Immune dysregulation in gestational diabetes mellitus: placental downregulation of CXCL9 and IL1RL1 and altered immune cell infiltration.

BACKGROUND

Immune dysregulation is implicated in pregnancy complications, particularly gestational diabetes mellitus (GDM). This study aimed to identify immune-related genes and characterize immune cell infiltration in GDM placentas.

METHODS

mRNA transcript expression profiles were retrieved from the GSE70493 dataset and integrated with immune-related genes (IRGs) extracted from the ImmPort database. Differentially expressed immune-related genes (DIRGs) were identified, followed by functional enrichment, protein-protein interaction (PPI) network, and immune infiltration analysis using CIBERSORT. Expression of candidate genes was validated by qRT-PCR and immunohistochemistry (IHC) in an independent cohort (50 GDM, 50 Non-GDM). Effect sizes (Cohen's d) were calculated.

RESULTS

Eleven DIRGs were identified between GDM pregnancies and normal pregnancies without maternal complications. GO analysis revealed significant enrichment in processes such as adaptive immune response, humoral immune response, immunoglobulin complex, and antigen binding. KEGG pathway analysis indicated enrichment in the Th1 and Th2 cell differentiation and cytokine-cytokine receptor interaction. In the discovery dataset (after correction for technical replicates: n = 30 GDM, n = 25 Non-GDM), CXCL9 was significantly downregulated in GDM (log2FC = -0.62; Cohen's d = -0.718, 95% CI: -1.27 to -0.166; p = 0.021), while IL1RL1 showed no significant difference (p = 0.053). In the independent validation cohort, both CXCL9 and IL1RL1 were significantly downregulated by qRT-PCR and IHC (p < 0.05). GDM placentas showed increased monocytes and macrophages M1, and decreased resting NK cells and T cells (p < 0.05).

CONCLUSION

CXCL9 and IL1RL1 are associated with immune dysregulation in GDM, as supported by external validation. However, the discovery dataset did not support their use as diagnostic biomarkers. Further large-scale studies are needed to clarify their roles.