The AHNAK induces increased IL-6 production in CD4+ T cells and serves as a potential diagnostic biomarker for recurrent pregnancy loss.

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Disorganized maternal–fetal immune tolerance contributes to the occurrence of unexplained recurrent pregnancy loss (RPL). AHNAK is a scaffolding protein participating in the regulation of Ca2+ entry into T cells and the pathophysiology of diverse diseases. We performed differential gene expression analysis in decidual immune cells (DICs) isolated from three patients with RPL and from three healthy controls via RNA-sequencing (RNA-seq), which revealed 407 differentially expressed genes (DEGs). Among these DEGs, we underscored the clinical significance of elevated AHNAK mRNA and protein levels in DICs, peripheral blood mononuclear cells (PBMCs), and decidua of the patients with RPL, suggesting its potential use as a biomarker for the diagnosis of RPL. Especially, the ratios of decidual and blood AHNAK+CD4+ T cells in the CD4+ T cell population were significantly increased in patients with RPL, and the loss of AHNAK was further shown to inhibit interleukin (IL)-6 secretion in the CD4+ Jurkat cell line. Similar patterns were also observed in the clinical decidual and blood specimens. We uncovered that the AHNAK+CD4+ T cells could secrete more IL-6 than that the corresponding AHNAK-CD4+ T cells. Moreover, the frequencies of decidual and blood IL-6+CD4+ T cells in the CD4+ T-cell population were also increased in patients with RPL and showed significant positive correlations with the frequencies of AHNAK+CD4+ T cells. Our findings suggest that the elevated AHNAK expressed by CD4+ T cells may be involved in the immune dysregulation of RPL by increasing IL-6 production, illustrating its potential as a novel intervention target for RPL.