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

Satu Wedenoja, Masahito Yoshihara, Hindrek Teder, Hannu Sariola, Mika Gissler, Shintaro Katayama, Juho Wedenoja, Inka M. Häkkinen, Sini Ezer, Nina Linder, Johan Lundin, Tiina Skoog, Ellika Sahlin, Erik Iwarsson, Karin Pettersson, Eero Kajantie, Mikael Mokkonen, Seppo Heinonen, Hannele Laivuori, Kaarel KrjutškovJuha Kere

    Research output: Contribution to journalArticleScientificpeer-review

    6 Citations (Scopus)
    11 Downloads (Pure)

    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.

    Original languageEnglish
    Article number102872
    JournalEbiomedicine
    Volume59
    DOIs
    Publication statusPublished - Sept 2020
    Publication typeA1 Journal article-refereed

    Keywords

    • Balancing selection
    • HLA-G
    • Interferon alpha
    • Preeclampsia
    • Sex ratio
    • Stillbirth

    Publication forum classification

    • Publication forum level 1

    ASJC Scopus subject areas

    • General Biochemistry,Genetics and Molecular Biology

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