Immune cell dysregulation and inflammatory mediators shape epilepsy risk

Background and objectives

Emerging evidence implicates immune dysregulation and neuroinflammation in the pathogenesis of epilepsy, yet the causal mechanisms remain unclear. This study aimed to investigate the causal effects of immune cells and inflammatory proteins on epilepsy and evaluate the mediating role of inflammatory proteins.

Methods

This study utilized the largest available genome-wide association study data on immune cell phenotypes and inflammatory proteins as exposures, and epilepsy genome-wide association study data from the FinnGen dataset as outcomes. Five Mendelian randomization (MR) methods were applied within a two-sample MR framework to assess causal effects. Furthermore, a two-step MR analysis was conducted to quantify the proportion of epilepsy and its subtypes influenced by immune cells through inflammatory proteins.

Results

The two-sample MR analysis identified 32 immune cell phenotypes associated with epilepsy risk (19 risk-increasing, e.g., CD19⁺ B cells; 13 protective, e.g., regulatory T cell subsets). Subtype analyses revealed 30 immune phenotypes associated with generalized epilepsy and 26 with focal epilepsy. Eight inflammatory proteins showed suggestive causal effects on epilepsy: C-C chemokine ligand 23, C-X-C motif chemokine ligand 6, C-X-C motif chemokine ligand 11, and vascular endothelial growth factor A increased epilepsy risk, while interleukin-13 (IL-13), leukemia inhibitory factor receptor, tumor necrosis factor, and osteoprotegerin conferred protection. Mediation analysis indicated that inflammatory proteins mediated 6.3–13.5% of the immune effects on epilepsy. Specifically, CD14⁺CD16⁺ monocytes increased epilepsy risk through elevated C-C chemokine ligand 23 levels (8.5% mediation), while effector memory double-negative (CD4⁻CD8⁻) T cells reduced epilepsy risk via upregulation of IL-13 (6.3%). Sensitivity analyses confirmed the robustness of these findings (P heterogeneity/pleiotropy > 0.05). Although no associations reached Bonferroni-corrected significance, the findings implicate B cells, monocytes, regulatory T cells, and cytokines (e.g., IL-13, leukemia inhibitory factor receptor) in the pathogenesis of epilepsy, with inflammatory proteins acting as partial mediators.

Conclusions

These results enhance our understanding of immune-inflammatory pathways in epilepsy and highlight potential therapeutic targets. Future studies should validate these findings across diverse populations and further elucidate the molecular mechanisms underlying the identified associations.