bims-reprim 2022-05-08 papers

Issue of 2022–05–08
seven papers selected by
Iva Filipovic, Karolinska Institutet

J Reprod Immunol. 2022 Apr 27. pii: S0165-0378(22)00161-9. [Epub ahead of print]151 103632

Immunological microenvironment at the maternal-fetal interface.

The immune cells, especially innate immune cells (Natural Killer cells and Macrophages) residing at the maternal-fetal interface are playing critical roles during pregnancy. Here we discuss the immunological characteristic at the maternal-fetal interface during normal pregnancy. These key decidual immune cells are reshaped of their uterus-specific homeostatic functions within this uterus microenvironment. Through emphasizing the similarities and differences between decidua immune microenvironments with tumor or transplantation immune microenvironments, distinctive immune cell niche with activated, tolerant, proangiogenic and nurturing characteristic at the maternal interface is exhibited. Deeper understanding of the immunological microenvironment during pregnancy yield important insight not only into the pathogenesis of various human pregnancy complications, but also suggest ways to better manipulate these immune cells in cancer and transplant organs.

Keywords: Decidual NK; Immune regulation; Maternal-fetal interface; Pregnancy; Uterus microenvironment

DOI: https://doi.org/10.1016/j.jri.2022.103632

J Reprod Immunol. 2022 Apr 16. pii: S0165-0378(22)00153-X. [Epub ahead of print]151 103624

Dynamic genome-wide gene expression and immune cell composition in the developing human placenta.

Hemant Suryawanshi, Klaas Max, Kimberly A Bogardus, Anuoluwapo Sopeyin, Michael S Chang, Pavel Morozov, Paula M Castano, Thomas Tuschl, Zev Williams.

Despite the central role of the placenta in supporting a pregnancy, relatively little is known about transcriptomic and immune-cell changes that occur across gestation. To generate a reference gene expression map of first (T1), second (T2) and third (T3) trimester human placenta, and assess differences in transcriptome in maternal versus fetal side tissues sections of full-term placenta, we performed RNA-Seq analysis on 64 biopsy samples from 18 placentas across all three gestations. We identified 1120 differentially expressed genes in placenta tissues from T1 and T3 samples using a generalized linear model within DESeq2. In total, 411 and 709 genes were positively associated with T1 and T3 placenta, respectively. Comparison of the top 200 differentially expressed genes in the T1 placenta with T3 showed that most of the top enriched biological processes were related to cell division and proliferation. T1 and T2 tissues shared expression of fibroblast-specific COL6A2, HGF, and SPP1 genes. In T3 samples, the expression of genes relating to vasculature development and regulation were highly enriched. Monocytes and NK cell population increased in T3 compared to T1 and T2, whereas Hofbauer cell proportion expanded significantly in T2 and then decreased in T3 samples. There were no significant gene expression differences in the maternal vs. fetal side in T3 placentas. Gene expression patterns shift temporally across trimesters but not spatially across the placenta, at least at the resolution of the biopsy samples. The genes and gene set we identified here represent a valuable resource for studying pathology in pregnancy-related disorders.

Keywords: Gene expression; Placenta; RNA-sequencing; Transcriptomics

DOI: https://doi.org/10.1016/j.jri.2022.103624

Clin Transl Med. 2022 May;12(5): e821

Single-cell atlas of peripheral blood mononuclear cells from pregnant women.

BACKGROUND: During pregnancy, mother-child interactions trigger a variety of subtle changes in the maternal body, which may be reflected in the status of peripheral blood mononuclear cells (PBMCs). Although these cells are easy to access and monitor, a PBMC atlas for pregnant women has not yet been constructed.
METHODS: We applied single-cell RNA sequencing (scRNA-seq) to profile 198,356 PBMCs derived from 136 pregnant women (gestation weeks 6 to 40) and a control cohort. We also used scRNA-seq data to establish a transcriptomic clock and thereby predicted the gestational age of normal pregnancy.
RESULTS: We identified reconfiguration of the peripheral immune cell phenotype during pregnancy, including interferon-stimulated gene upregulation, activation of RNA splicing-related pathways and immune activity of cell subpopulations. We also developed a cell-type-specific model to predict gestational age of normal pregnancy.
CONCLUSIONS: We constructed a single-cell atlas of PBMCs in pregnant women spanning the entire gestation period, which should help improve our understanding of PBMC composition turnover in pregnant women.

