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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
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.
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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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