Immunocyte phenotypes underlying the causal autoimmune features in narcolepsy type 1.

BACKGROUND: Narcolepsy is a neurological sleep disorder associated with immune response. However, the autoimmune basis for narcolepsy remains unclear. This study aimed to evaluate the causal relationship between immune cells and narcolepsy type 1 (NT1). METHODS: We used a two-sample Mendelian randomization (MR) method to investigate the associations between 731 immune cell traits and NT1 based on a genome-wide association study (GWAS) database from the FinnGen consortium. The inverse-variance weighted (IVW) method was used as the primary method, followed by sensitivity analyses, including the MR-Egger intercept test, Cochran's Q test, and MR pleiotropy residual sum and outlier (MR-PRESSO). Additional mediation analysis was conducted to investigate the mediating effect of 91 cytokines on immune cells to facilitate the immune processes in NT1. RESULTS: Immune cell traits showed significant causal associations with NT1. Risk-associated traits mainly involved human leukocyte antigen-DR (HLA-DR)-related monocyte phenotypes, T-cell-related traits, natural killer (NK) cell-related traits, and natural killer T (NKT) cell-related traits, whereas protective traits mainly involved CD4+ T-cell-related, plasmacytoid dendritic cell-related, monocyte-related, and B-cell-related phenotypes. Overall, ten immune cell traits were associated with an increased risk of narcolepsy, whereas five were associated with a reduced risk. Mediation analysis further indicated that interleukin-6 (IL-6) mediates the immune-inflammatory pathway linking monocyte-related traits to NT1. These findings remained consistent in all sensitivity analyses. CONCLUSIONS: Our study identified immunophenotypes that are related to the development of NT1, providing insight into the autoimmune pathogenesis of NT1 and subsequent immunotherapy.