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

Abstract

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.

Myeloid‐derived suppressor cells as a potential biomarker for recurrent pregnancy loss and recurrent implantation failure

“…However, and not in contradiction with this concept, we have observed significantly increased MDSCs in non-pregnant RPL and RIF women, which might be reflecting (surrogate marker) a proinflammatory status in these patients. Based on this and previous results, 9,10,14,37,38 a subgroup of patients with RPL and RIF may present a proinflammatory status, a baseline inflammation. Different alterations in the immune system can be observed, such as this increase in MDSCs.…”

“…13 More recent data suggest other changes in the immunological landscape such as increased IL6+ CD4+ T cells in patients with RPL. 14 Despite accumulated evidence, only screening of antiphospholipid syndrome and thyroid dysfunction are recommended in an immunologic clinical setting by international guidelines.…”

“…Additionally, growing evidence suggests an association with deleterious combinations of the mother killer immunoglobulin‐like NK receptors (KIR) and the embryo HLA‐C and altered placentation and pre‐eclampsia 13 . More recent data suggest other changes in the immunological landscape such as increased IL6+ CD4+ T cells in patients with RPL 14 . Despite accumulated evidence, only screening of antiphospholipid syndrome and thyroid dysfunction are recommended in an immunologic clinical setting by international guidelines.…”

Dupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells

“…Despite sustained levels of IL13 gene expression, we found ITM2A , a target gene of the prototypical type 2 transcription factor GATA3 38 , as well as the type 2 associated marker AREG 39 , to be significantly downregulated in multiple T cell subsets in DAHND lesions (Figure S2 ), confirming overall dampened type 2 immune responses. In contrast to the normalization or downregulation of these inflammatory mediators, we found increased expression of the keratinocyte adhesion molecule desmoyokin AHNAK in DAHND, an enhancer of overall T cell function (Figure S2 ) 40 , 41 .…”

AHNAKs roles in physiology and malignant tumors

“…In the single nucleated cells and membrane tissues peripheral blood from patients with habitual abortion, the mRNA and protein levels of AHNAK are elevated. And AHNAK with increased CD4+ T cell expression may be involved in the immune dysregulation of RPL in habitual abortion by elevating IL-6 production ( 36 ).…”