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. K. Häkkinen; Sini Ezer; Nina Linder; Johan Lundin; Tiina Skoog; Ellika Sahlin; Erik Iwarsson; Karin Pettersson; Eero Kajantie; Mikael Mokkonen; Seppo Heinonen; Hannele Laivuori; Kaarel Krjutskov; 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. K. Häkkinen, Sini Ezer, Nina Linder, Johan Lundin, Tiina Skoog, Ellika Sahlin, Erik Iwarsson, Karin Pettersson, Eero Kajantie, Mikael Mokkonen, Seppo Heinonen, Hannele Laivuori, Kaarel KrjutskovJuha Kere

Research output: Contribution to journal › Article › Scientific › peer-review

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 (IFN alpha) 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. (C) 2020 The Authors. Published by Elsevier B.V.

Original language	English
Article number	102872
Journal	EBioMedicine
Volume	59
Number of pages	13
ISSN	2352-3964
DOIs	https://doi.org/10.1016/j.ebiom.2020.102872
Publication status	Published - Sept 2020
MoE publication type	A1 Journal article-refereed

Fields of Science

3' UNTRANSLATED REGION
BALANCING SELECTION
Balancing selection
EXTRAVILLOUS TROPHOBLASTS
GENE-EXPRESSION
HLA-G
I INTERFERONS
Interferon alpha
MATERNAL CIRCULATION
PREGNANCY
Preeclampsia
SELECTIVE ADVANTAGE
SEX-RATIO
SINGLE-CELL TRANSCRIPTOME
Sex ratio
Stillbirth
3121 General medicine, internal medicine and other clinical medicine

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10.1016/j.ebiom.2020.102872

PIIS2352396420302474Final published version, 1.89 MBLicence: CC BY-NC-ND

Cite this

Wedenoja, S., Yoshihara, M., Teder, H., Sariola, H., Gissler, M., Katayama, S., Wedenoja, J., Häkkinen, I. M. K., 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, Article 102872. https://doi.org/10.1016/j.ebiom.2020.102872

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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 (IFN alpha) 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. (C) 2020 The Authors. Published by Elsevier B.V.",

keywords = "3' UNTRANSLATED REGION, BALANCING SELECTION, Balancing selection, EXTRAVILLOUS TROPHOBLASTS, GENE-EXPRESSION, HLA-G, I INTERFERONS, Interferon alpha, MATERNAL CIRCULATION, PREGNANCY, Preeclampsia, SELECTIVE ADVANTAGE, SEX-RATIO, SINGLE-CELL TRANSCRIPTOME, Sex ratio, Stillbirth, 3121 General medicine, internal medicine and other clinical medicine",

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. K.} 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 Krjutskov and Juha Kere",

year = "2020",

month = sep,

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

language = "English",

volume = "59",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier Scientific Publ. Co",

}

Wedenoja, S, Yoshihara, M, Teder, H, Sariola, H, Gissler, M, Katayama, S, Wedenoja, J, Häkkinen, IMK, Ezer, S, Linder, N , Lundin, J, Skoog, T, Sahlin, E, Iwarsson, E, Pettersson, K, Kajantie, E, Mokkonen, M, Heinonen, S , Laivuori, H, Krjutskov, K & Kere, J 2020, 'Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia', EBioMedicine, vol. 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. K.

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 - Krjutskov, Kaarel

AU - Kere, Juha

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 (IFN alpha) 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. (C) 2020 The Authors. Published by Elsevier B.V.

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 (IFN alpha) 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. (C) 2020 The Authors. Published by Elsevier B.V.

KW - 3' UNTRANSLATED REGION

KW - BALANCING SELECTION

KW - Balancing selection

KW - EXTRAVILLOUS TROPHOBLASTS

KW - GENE-EXPRESSION

KW - HLA-G

KW - I INTERFERONS

KW - Interferon alpha

KW - MATERNAL CIRCULATION

KW - PREGNANCY

KW - Preeclampsia

KW - SELECTIVE ADVANTAGE

KW - SEX-RATIO

KW - SINGLE-CELL TRANSCRIPTOME

KW - Sex ratio

KW - Stillbirth

KW - 3121 General medicine, internal medicine and other clinical medicine

U2 - 10.1016/j.ebiom.2020.102872

DO - 10.1016/j.ebiom.2020.102872

M3 - Article

SN - 2352-3964

VL - 59

JO - EBioMedicine

JF - EBioMedicine

M1 - 102872

ER -