Functional NK surrogate biomarkers for inflammatory recurrent pregnancy loss and recurrent implantation failure

Comins-Boo, Alejandra; Cristóbal, Ignacio; Fernández‐Arquero, Miguel; Frías, Edgard Rodríguez de; Urrutia, Marta Calvo; Suárez, L. Pilar; Escorial, Pilar Gasca; Herráiz, M.; Sánchez-Ramón, Silvia

doi:10.1111/aji.13426

Cited by 10 publications

(16 citation statements)

References 69 publications

(141 reference statements)

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“…In addition, AHNAK in the PBMCs was indicated to be valuable in the diagnosis of RPL with a high AUC (0.742). As previously reported, certain genes and miRNAs in PBMCs or immune cells have been considered to be diagnostic or predictive biomarkers for immune-related diseases [ 28 , 29 ]. Compared to serum biomarkers, whether biomarkers in PBMCs have advantages in the diagnosis of immune-related conditions requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

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

Liu

Feng

et al. 2022

Clinical and Experimental Immunology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Liu

Feng

et al. 2022

Clinical and Experimental Immunology

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“…Moreover, in women with RPL, differences in peripheral blood NK cell receptor expression have been described for example by Fukui et al 20 . Comins et al 21 . and Strobel et al 22 .…”

Section: Introductionmentioning

confidence: 95%

“…18 Given their suggested important role in pregnancy, several studies explored the association between NK cell numbers and reproductive success, though the results between these studies are not fully conclusive yet. 19 Moreover, in women with RPL, differences in peripheral blood NK cell receptor expression have been described for example by Fukui et al 20 Comins et al 21 and Strobel et al 22 who primarily focused on activating receptors, and by Zhu et al, 23 Ntrivalas et al 24 and Emmer et al 25 focusing on CD16 in combination with inhibitory KIRs and NKG2A. The immune checkpoint receptors have not been thoroughly studied in relation to RPL, except for TIM-3.…”

Section: Introductionmentioning

confidence: 99%

Natural killer cell profiles in recurrent pregnancy loss: Increased expression and positive associations with TACTILE and LILRB1

Habets

Schlütter

Kuijk

et al. 2022

American J Rep Immunol

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Problem: NK cells are important for healthy pregnancy and aberrant phenotypes or effector functions have been associated with RPL. We compared expression of a broad panel of NK cell receptors, including immune checkpoint receptors, and investigated their clinical association with RPL as this might improve patient stratification and prediction of RPL. Method of study:Peripheral blood mononuclear cells were isolated from 52 women with RPL and from 2 women with an uncomplicated pregnancy for flowcytometric analysis and plasma was used to determine anti-CMV IgG antibodies. Results:Between RPL and controls, we observed no difference in frequencies of T-, NKT or NK cells, in CD56dimCD16+ or CD56brightCD16-NK cell subsets or in the expression of KIRs, NKG2A, NKG2C, NKG2D, NKp30, NKp44, NKp46 or DNAM1. NK cells from women with RPL had a higher expression of LILRB1 and TACTILE and this was associated with the number of losses. The immune checkpoint receptors PD1, TIM3 and LAG3 were not expressed on peripheral blood NK cells. In RPL patients, there was a large variation in NKG2C expression and higher levels could be explained by CMV seropositivity. Conclusion:Our study identified LILRB1 and TACTILE as NK cell receptors associated with RPL. Moreover, we provide first support for the potential role of CMV in RPL via its impact on the NK cell compartment. Thereby our study could guide future studies to confirm the clinical association of LILRB1, TACTILE and NKG2C with RPL in a larger cohort and to explore their functional relevance in reproductive success.

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“…Previous studies have focused on the role of NK cells in recurrent spontaneous abortion and RIF. The expression of NKP30 on cytotoxic NK cells (CD56dim CD16pos/neg) significantly increased in RIF (31). High NK cell numbers may be adisadvantage for ovarian reserve or function (32).…”

Section: Discussionmentioning

confidence: 99%

Recurrent Implantation Failure May Be Identified by a Combination of Diagnostic Biomarkers: An Analysis of Peripheral Blood Lymphocyte Subsets

et al. 2022

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BackgroundRecurrent implantation failure (RIF) is a challenge during assisted reproductive technology (ART). In the present study, potential diagnostic biomarkers for the immune status of peripheral blood lymphocyte subsets in patients with RIF were analyzed, with the aim of identifying novel biomarkers that may predict RIF.MethodsA total of 41 participants, including 21 women with RIF and 20 fertile controls, were included in the present study. Functional analysis was performed and the cytokine status of natural killer (NK), T, CD8+ T, T helper (Th), and γδ T cells which are lymphocyte subsets in peripheral blood was measured using flow cytometry. Binary logistic regression analysis adjusted for T follicular helper 1 (Tfh1), Tfh2, Tfh17, and early NK cells was performed to determine the relationship between the peripheral blood lymphocyte subsets and RIF. Potential diagnostic biomarkers were assessed by logistic regression analysis and receiver operating characteristic curves.ResultsThere were significantly more Tfh1, Tfh17, and NK cells in the RIF group compared with the control group (all P < 0.05). However, the percentage of T, regulatory T (Tregs), and Tfh2 cells, as well as early inhibitory NK cells, was significantly lower in the RIF group compared with the control group (all P < 0.05). Following logistics regression analysis, Treg, Tfh17, and early inhibitory NK cells exhibited significant differences between the two groups. Combination diagnosis using these 3 biomarkers had a higher area under the curve of 0.900 (95% confidence interval: 0.808–0.992, P < 0.001) in the RIF group compared with that in the control group.ConclusionT, Tregs, Tfh1, Tfh2, Tfh17, NK cells, and early inhibitory NK cells may play important regulatory roles in embryo implantation. The combination of 3 molecular markers (Treg, Tfh17, and early inhibitory NK cells) could provide a high diagnostic value for women with RIF, thus providing novel potential biomarkers for RIF in ART. The present findings could provide a reference either for the clinical treatment of patients with RIF or for future large, well-designed studies.

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Functional NK surrogate biomarkers for inflammatory recurrent pregnancy loss and recurrent implantation failure

Cited by 10 publications

References 69 publications

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

Natural killer cell profiles in recurrent pregnancy loss: Increased expression and positive associations with TACTILE and LILRB1

Recurrent Implantation Failure May Be Identified by a Combination of Diagnostic Biomarkers: An Analysis of Peripheral Blood Lymphocyte Subsets

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