Pyruvate Kinase M2 Upregulation Is Associated With Guillain-Barré Syndrome Risk and Immune Dysregulation: Insights...

This study aimed to investigate the potential involvement of pyruvate kinase M2 (PKM2) in the pathogenesis of Guillain-Barré syndrome (GBS).

Mendelian randomization (MR) analysis was used to evaluate the causal association between PKM2 expression and GBS susceptibility, with mediation analysis performed to explore immune cell-mediated pathways. The association between PKM2 methylation and GBS risk was further examined using GoDMC mQTL data and GRT-qPCRWAS Data Hub profiling. To validate these findings experimentally, an experimental autoimmune neuritis (EAN) mouse model was established in male C57BL/6 mice (6-8 weeks) by immunization with P0180-199 peptide, with tissues collected at disease initiation (Day 8) and peak stage (Day 16). PKM2 expression dynamics, Th17/Treg (regulatory T cells) balance, and histopathological changes were assessed using, Western blot, immunohistochemistry, immunofluorescence, flow cytometry, and H&E/Luxol fast blue (LFB) staining.

MR analysis revealed that elevated PKM2 expression in the tibial nerve was significantly associated with an increased risk of GBS (OR: 1.75-6.14, p < 0.05). In the EAN model, PKM2 expression in the sciatic nerve exhibited a time-dependent increase (p < 0.01), primarily localized to inflammatory infiltrates. Mechanistic studies demonstrated that PKM2 upregulation in CD4+ T cells was associated with promoted Th17 differentiation, as evidenced by the upregulation of IL-17a and RORγt (p < 0.05), concomitant with a reduction in Treg cells (p < 0.01). To further elucidate the upstream epigenetic regulation, the association between PKM2 methylation and GBS risk was investigated using GoDMC mQTL data. Among the four selected methylation sites, two-sample MR analyses indicated that cg24327132 were positively associated with GBS risk (p < 0.05). Furthermore, analysis of the GWAS Data Hub revealed that cg24327132 appeared to be preferentially hypomethylated in adaptive immune cells including regulatory T cells, CD4+ T cells, and B cells (Beta ≈ 0-0.05), visually distinct from innate immune populations (Beta ≈ 0.10-0.20), suggesting that perturbation of this hypomethylated state may dysregulate PKM2 expression and contribute to GBS susceptibility.

PKM2 upregulation is associated with GBS risk and immune dysfunction. PKM2 methylation may represent a key regulatory mechanism underlying this association. PKM2 may represent a mechanism target warranting further therapeutic investigation.