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 Krjutškov; Juha Kere

doi:10.1016/j.ebiom.2020.102872

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

Tutkimustuotos: Artikkeli › Scientific › vertaisarvioitu

6 Sitaatiot (Scopus)

9 Lataukset (Pure)

Abstrakti

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.

Alkuperäiskieli	Englanti
Artikkeli	102872
Julkaisu	Ebiomedicine
Vuosikerta	59
DOI - pysyväislinkit	https://doi.org/10.1016/j.ebiom.2020.102872
Tila	Julkaistu - syysk. 2020
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Julkaisufoorumi-taso

Jufo-taso 1

!!ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Pääsy asiakirjaan

10.1016/j.ebiom.2020.102872Lisenssi: CC BY-NC-ND

1-s2.0-S2352396420302474-mainFinal published version, 1,78 MBLisenssi: CC BY-NC-ND

http://urn.fi/URN:NBN:fi:tuni-202012148785Lisenssi: CC BY-NC-ND

Siteeraa tätä

Wedenoja, S., Yoshihara, M., Teder, H., Sariola, H., Gissler, M., Katayama, S., Wedenoja, J., Häkkinen, I. M., Ezer, S., Linder, N., Lundin, J., Skoog, T., Sahlin, E., Iwarsson, E., Pettersson, K., Kajantie, E., Mokkonen, M., Heinonen, S., Laivuori, H., ... Kere, J. (2020). Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia. Ebiomedicine, 59, [102872]. https://doi.org/10.1016/j.ebiom.2020.102872

@article{ea3505b2b58844beb08b70902f67e423,

title = "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 (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, P{\"a}ivikki 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 H{\"a}lsa, Sigrid Jus{\'e}lius Foundation, Helsinki University Hospital and University of Helsinki, Jane and Aatos Erkko Foundation, Academy of Finland, Finska L{\"a}kares{\"a}llskapet, Novo Nordisk Foundation, Finnish Foundation for Pediatric Research, and Emil Aaltonen Foundation.",

keywords = "Balancing selection, HLA-G, Interferon alpha, Preeclampsia, Sex ratio, Stillbirth",

author = "Satu Wedenoja and Masahito Yoshihara and Hindrek Teder and Hannu Sariola and Mika Gissler and Shintaro Katayama and Juho Wedenoja and H{\"a}kkinen, {Inka M.} and Sini Ezer and Nina Linder and Johan Lundin and Tiina Skoog and Ellika Sahlin and Erik Iwarsson and Karin Pettersson and Eero Kajantie and Mikael Mokkonen and Seppo Heinonen and Hannele Laivuori and Kaarel Krjut{\v s}kov and Juha Kere",

note = "Funding Information: Dr. Katayama reports grants from Jane and Aatos Erkko Foundation, grants from Swedish Research Council, during the conduct of the study. Dr. Laivuori reports grants from Jane and Aatos Erkko Foundation, grants from P{\"a}ivikki and Sakari Sohlberg Foundation, during the conduct of the study; grants from The Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital, grants from Tampere University Hospital Foundation, outside the submitted work. Drs. Krjut{\v s}kov and Kere have a patent on the TAC-seq method pending. Other authors have nothing to disclose. Funding Information: SW received funding from the Finnish Medical Foundation, and P{\"a}ivikki and Sakari Sohlberg Foundation. MY was supported by the Karolinska Institutet Research Foundation, Scandinavia-Japan Sasakawa Foundation, Japan Eye Bank Association, Astellas Foundation for Research on Metabolic Disorders, and Japan Society for the Promotion of Science Overseas Research Fellowships. Work in the JK laboratory is supported by Knut and Alice Wallenberg Foundation (KAW 2015.0096), Swedish Research Council, Medical Society Liv och H{\"a}lsa (Life and Health), and Sigrid Jus{\'e}lius Foundation. JK is a recipient of the Wolfson Research Merit Award by the Royal Society. The FINNPEC study has received funding from the Competitive State Research Financing of the Expert Responsibility area of Helsinki University Hospital (TYH2018305), Jane and Aatos Erkko Foundation, P{\"a}ivikki and Sakari Sohlberg Foundation, Academy of Finland (grants 121196, 134957 and 278941), Research Funds of the University of Helsinki, Finnish Medical Foundation, Finska L{\"a}kares{\"a}llskapet, Novo Nordisk Foundation, Finnish Foundation for Pediatric Research, Emil Aaltonen Foundation, and Sigrid Jus{\'e}lius Foundation. The funders had no role in study design, data collection, data analysis, interpretation, or writing of the report. Publisher Copyright: {\textcopyright} 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = sep,

