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.
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