The AHNAK induces increased IL-6 production in CD4+T cells and serves as a potential diagnostic biomarker for recurrent pregnancy loss
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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DOI：
10.1093/cei/uxac067
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发表时间：
2022-08-04
影响因子：
4.6
通讯作者：
Li, Hong
中科院分区：
文献类型：
--
作者：
Li, Liman;Liu, Yuan;Li, Hong
反复妊娠丢失的患者的蜕膜免疫细胞中的转录组发生了改变。在其差异表达基因中，CD4+ T细胞表达的AHNAK升高可能通过增加IL-6的产生参与RPL的免疫失调，这说明其作为RPL的新干预靶点的潜力。 母胎免疫耐受紊乱导致不明原因的复发性妊娠流产（RPL）的发生。 AHNAK 是一种支架蛋白，参与调节 Ca2+ 进入 T 细胞和多种疾病的病理生理学。我们通过 RNA 测序 (RNA-seq) 对从三名 RPL 患者和三名健康对照中分离的蜕膜免疫细胞 (DIC) 进行差异基因表达分析，揭示了 407 个差异表达基因 (DEG)。在这些 DEG 中，我们强调了 RPL 患者的 DIC、外周血单核细胞 (PBMC) 和蜕膜中 AHNAK mRNA 和蛋白水平升高的临床意义，表明其有可能用作诊断 RPL 的生物标志物。特别是，RPL患者中CD4+ T细胞群中蜕膜和血液AHNAK+CD4+ T细胞的比例显着增加，并且AHNAK的缺失进一步显示抑制CD4+ Jurkat细胞系中白细胞介素（IL）-6的分泌。在临床蜕膜和血液标本中也观察到类似的模式。我们发现 AHNAK+CD4+ T 细胞比相应的 AHNAK-CD4+ T 细胞能够分泌更多的 IL-6。此外，RPL患者中CD4+T细胞群中蜕膜和血液IL-6+CD4+T细胞的频率也增加，并且与AHNAK+CD4+T细胞的频率呈显着正相关。我们的研究结果表明，CD4+ T 细胞表达的 AHNAK 升高可能通过增加 IL-6 的产生参与 RPL 的免疫失调，说明其作为 RPL 的新型干预靶点的潜力。
Patients with recurrent pregnancy loss exhibited an altered transcriptome in decidual immune cells. Among their differentially expressed genes, 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.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.