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

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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 (IFNα) 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.

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Most cited references 86

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Circulating angiogenic factors and the risk of preeclampsia.

Richard J. Levine, Sharon E. Maynard, Cong Qian … (2004)

The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia. Copyright 2004 Massachusetts Medical Society

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Single-cell RNA sequencing (RNA-seq) is a powerful tool to reveal cellular heterogeneity, discover new cell types and characterize tumor microevolution. However, losses in cDNA synthesis and bias in cDNA amplification lead to severe quantitative errors. We show that molecular labels--random sequences that label individual molecules--can nearly eliminate amplification noise, and that microfluidic sample preparation and optimized reagents produce a fivefold improvement in mRNA capture efficiency.

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Characterization of the single-cell transcriptional landscape by highly multiplex RNA-seq.

Saiful Islam, Una Kjällquist, Annalena Moliner … (2011)

Our understanding of the development and maintenance of tissues has been greatly aided by large-scale gene expression analysis. However, tissues are invariably complex, and expression analysis of a tissue confounds the true expression patterns of its constituent cell types. Here we describe a novel strategy to access such complex samples. Single-cell RNA-seq expression profiles were generated, and clustered to form a two-dimensional cell map onto which expression data were projected. The resulting cell map integrates three levels of organization: the whole population of cells, the functionally distinct subpopulations it contains, and the single cells themselves-all without need for known markers to classify cell types. The feasibility of the strategy was demonstrated by analyzing the transcriptomes of 85 single cells of two distinct types. We believe this strategy will enable the unbiased discovery and analysis of naturally occurring cell types during development, adult physiology, and disease.

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Author and article information

Contributors

Satu Wedenoja

Juha Kere

Journal

Journal ID (nlm-ta): EBioMedicine

Journal ID (iso-abbrev): EBioMedicine

Title: EBioMedicine

Publisher: Elsevier

ISSN (Electronic): 2352-3964

Publication date PMC-release: 14 July 2020

Publication date Collection: September 2020

Publication date (Electronic): 14 July 2020

Volume: 59

Electronic Location Identifier: 102872

Affiliations

[a ]Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland

[b ]Stem Cells and Metabolism Research Program, University of Helsinki, and Folkhälsan Research Center, 00290 Helsinki, Finland

[c ]Department of Biosciences and Nutrition, Karolinska Institutet, 14183 Huddinge, Sweden

[d ]Competence Centre of Health Technologies, 50411 Tartu, Estonia

[e ]Institute of Biomedicine and Translational Medicine, University of Tartu, 50090 Tartu, Estonia

[f ]University of Helsinki and HUSLAB Pediatric Pathology, 00290 Helsinki, Finland

[g ]Information Services Department, Finnish Institute for Health and Welfare, 00300 Helsinki, Finland

[h ]Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 17177 Stockholm, Sweden

[i ]Research Centre for Child Psychiatry, University of Turku, 20500 Turku, Finland

[j ]Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland

[k ]Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, 00290 Helsinki, Finland

[l ]Department of Women's and Children's Health, International Maternal and Child Health, Uppsala University, 75105 Uppsala, Sweden

[m ]Department of Public Health Sciences, Karolinska Institutet, 17177 Stockholm, Sweden

[n ]Department of Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, 17176 Stockholm, Sweden

[o ]Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, and Department of Obstetrics, Karolinska University Hospital, 17176 Stockholm, Sweden

[p ]Public Health Promotion Unit, Finnish Institute for Health and Welfare, 00300 Helsinki and 90220 Oulu, Finland

[q ]PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, 90570 Oulu, Finland

[r ]Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway

[s ]Children's Hospital, Helsinki University Hospital and University of Helsinki, 00290 Helsinki, Finland

[t ]Department of Biology, Kwantlen Polytechnic University, Surrey, BC V3W 2M8, Canada

[u ]Department of Biological Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada

[v ]Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland

[w ]Department of Obstetrics and Gynecology, Tampere University Hospital and Tampere University, Faculty of Medicine and Health Technology, 33520 Tampere, Finland

Author notes

[* ]Corresponding author at: Stem Cells and Metabolism Research Program, University of Helsinki, and Folkhälsan Research Center, 00290 Helsinki, Finland. satu.wedenoja@ 123456helsinki.fi juha.kere@ 123456ki.se

[1]

Equal contribution.

Article

Publisher ID: S2352-3964(20)30247-4 Publisher ID: 102872

DOI: 10.1016/j.ebiom.2020.102872

PMC ID: 7502669

PubMed ID: 32680723

SO-VID: 5d58ee87-7bca-4b86-aea6-d90f1a15d695

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 16 March 2020

Date revision received : 17 June 2020

Date accepted : 18 June 2020

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

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Abstract

Background

Methods

Findings

Interpretation

Funding

Graphical Abstract

Related collections

HLA-G and immune tolerance in pregnancy

Most cited references 86

Circulating angiogenic factors and the risk of preeclampsia.

Quantitative single-cell RNA-seq with unique molecular identifiers.

Characterization of the single-cell transcriptional landscape by highly multiplex RNA-seq.

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Contributors

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Author notes

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Cited by 17