Dual-Axis Pattern of Peripheral Immunity in Myasthenia Gravis Susceptibility: A Prospective Cohort Study and Mendelian Randomization Analysis

Background: Previous studies have revealed peripheral immune abnormalities in myasthenia gravis (MG). However, it remains uncertain whether these abnormalities precede the onset of clinical symptoms and affect susceptibility to MG. Methods: A prospective study was performed involving 420,936 UK Biobank participants without MG at baseline. Cox proportional hazards models were utilized to evaluate the association between peripheral immune markers and incident MG. Additionally, a two-sample MR analysis was conducted using 731 immune cell traits as exposures and summary statistics for MG from FinnGen as the outcome to assess potential causal effects on MG risk. Results: The prospective analysis indicated that elevated neutrophil counts and inflammation-related markers were associated with an increased risk of MG, while higher lymphocyte and monocyte counts were associated with a reduced risk. We identified 22 immune cell traits that showed suggestive associations with MG risk. Among these, dendritic cell/plasmacytoid dendritic cell phenotypes and a higher proportion of CD39+ resting CD4+ regulatory T cells were associated with lower MG risk, whereas inflammatory monocyte and HLA-DR+ activated natural killer cell phenotypes were associated with increased risk. Notably, the proportion of CD14−CD16+ monocytes showed the strongest risk effect (OR = 2.231, 95% CI 1.370–3.632). After Benjamini–Hochberg FDR correction, none of the 22 associations remained significant, and none showed evidence of colocalization with MG (all PP.H4 < 0.8). Conclusions: Peripheral immune alterations were associated with subsequent risk of recorded MG, and exploratory MR analysis suggested a possible dual-axis pattern of pro-inflammatory innate immune activation and impaired immune regulation in MG. These findings require validation in clinically well-characterized MG cohorts.