Keywords: PBMCs; interferon; pregnancy; scRNA-seq

DOI: https://doi.org/10.1002/ctm2.821

Front Immunol. 2022 ;13 866937

Pregnancy and Tumour: The Parallels and Differences in Regulatory T Cells.

Prerana Muralidhara, Vanshika Sood, Vishnu Vinayak Ashok, Kushagra Bansal.

Immunological tolerance plays a critical role during pregnancy as semi-allogeneic fetus must be protected from immune responses during the gestational period. Regulatory T cells (Tregs), a subpopulation of CD4+ T cells that express transcription factor Foxp3, are central to the maintenance of immunological tolerance and prevention of autoimmunity. Tregs are also known to accumulate at placenta in uterus during pregnancy, and they confer immunological tolerance at maternal-fetal interface by controlling the immune responses against alloantigens. Thus, uterine Tregs help in maintaining an environment conducive for survival of the fetus during gestation, and low frequency or dysfunction of Tregs is associated with recurrent spontaneous abortions and other pregnancy-related complications such as preeclampsia. Interestingly, there are many parallels in the development of placenta and solid tumours, and the tumour microenvironment is considered to be somewhat similar to that at maternal-fetal interface. Moreover, Tregs play a largely similar role in tumour immunity as they do at placenta- they create a tolerogenic system and suppress the immune responses against the cells within tumour and at maternal-fetal interface. In this review, we discuss the role of Tregs in supporting the proper growth of the embryo during pregnancy. We also highlight the similarities and differences between Tregs at maternal-fetal interface and tumour Tregs, in an attempt to draw a comparison between their roles in these two physiologic and pathologic states.

Keywords: immunological tolerance; immunotherapy; maternal-fetal interface; regulatory T cells (Tregs); tumour

DOI: https://doi.org/10.3389/fimmu.2022.866937

J Infect Dis. 2022 May 02. pii: jiac171. [Epub ahead of print]

MAIT cells are preserved in the cervical mucosa of HIV-infected women and exhibit a dominant expression of the TRAV1-2-TRAJ20 TCRα chain.

Anna Gibbs, Katie Healy, Vilde Kaldhusdal, Christopher Sundling, Mathias Franzén-Boger, Gabriella Edfeldt, Marcus Buggert, Julie Lajoie, Keith R Fowke, Joshua Kimani, Douglas S Kwon, Sonia Andersson, Johan K Sandberg, Kristina Broliden, Haleh Davanian, Margaret Sällberg Chen, Annelie Tjernlund.

BACKGROUND: MAIT cells are innate-like T cells with specialized antimicrobial functions. Circulating MAIT cells are depleted in chronic HIV infection but studies examining this effect in peripheral tissues, such as the female genital tract, are lacking.
METHODS: Flow cytometry was used to investigate circulating MAIT cells in a cohort of HIV+ and HIV- female sex workers (HIV+FSW, HIV-FSW, respectively), and HIV-low-risk women (HIV-LR). In situ staining and qPCR were performed to explore the phenotype of MAIT cells residing in paired cervicovaginal tissue. The cervicovaginal microbiome was assessed by 16S rRNA gene sequencing.
RESULTS: MAIT cells in the HIV+FSW group were low in frequency in the circulation but preserved in the ectocervix. MAIT cell T cell receptor (TCR) gene segment usage differed between the HIV+FSW and HIV-FSW groups. The TRAV1-2-TRAJ20 transcript was the most highly expressed MAIT TRAJ gene detected in the ectocervix in the HIV+FSW group. MAIT TRAVJ usage was not associated with specific genera in the vaginal microbiome.
CONCLUSIONS: MAIT cells residing in the ectocervix are numerically preserved irrespective of HIV infection status and displayed dominant expression of TRAV1-2-TRAJ20. These findings have implications for understanding the role of cervical MAIT cells in health and disease.

