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Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia
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 an...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502669/ https://www.ncbi.nlm.nih.gov/pubmed/32680723 http://dx.doi.org/10.1016/j.ebiom.2020.102872 |
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author | Wedenoja, Satu Yoshihara, Masahito Teder, Hindrek Sariola, Hannu Gissler, Mika Katayama, Shintaro Wedenoja, Juho Häkkinen, Inka M. Ezer, Sini Linder, Nina Lundin, Johan Skoog, Tiina Sahlin, Ellika Iwarsson, Erik Pettersson, Karin Kajantie, Eero Mokkonen, Mikael Heinonen, Seppo Laivuori, Hannele Krjutškov, Kaarel Kere, Juha |
author_facet | Wedenoja, Satu Yoshihara, Masahito Teder, Hindrek Sariola, Hannu Gissler, Mika Katayama, Shintaro Wedenoja, Juho Häkkinen, Inka M. Ezer, Sini Linder, Nina Lundin, Johan Skoog, Tiina Sahlin, Ellika Iwarsson, Erik Pettersson, Karin Kajantie, Eero Mokkonen, Mikael Heinonen, Seppo Laivuori, Hannele Krjutškov, Kaarel Kere, Juha |
author_sort | Wedenoja, Satu |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7502669 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-75026692020-09-28 Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia Wedenoja, Satu Yoshihara, Masahito Teder, Hindrek Sariola, Hannu Gissler, Mika Katayama, Shintaro Wedenoja, Juho Häkkinen, Inka M. Ezer, Sini Linder, Nina Lundin, Johan Skoog, Tiina Sahlin, Ellika Iwarsson, Erik Pettersson, Karin Kajantie, Eero Mokkonen, Mikael Heinonen, Seppo Laivuori, Hannele Krjutškov, Kaarel Kere, Juha EBioMedicine Research Paper 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. Elsevier 2020-07-14 /pmc/articles/PMC7502669/ /pubmed/32680723 http://dx.doi.org/10.1016/j.ebiom.2020.102872 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Wedenoja, Satu Yoshihara, Masahito Teder, Hindrek Sariola, Hannu Gissler, Mika Katayama, Shintaro Wedenoja, Juho Häkkinen, Inka M. Ezer, Sini Linder, Nina Lundin, Johan Skoog, Tiina Sahlin, Ellika Iwarsson, Erik Pettersson, Karin Kajantie, Eero Mokkonen, Mikael Heinonen, Seppo Laivuori, Hannele Krjutškov, Kaarel Kere, Juha Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia |
title | Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia |
title_full | Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia |
title_fullStr | Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia |
title_full_unstemmed | Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia |
title_short | Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia |
title_sort | fetal hla-g mediated immune tolerance and interferon response in preeclampsia |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502669/ https://www.ncbi.nlm.nih.gov/pubmed/32680723 http://dx.doi.org/10.1016/j.ebiom.2020.102872 |
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