doi = "10.1016/j.ebiom.2020.102872",

language = "English",

volume = "59",

}

Wedenoja, S, Yoshihara, M, Teder, H, Sariola, H, Gissler, M, Katayama, S, Wedenoja, J, Häkkinen, IM, Ezer, S, Linder, N, Lundin, J, Skoog, T, Sahlin, E, Iwarsson, E, Pettersson, K, Kajantie, E, Mokkonen, M, Heinonen, S, Laivuori, H, Krjutškov, K & Kere, J 2020, 'Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia', Ebiomedicine, Vuosikerta 59, 102872. https://doi.org/10.1016/j.ebiom.2020.102872

TY - JOUR

T1 - Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia

AU - Wedenoja, Satu

AU - Yoshihara, Masahito

AU - Teder, Hindrek

AU - Sariola, Hannu

AU - Gissler, Mika

AU - Katayama, Shintaro

AU - Wedenoja, Juho

AU - Häkkinen, Inka M.

AU - Ezer, Sini

AU - Linder, Nina

AU - Lundin, Johan

AU - Skoog, Tiina

AU - Sahlin, Ellika

AU - Iwarsson, Erik

AU - Pettersson, Karin

AU - Kajantie, Eero

AU - Mokkonen, Mikael

AU - Heinonen, Seppo

AU - Laivuori, Hannele

AU - Krjutškov, Kaarel

AU - Kere, Juha

N1 - Funding Information: Dr. Katayama reports grants from Jane and Aatos Erkko Foundation, grants from Swedish Research Council, during the conduct of the study. Dr. Laivuori reports grants from Jane and Aatos Erkko Foundation, grants from Päivikki and Sakari Sohlberg Foundation, during the conduct of the study; grants from The Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital, grants from Tampere University Hospital Foundation, outside the submitted work. Drs. Krjutškov and Kere have a patent on the TAC-seq method pending. Other authors have nothing to disclose. Funding Information: SW received funding from the Finnish Medical Foundation, and Päivikki and Sakari Sohlberg Foundation. MY was supported by the Karolinska Institutet Research Foundation, Scandinavia-Japan Sasakawa Foundation, Japan Eye Bank Association, Astellas Foundation for Research on Metabolic Disorders, and Japan Society for the Promotion of Science Overseas Research Fellowships. Work in the JK laboratory is supported by Knut and Alice Wallenberg Foundation (KAW 2015.0096), Swedish Research Council, Medical Society Liv och Hälsa (Life and Health), and Sigrid Jusélius Foundation. JK is a recipient of the Wolfson Research Merit Award by the Royal Society. The FINNPEC study has received funding from the Competitive State Research Financing of the Expert Responsibility area of Helsinki University Hospital (TYH2018305), Jane and Aatos Erkko Foundation, Päivikki and Sakari Sohlberg Foundation, Academy of Finland (grants 121196, 134957 and 278941), Research Funds of the University of Helsinki, Finnish Medical Foundation, Finska Läkaresällskapet, Novo Nordisk Foundation, Finnish Foundation for Pediatric Research, Emil Aaltonen Foundation, and Sigrid Jusélius Foundation. The funders had no role in study design, data collection, data analysis, interpretation, or writing of the report. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/9

Y1 - 2020/9

N2 - 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.

AB - 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.

KW - Balancing selection

KW - HLA-G

KW - Interferon alpha

KW - Preeclampsia

KW - Sex ratio

KW - Stillbirth

U2 - 10.1016/j.ebiom.2020.102872

DO - 10.1016/j.ebiom.2020.102872

M3 - Article

C2 - 32680723

AN - SCOPUS:85089288973

VL - 59

M1 - 102872

ER -

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

Abstrakti

Julkaisufoorumi-taso

!!ASJC Scopus subject areas

Pääsy asiakirjaan

Sormenjälki

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