseases, 731 immune cell traits, and ISSNHL were collected. The inverse-variance weighted (IVW) method was used to assess the causal relationships among exposures, immune cells, and the disease. Furthermore, Mendelian randomization-Egger (MR-Egger) regression, the weighted median method, the simple mode, and the weighted mode were applied for sensitivity analyses and validation. Results　All GWAS summary data included in this study were derived from populations of European ancestry. Among the 12 immune-related and inflammatory diseases, 8 showed a significant positive causal association with the risk of ISSNHL, including allergic rhinitis (OR=1.135, 95% CI: 1.018 - 1.266, P=0.023), ankylosing spondylitis (OR=1.498, 95% CI: 1.169 - 1.920, P=0.001), gastroesophageal reflux disease (OR=1.363, 95% CI: 1.120 - 1.658, P=0.002), psoriasis (OR=1.054, 95% CI: 1.001 -
1.110, P=0.045), eczema (OR=2.505, 95% CI: 1.325 - 4.736, P=0.005), asthma (OR=2.853, 95% CI: 1.124 - 7.240, P=0.027), Crohn's disease (OR=1.057, 95% CI: 1.008 - 1.107, P=0.021), and inflammatory bowel disease (OR=1.058, 95% CI: 1.005 - 1.114, P=0.032). No significant genetic causal associations with ISSNHL were observed for the remaining 4 diseases (type 1 diabetes, type 2 diabetes, ulcerative colitis, and rheumatoid arthritis). Extensive sensitivity analyses detected no significant horizontal pleiotropy, indicating the robustness of these causal estimates. Notably, mediation MR analysis indicated that CD3 on CD4+ T cells played a significant mediating role in the impact of allergic rhinitis on ISSNHL, mediating 60% of the total effect (b=0.076, OR=1.079, 95% CI: 1.007 - 1.195). Conclusion　Genetic susceptibility to multiple immune-related and inflammatory diseases is interlinked and may elevate the risk of ISSNHL. The observed downregulation of CD3 expression on CD4+ T cells serves as a key genetically predicted factor mediating the association between allergic rhinitis and ISSNHL.