bims-reprim 2021-10-31 papers

bims-reprim

Biomed News

on Reproductive immunology

Issue of 2021–10–31
seven papers selected by
Iva Filipovic, Karolinska Institutet

Decidual CXCR4+ CD56bright NK cells as a novel NK subset in maternal-foetal immune tolerance to alleviate early pregnancy failure.
Interleukin-33 activates group 2 innate lymphoid cell expansion and modulates endometriosis.
NF-κB regulation in maternal immunity during normal and IUGR pregnancies.
Chronic Villitis of unknown etiology (VUE): Obstetrical features, outcome and treatment.
Evaluation of BCL6 and SIRT1 as Non-Invasive Diagnostic Markers of Endometriosis.
Systematic proteomics analysis of lysine acetylation reveals critical features of placental proteins in pregnant women with preeclampsia.
Discovery of novel serum metabolic biomarkers in patients with polycystic ovarian syndrome and premature ovarian failure.

Clin Transl Med. 2021 Oct;11(10): e540

Decidual CXCR4+ CD56bright NK cells as a novel NK subset in maternal-foetal immune tolerance to alleviate early pregnancy failure.

Yu Tao, Yan-Hong Li, Di Zhang, Ling Xu, Jia-Jia Chen, Yi-Fei Sang, Hai-Lan Piao, Xue-Ling Jing, Min Yu, Qiang Fu, Sheng-Tao Zhou, Da-Jin Li, Mei-Rong Du.

  Natural killer (NK) cells preferentially accumulate at maternal-foetal interface and are believed to play vital immune-modulatory roles during early pregnancy and related immunological dysfunction may result in pregnant failure such as recurrent miscarriage (RM). However, the mechanisms underlying the establishment of maternal-foetal immunotolerance are complex but clarifying the roles of decidual NK (dNK) cells offers the potential to design immunotherapeutic strategies to assist RM patients. In this report, we analysed RNA sequencing on peripheral NK (pNK) and decidual NK cells during early pregnancy; we identified an immunomodulatory dNK subset CXCR4+ CD56bright dNK and investigated its origin and phenotypic and functional characteristics. CXCR4+ CD56bright dNK displayed a less activated and cytotoxic phenotype but an enhanced immunomodulatory potential relative to the CXCR4 negative subset. CXCR4+ CD56bright dNK promote Th2 shift in an IL-4-dependent manner and can be recruited from peripheral blood and reprogramed by trophoblasts, as an active participant in the establishment of immune-tolerance during early pregnancy. Diminished CXCR4+ dNK cells and their impaired ability to induce Th2 differentiation were found in RM patients and mouse models of spontaneous abortion. Moreover, adoptive transfer of CXCR4+ dNK cells to NK-deficient (Nfil3-/-) mice showed great therapeutic potential of CXCR4+ dNK via recovering the Th2/Th1 bias and reducing embryo resorption rates. The identification of this new dNK cell subset may lay the foundation for understanding NK cell mechanisms in early pregnancy and provide potential prognostic factors for the diagnosis and therapy of RM.

Keywords:  CXCR4+CD56brightNK cells; NK cell-based immunotherapy; maternal-foetal immunotolerance; recurrent miscarriage

DOI:  https://doi.org/10.1002/ctm2.540
JCI Insight. 2021 Oct 26. pii: e149699. [Epub ahead of print]

Interleukin-33 activates group 2 innate lymphoid cell expansion and modulates endometriosis.

Jessica E Miller, Harshavardhan Lingegowda, Lindsey K Symons, Olga Bougie, Steven L Young, Bruce A Lessey, Madhuri Koti, Chandrakant Tayade.

  Chronic inflammation and localized alterations in immune cell function are suspected to contribute to the progression of endometriosis and its associated symptoms. In particular, the alarmin, Interleukin (IL)-33 is elevated in the plasma, peritoneal fluid, and endometriotic lesions from endometriosis patients; however, the exact role of IL-33 in the pathophysiology of endometriosis is not well understood. In this study, we demonstrate, in both human patients and a murine model, that IL-33 contributes to the expansion of the novel group 2 innate lymphoid cells (ILC2s) and this IL-33 induced ILC2 expansion modulates the endometriosis lesion microenvironment. Importantly, we show that IL-33 drives hallmarks of severe endometriosis including elevated inflammation, lesion proliferation, and fibrosis and that this IL-33 induced aggravation is mediated by ILC2s. Finally, we demonstrate the functionality of IL-33 neutralization as a promising and novel therapeutic avenue for treating the debilitating symptoms of endometriosis.

