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Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia.

ABSTRACT: BACKGROUND:Fetal immune tolerance is crucial for pregnancy success. We studied the link between preeclampsia, a severe pregnancy disorder with uncertain pathogenesis, and fetal human leukocyte antigen G (HLA-G) and other genes regulating maternal immune responses. METHODS:We assessed sex ratios and regulatory HLA-G haplotypes in population cohorts and series of preeclampsia and stillbirth. We studied placental mRNA expression of 136 genes by sequencing and HLA-G and interferon alpha (IFN?) protein expression by immunohistochemistry. FINDINGS:We found underrepresentation of males in preeclamptic births, especially those delivered preterm or small for gestational age. Balancing selection at HLA-G associated with the sex ratio, stillbirth, and preeclampsia. We observed downregulation of HLA-G, its receptors, and many other tolerogenic genes, and marked upregulation of IFNA1 in preeclamptic placentas. INTERPRETATION:These findings indicate that an evolutionary trade-off between immune tolerance and protection against infections at the maternal-fetal interface promotes genetic diversity in fetal HLA-G, thereby affecting survival, preeclampsia, and sex ratio. We highlight IFNA1 as a potential mediator of preeclampsia and a target for therapeutic trials. FUNDING:Finnish Medical Foundation, Päivikki and Sakari Sohlberg Foundation, Karolinska Institutet Research Foundation, Scandinavia-Japan Sasakawa Foundation, Japan Eye Bank Association, Astellas Foundation for Research on Metabolic Disorders, Japan Society for the Promotion of Science, Knut and Alice Wallenberg Foundation, Swedish Research Council, Medical Society Liv och Hälsa, Sigrid Jusélius Foundation, Helsinki University Hospital and University of Helsinki, Jane and Aatos Erkko Foundation, Academy of Finland, Finska Läkaresällskapet, Novo Nordisk Foundation, Finnish Foundation for Pediatric Research, and Emil Aaltonen Foundation.

SUBMITTER: Wedenoja S

PROVIDER: S-EPMC7502669 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia.

Wedenoja Satu S Yoshihara Masahito M Teder Hindrek H Sariola Hannu H Gissler Mika M Katayama Shintaro S Wedenoja Juho J Häkkinen Inka M IM Ezer Sini S Linder Nina N Lundin Johan J Skoog Tiina T Sahlin Ellika E Iwarsson Erik E Pettersson Karin K Kajantie Eero E Mokkonen Mikael M Heinonen Seppo S Laivuori Hannele H Krjutškov Kaarel K Kere Juha J

EBioMedicine 20200714

<h4>Background</h4>Fetal immune tolerance is crucial for pregnancy success. We studied the link between preeclampsia, a severe pregnancy disorder with uncertain pathogenesis, and fetal human leukocyte antigen G (HLA-G) and other genes regulating maternal immune responses.<h4>Methods</h4>We assessed sex ratios and regulatory HLA-G haplotypes in population cohorts and series of preeclampsia and stillbirth. We studied placental mRNA expression of 136 genes by sequencing and HLA-G and interferon alp ...[more]

PMID: 32680723

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Project description:BackgroundPreeclampsia is a pregnancy-specific disorder that always causes maternal and fetal serious adverse outcome. Disturbances in maternal immune tolerance to embryo at the maternal-fetal interface (MFI) may be associated with preeclampsia onset. Recent studies have revealed the reduced expression pattern of HLA-F at the MFI in preeclampsia, while the mechanism of it mediating maternal fetal immune tolerance has not been revealed.MethodsSingle-cell RNA sequencing on placental decidua was performed to reveal the immune disturbances landscape at the MFI in preeclampsia. Human Jar cells and NK-92MI cells were employed to study the role of HLA-F in trophoblasts and lymphocyte.ResultsA total of 101,250 cells were classified into 22 cell clusters. Disease-related IGFBP1+SPP1+ extracellular villus trophoblast (EVT) was identified in the preeclamptic placental decidua, accompanied by newly discovered immune cellular dysfunction such as reduced ribosomal functions of NK populations and abnormal expression of antigen-presenting molecules in most cell clusters. Certain genes that are characteristic of the intermediate stage of myeloid or EVT cell differentiation were found to have unexplored but important functions in the pathogenesis of preeclampsia; specifically, we detected enhanced cell cross-talk between IGFBP1+SPP1+ EVT2 or SPP1+M1 cells and their receptor cell populations at the MFI of PE patients compared to controls. With respect to HLA-F, mIF staining confirmed its reduced expression in PE samples compared to controls. Over-expression of HLA-F in Jar cells promoted cell proliferation, invasion, and migration while under-expression had the opposite effect. In NK-92MI cells, over-expression of HLA-F increased the secretion of immunoregulation cytokines such as CSF1 and CCL22, and promoted adaptive NKG2C+NK cell transformation.ConclusionsWe revealed the immune disturbance landscape at the MFI in preeclampsia. Our findings regarding cellular heterogeneity and immune cellular dysfunction, as revealed by scRNA-seq, and the function of HLA-F in cells provide new perspectives for further investigation of their roles in the pathogenesis of preeclampsia, and then provide potential new therapeutic target.

Project description:Background and objectiveThe establishment of maternal-fetal interface immune tolerance is essential for successful pregnancy. Studies have shown that spontaneous abortion, recurrent abortion, and fetal growth restriction are related to maternal-fetal interface immune dysfunction. Preeclampsia is an idiopathic condition related to pregnancy which manifests as hypertension, proteinuria, and other target organ damage after 20 weeks of gestation. Although the etiology of preeclampsia is still unknown, its pathogenesis is thought to be related to genetics, environment, and metabolism. In recent years, more and more studies have been conducted on the mechanism of immune tolerance at the maternal-fetal interface and the relationship between immune dysregulation and the pathogenesis of preeclampsia. This paper summarizes the latest studies on this topic in order to find new insights into the pathogenesis of preeclampsia and make a reflection on clinical diagnosis and treatment in different phenotype of preeclampsia.MethodsThe research and latest progress published from 2000 to December 2021 on the relationship between maternal-fetal interface immune tolerance and preeclampsia were broadly retrieved and researched using PubMed and Web of Science databases.Key content and findingsThe mechanism of natural killer cells (NK cells) and macrophages at the maternal-fetal interface in immune tolerance, as well as their cytotoxicity and cytokine secretion dysfunction, may be related to the pathogenesis of preeclampsia. The expression of nonclassical type I human leukocyte antigen (HLA) on extravillous trophoblast (EVT) cell were down-regulated in decidua of preeclampsia, which may induce increase EVT death caused by activating of cytotoxic NK cell. In addition, genetic polymorphism of nonclassical type I HLA on the EVT cell membrane may be related to the pathogenesis of preeclampsia, although this is likely to be a combination of 3 nonclassical type I HLA genotypes and requires sequencing to verify.ConclusionsWe demonstrated how the maternal-fetal interface immune dysfunction contribute to the pathogenesis of preeclampsia, further study and clinical trial based on this theory of pathogenesis may reveal new immune treatment method of preeclampsia.

Dataset Information

Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia.

Publications

Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia.

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