Keywords: TRAV1-2-TRAJ20 ; HIV; MAIT; TCR usage; cervical mucosa; microbiome

DOI: https://doi.org/10.1093/infdis/jiac171

Semin Immunopathol. 2022 May 04.

Establishment of tissue-resident immune populations in the fetus.

Dorien Feyaerts, Christopher Urbschat, Ina A Stelzer.

The immune system establishes during the prenatal period from distinct waves of stem and progenitor cells and continuously adapts to the needs and challenges of early postnatal and adult life. Fetal immune development not only lays the foundation for postnatal immunity but establishes functional populations of tissue-resident immune cells that are instrumental for fetal immune responses amidst organ growth and maturation. This review aims to discuss current knowledge about the development and function of tissue-resident immune populations during fetal life, focusing on the brain, lung, and gastrointestinal tract as sites with distinct developmental trajectories. While recent progress using system-level approaches has shed light on the fetal immune landscape, further work is required to describe precise roles of prenatal immune populations and their migration and adaptation to respective organ environments. Defining points of prenatal susceptibility to environmental challenges will support the search for potential therapeutic targets to positively impact postnatal health.

Keywords: Embryogenesis; Fetal immunity; Immune ontogeny; Prenatal development

DOI: https://doi.org/10.1007/s00281-022-00931-x

Reprod Fertil. 2022 Apr 01. 3(2): R51-R65

Insights from genomic studies on the role of sex steroids in the aetiology of endometriosis.

Philippa T K Saunders.

Endometriosis is a chronic neuro-inflammatory disorder the defining feature of which is the growth of tissue (lesions) that resembles the endometrium outside the uterus. Estimates of prevalence quote rates of ~10% of women of reproductive age, equating to at least 190 million women world-wide. Genetic, hormonal and immunological factors have all been proposed as contributing to risk factors associated with the development of lesions. Twin studies report the heritable component of endometriosis as ~50%. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that appear over-represented in patients with endometriosis, particularly those with more extensive disease (stage III/IV). In different sample populations, there has been replication of SNPs near genes involved in oestrogen and other steroid regulated pathways including ESR1 (oestrogen receptor alpha), GREB1, HOXA10, WNT4 and MAPK kinase signalling. Comparisons with GWAS conducted on other patient cohorts have found links with reproductive traits (age at menarche) and disorders (fibroids, endometrial and ovarian cancer) and common co-morbidities (migraine, depression, asthma). In summary, genetic analyses have provided new insights into the hormone-regulated pathways that may contribute to increased risk of developing endometriosis some of which may act in early life. New studies are needed to clarify the relationship between the many SNPs identified, the genes that they regulate and their contribution(s) to development of different forms of endometriosis. We hope that more advanced methods allowing integration between GWAS, epigenetic and tissue expression data will improve risk analysis and reduce diagnositic delay.
Lay summary: Endometriosis is a debilitating reproductive disorder affecting ~10% of reproductive-age women, and those assigned female at birth, which causes a range of symptoms including chronic pain and infertility. The reason why some, but not all these individuals, develop the lesions that characterise the disease are poorly understood, but recently attention has focused on genetic risk factors to explain why the incidence is higher in some families. Studies on large cohorts of patients with comparison of their DNA to women without endometriosis or with other disorders have documented changes in genes associated with steroid hormone production or action. The results provide further evidence that endometriosis shares genetic risk factors with other disorders of the reproductive system and a platform for new ideas related to risk, biomarkers and therapies.

Keywords: androgens; endometriosis; genome-wide association studies (GWAS); oestrogens; single nucleotide polymorphism (SNP); women’s health

DOI: https://doi.org/10.1530/RAF-21-0078