Wedenoja, Satu; Yoshihara, Masahito; Teder, Hindrek; Sariola, Hannu; Gissler, Mika; Katayama, Shintaro; Wedenoja, Juho; Häkkinen, Inka M. K.; Ezer, Sini; Linder, Nina; Lundin, Johan; Skoog, Tiina; Sahlin, Ellika; Iwarsson, Erik; Pettersson, Karin; Kajantie, Eero; Mokkonen, Mikael; Heinonen, Seppo; Laivuori, Hannele; Krjutskov, Kaarel; Kere, Juha
(2020)
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.