Keywords:  Cellular immune response; Immunology; Mouse models; Reproductive Biology; Th2 response

DOI:  https://doi.org/10.1172/jci.insight.149699
Sci Rep. 2021 Oct 25. 11(1): 20971

NF-κB regulation in maternal immunity during normal and IUGR pregnancies.

Gaayathri Ariyakumar, Jonathan M Morris, Kelly J McKelvey, Anthony W Ashton, Sharon A McCracken.

Intrauterine Growth Restriction (IUGR) is a leading cause of perinatal death with no effective cure, affecting 5-10% pregnancies globally. Suppressed pro-inflammatory Th1/Th17 immunity is necessary for pregnancy success. However, in IUGR, the inflammatory response is enhanced and there is a limited understanding of the mechanisms that lead to this abnormality. Regulation of maternal T-cells during pregnancy is driven by Nuclear Factor Kappa B p65 (NF-κB p65), and we have previously shown that p65 degradation in maternal T-cells is induced by Fas activation. Placental exosomes expressing Fas ligand (FasL) have an immunomodulatory function during pregnancy. The aim of this study is to investigate the mechanism and source of NF-κB regulation required for successful pregnancy, and whether this is abrogated in IUGR. Using flow cytometry, we demonstrate that p65+ Th1/Th17 cells are reduced during normal pregnancy, but not during IUGR, and this phenotype is enforced when non-pregnant T-cells are cultured with normal maternal plasma. We also show that isolated exosomes from IUGR plasma have decreased FasL expression and are reduced in number compared to exosomes from normal pregnancies. In this study, we highlight a potential role for FasL+ exosomes to regulate NF-κB p65 in T-cells during pregnancy, and provide the first evidence that decreased exosome production may contribute to the dysregulation of p65 and inflammation underlying IUGR pathogenesis.

DOI: https://doi.org/10.1038/s41598-021-00430-3
J Reprod Immunol. 2021 Oct 23. pii: S0165-0378(21)00168-6. [Epub ahead of print]148 103438

Chronic Villitis of unknown etiology (VUE): Obstetrical features, outcome and treatment.

Mekinian Arsène, Kamila Kolanska, Meryam Cheloufi, Aurore Coulomb, Jonathan Cohen, Noémie Abisror, Marie Bornes, Gilles Kayem, Jaume Alijotas-Reig, Olivier Fain.

  Villitis of unknown etiology (VUE) is characterized by lympho-histiocytic infiltrates, which are predominant within the villous stroma. VUE can be of low grade i.e. affecting less than 10 contiguous villi or high grade with either patchy or diffuse subgroups (the later concerning more than 30 % of distal villi). Several other placental lesions could be associated with VUE, in particular in diffuse subgroups, such as diffuse perivillous fibrin deposition and chronic intervillositis. One of the most characteristic features of VUE is the late onset of fetal growth restriction after 32 weeks of gestation, and earlier detection of villitis should first raise an infectious origin. High grade VUE has been associated with fetal growth restriction, prematurity, fetal deaths, recurrent pregnancy loss, central nervous system injury and is characterized by relatively high risk of recurrence (25-50 %). Prospective and well-designed studies are necessary to determine the real prevalence of these adverse pregnancy events associated with VUE. Data about the management of VUE are extremely scarce and thus no recommendation based on the literature review could be actually done.

Keywords:  Chronic Villitis; Villitis of unknown etiology

DOI:  https://doi.org/10.1016/j.jri.2021.103438
Curr Issues Mol Biol. 2021 Sep 28. 43(3): 1350-1360

Evaluation of BCL6 and SIRT1 as Non-Invasive Diagnostic Markers of Endometriosis.

Alison M Sansone, Brooke V Hisrich, R Brandt Young, William F Abel, Zachary Bowens, Bailey B Blair, Avery T Funkhouser, David P Schammel, Lisa J Green, Bruce A Lessey, Anna V Blenda.

