bims-reprim 2021-05-30 papers

Issue of 2021–05–30
four papers selected by
Iva Filipovic, Karolinska Institutet

J Reprod Immunol. 2021 May 12. pii: S0165-0378(21)00060-7. [Epub ahead of print]146 103330

Decidual stromal cells support tolerance at the human foetal-maternal interface by inducing regulatory M2 macrophages and regulatory T-cells.

R Lindau, S Vondra, J Spreckels, M Solders, J Svensson-Arvelund, G Berg, J Pollheimer, H Kaipe, M C Jenmalm, J Ernerudh.

During pregnancy, the semi-allogeneic nature of the foetus requires maternal immune adaption and acquisition of tolerance at the foetal-maternal interface. Macrophages with regulatory properties and regulatory T (Treg) cells are central in promoting foetal tolerance and are enriched in the decidua (the uterine endometrium during pregnancy). Although tissue-resident decidual stromal cells (DSC) have been implicated in regulatory functions, it is not known if they are able to induce the regulatory phenotype of macrophages and T-cells. In this study we report that maternally derived DSC are able to induce homeostatic M2 macrophages and Treg cells. CD14+ monocytes and CD4+ T-cells from healthy non-pregnant women were cultured in the presence or absence of conditioned medium (CM) from DSC isolated from 1st trimester and term placentas. DSC-CM alone was able to promote the survival of macrophages and to induce a regulatory CD14brightCD163+CD209+CD86dim phenotype, typical for decidual macrophages and similar to that induced by M-CSF. Interestingly, DSC-CM was also able to overrule the pro-inflammatory effects of GM-CSF by upregulating CD14, CD163 and CD209. Protein-profiling showed that M-CSF was secreted by DSC, and blocking of M-CSF partially reversed the M2 phenotype and reduced viability. DSC-CM also expanded CD25brightFoxp3+ Treg cells, an expansion that was abolished by a SMAD3-inhibitor, indicating the contribution of TGF-β signaling. In conclusion, our findings collectively emphasize the role of tissue-resident stromal cells in shaping the tolerogenic environment at the foetal-maternal interface.

Keywords: Decidua; Foetal-maternal interface; Immune regulation; Macrophage; Stromal cell; Treg cell

DOI: https://doi.org/10.1016/j.jri.2021.103330

Am J Reprod Immunol. 2021 May 22. e13469

Identifying novel ovarian tumor biomarkers through mining of the transcriptome of circulating immune cells: A proof-of-concept study.

Shitanshu Uppal, Erin Medlin, Mildred Felder, Arvinder Kapur, Robert C Sterner, Jessica Vazquez, Payton N Lindner, Aleksandar K Stanic, Lisa Barroilhet, Jesus Gonzalez-Bosquet, Manish S Patankar.

OBJECTIVE: Treatment of high-grade serous ovarian cancer (HGSOC) will benefit from early detection of the cancer. Here, we provide proof-of-concept data supporting the hypothesis that circulating immune cells, because of their early recognition of tumors and the tumor microenvironment, can be considered for biomarker discovery.
METHODS: Longitudinal blood samples from C57BL/6 mice bearing syngeneic ovarian tumors and peripheral blood mononuclear cells (PBMC) from healthy postmenopausal women and newly diagnosed for HGSOC patients were subjected to RNASeq. The results from human immune cells were validated using Affymetrix microarrays. Differentially expressed transcripts in immune cells from tumor-bearing mice and HGSOC patients were compared to matching controls.
RESULTS: A total of 1282 transcripts (798 and 484, up- and down-regulated, respectively) were differentially expressed in the tumor bearing mice as compared to controls. Top 100 genes showing longitudinal changes in gene expression 2, 4, 7 and 18 days after tumor implantation were identified. Analysis of the PBMC from healthy post-menopausal women and HGSOC patients identified 4,382 differentially expressed genes and 519 of these were validated through Affymetrix microarray analysis. A total of 384 genes, including IL-1R2, CH3L1, Infitm1, FP42, CXC42, Hdc, Spib, and Sema6b, were differentially expressed in the human and mouse datasets.
CONCLUSION: The PBMC transcriptome shows longitudinal changes in response to the progressing tumor. Several potential biomarker transcripts were identified in HGSOC patients and the mouse models. Monitoring their expression in individual PBMC subsets can serve as additional discriminator for the diagnosis of HGSOC.

Keywords: Immune surveillance; Ovarian cancer; biomarkers; immune cells; transcriptome

DOI: https://doi.org/10.1111/aji.13469

Cell. 2021 May 27. pii: S0092-8674(21)00576-6. [Epub ahead of print]184(11): 2807-2824

Endometriosis: Etiology, pathobiology, and therapeutic prospects.

Philippa T K Saunders, Andrew W Horne.

Endometriosis is a common condition associated with infertility that causes chronic pain in many, but not all, women. It is defined by the presence of endometrial-like tissue outside the uterus. Although the cause and natural history of the disorder remain uncertain, hormonal, neurological, and immunological factors are all implicated in the mechanisms contributing to development of symptoms. Because definitive diagnosis requires surgery, there is often a long diagnostic delay after onset of symptoms. Current interventions for endometriosis have limited efficacy and unacceptable side effects/risks and are associated with high rates of symptom recurrence. Here, we review recent advances in our understanding of the etiology of endometriosis, discuss current diagnostic and treatment strategies, highlight current clinical trials, and consider how recent results offer new avenues for the identification of endometriosis biomarkers and the development of effective non-surgical therapies that are fertility-sparing.

Keywords: biomarker; hormone; infertility; inflammation; metabolism; neuroangiogenesis; pelvic pain; peritoneum; surgery

DOI: https://doi.org/10.1016/j.cell.2021.04.041

J Reprod Immunol. 2021 May 19. pii: S0165-0378(21)00061-9. [Epub ahead of print]146 103331

Circulating HLA-G and its association with cardiovascular markers in pregnancy.

Tove Lekva, Daniel P Jacobsen, Meryam Sugulle, Kjartan Moe, Heidi E S Fjeldstad, Ralf Dechend, Anne Cathrine Staff.

Human Leukocyte Antigen-G (HLA-G) prevents the activity of immune cells and is decreased in women with preeclampsia. We aimed to investigate the associations between circulating soluble HLA-G (sHLA-G) and 92 cardiovascular disease-related biomarkers from a previously published multiplex study in women with preeclampsia and controls. We found 15 markers significantly associated with circulating sHLA-G in univariate analyses. After multivariable adjusted regression, only proto-oncogene tyrosine-protein kinase Src (SRC) and vascular endothelial growth factor D were significantly associated with sHLA-G. Low SRC, previously observed in the circulation of preeclamptic women, may be regulated by low sHLA-G, and reflect decreased trophoblast differentiation and syncytical formation.

Keywords: CVD; Multiplex; Preeclampsia; SRC; VEGFD

DOI: https://doi.org/10.1016/j.jri.2021.103331