  (1) Background: Endometriosis is characterized by the presence of endometrial glands and stroma outside of the uterus and is often associated with severe pelvic pain and infertility. Our study explored the utilization of B-Cell Lymphoma 6 (BCL6) and Sirtuin 1 (SIRT1) as potential biomarkers in serum, plasma, urine, and cervical mucus for a non-invasive diagnostic test for endometriosis. BCL6 was chosen based on its previously reported elevated expression in endometrial biopsies, and SIRT1 is co-expressed and upregulated in the endometrium of women with endometriosis. (2) Methods: BCL6 and SIRT1 levels were measured using enzyme-linked immunoassay (ELISA) in samples from 20 women with endometriosis (ten with stages I/II and ten with stages III/IV) and ten women without endometriosis. (3) Results: Levels of SIRT1 in sera showed a statistically significant elevation in advanced stages III/IV compared to controls and stages I/II. No significant differences were found in other bodily fluids for SIRT1 or any bodily fluids tested for BCL6. (4) Conclusions: These results suggest some potential of SIRT1 expression within serum as a predictor of advanced asymptomatic stages of endometriosis. Using immunohistochemistry (IHC) staining and H-SCORE values for the elevated BCL6 (and potentially SIRT1) levels in endometrial biopsy samples seems to have higher diagnostic potential based on the previously published studies.

Keywords:  BCL6; ELISA; SIRT1; biomarker; endometriosis; infertility; laparoscopic surgery; non-invasive

DOI:  https://doi.org/10.3390/cimb43030096
J Cell Mol Med. 2021 Oct 26.

Systematic proteomics analysis of lysine acetylation reveals critical features of placental proteins in pregnant women with preeclampsia.

Yu Shangguan, Yinglan Wang, Wei Shi, Ruonan Guo, Zhipeng Zeng, Wenlong Hu, Wanxia Cai, Qiang Yan, Yong Xu, Donge Tang, Yong Dai.

  Preeclampsia (PE) is a dangerous hypertensive disorder that occurs during pregnancy. The specific aetiology and pathogenesis of PE have yet to be clarified. To better reveal the specific pathogenesis of PE, we characterized the proteome and acetyl proteome (acetylome) profile of placental tissue from PE and normal-term pregnancy by label-free quantification proteomics technology and PRM analysis. In this research, 373 differentially expressed proteins (DEPs) were identified by proteome analysis. Functional enrichment analysis revealed significant enrichment of DEPs related to angiogenesis and the immune system. COL12A1, C4BPA and F13A1 may be potential biomarkers for PE diagnosis and new therapeutic targets. Additionally, 700 Kac sites were identified on 585 differentially acetylated proteins (DAPs) by acetylome analyses. These DAPs may participate in the occurrence and development of PE by affecting the complement and coagulation cascades pathway, which may have important implications for better understand the pathogenesis of PE. In conclusion, this study systematically analysed the reveals critical features of placental proteins in pregnant women with PE, providing a resource for exploring the contribution of lysine acetylation modification to PE.

Keywords:  angiogenesis; complement and coagulation cascades; immune system; lysine acetylation; preeclampsia; proteomics

DOI:  https://doi.org/10.1111/jcmm.16997
Bioengineered. 2021 Dec;12(1): 8778-8792

Discovery of novel serum metabolic biomarkers in patients with polycystic ovarian syndrome and premature ovarian failure.

Jiying Chen, Qinger Zhou, Yonggang Zhang, Wenqing Tan, Hanchao Gao, Liying Zhou, Shuixiu Xiao, Jinhua Gao, Jing Li, Zhiying Zhu.

  Several widely recognized metabolites play a role in regulating the pathophysiological processes of various disorders. Nonetheless, the lack of effective biomarkers for the early diagnosis of polycystic ovarian syndrome (PCOS) and premature ovarian failure (POF) has led to the discovery of serum-based metabolic biomarkers for these disorders. We aimed to identify various differentially expressed metabolites (DEMs) through serum-based metabolic profiling in patients with PCOS and POF and in healthy individuals by using liquid chromatography-mass spectrometry analysis. Furthermore, heatmap clustering, correlation, and Z-score analyses were performed to identify the top DEMs. Kyoto Encyclopedia of Genes and Genomes enriched pathways of DEMs were determined using metabolite-based databases. Moreover, the clinical significance of these DEMs was evaluated on the basis of area under the receiver operating characteristic curve. Significantly dysregulated expressions of several metabolites were observed in the intergroup comparisons of the PCOS, POF, and healthy control groups. Furthermore, 6 DEMs were most frequently observed among the three groups. The expressions of these DEMs were not only directly correlated but also exhibited potential significance in patients with PCOS and POF. Novel metabolites with up/downregulated expressions can be discovered in patients with PCOS and POF using serum-based metabolomics; these metabolites show good diagnostic performance and can act as effective biomarkers for the early detection of PCOS and POF. Furthermore, these metabolites might be involved in the pathophysiological mechanisms of PCOS and POF via interplay with corresponding genes.

Keywords:  metabolic biomarkers; polycystic ovarian syndrome; premature ovarian failure

DOI:  https://doi.org/10.1080/21655979.2021.1982312