Am J Reprod Immunol. 2018;e12969. wileyonlinelibrary.com/journal/aji | 1 of 9 https://doi.org/10.1111/aji.12969 © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 1 | INTRODUCTION Pre-eclampsia (PE) is a pregnancy-specific human disorder affecting 2%-10% of pregnant women worldwide. 1 PE comprises an immense threat for the mother’s life as well as for the fetus that is affected by a dysfunctional placenta, increasing the risk for growth restriction, preterm delivery, and perinatal mortality. Unrecognized or left un- treated, PE develops into its final stage—eclampsia, a dramatic state of convulsions with a high maternal mortality rate. 1,2 Received: 20 March 2018 | Accepted: 9 April 2018 DOI: 10.1111/aji.12969 ORIGINAL ARTICLE Enhanced Th1 and inflammatory mRNA responses upregulate NK cell cytotoxicity and NKG2D ligand expression in human pre-eclamptic placenta and target it for NK cell attack Marie-Therese Vinnars 1 | Emma Björk 1 | Ivan Nagaev 1 | Ulrika Ottander 2 | Katarina Bremme 3 | Ulrika Holmlund 4 | Eva Sverremark-Ekström 4 | Lucia Mincheva-Nilsson 1 Sverremark-Ekström and Mincheva-Nilsson shared authorship. 1 Department of Clinical Microbiology, Infection and Immunology, Umeå University, Umeå, Sweden 2 Department of Clinical Sciences/Obstetrics and Gynaecology, Umeå University, Umeå, Sweden 3 Department of Women’s and Children’s Health, Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden 4 Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden Correspondence Lucia Mincheva-Nilsson, Department of Clinical Microbiology, Infection and Immunology, Umeå University, Umeå, Sweden. Email: lucia.mincheva-nilsson@umu.se Funding information Cancerfonden, Swedish Cancer Society, Grant/Award Number: CAN 2015/512 15 0832; Swedish Research Council, Grant/ Award Number: 57X-15160-07-03, 57x- 15160-10-4 and 18-20 - 345240311 Problem: Pre-eclampsia (PE), a severe human pregnancy disorder, is associated with exaggerated systemic inflammation, enhanced cytokine production, and increased shedding of microvesicles leading to endothelial dysfunction, coagulopathy, and ex- tensive placenta destruction. The cause of PE is still unclear. Evidence suggests that its origin lies in the placenta and that the maternal immune system is involved. A shift in cytokine production in PE pregnancy promotes NK cell activation, suggested to be important in PE pathogenesis. In line with this suggestion, we studied NK cell cyto- toxicity in peripheral blood of PE patients and controls and the mRNA expression of cytokines and of the NKG2D receptor and its ligands MICA/B and ULBP1-3 in PE- and normal placenta. Method of study: The cytotoxic capacity of peripheral blood NK cells was analyzed using K562 target cells. The cytokine mRNA profiles and the mRNA expression of the NKG2D receptor and its ligands MICA/B and ULBP 1-3 in PE placenta were assessed and compared to those in normal placenta using real-time quantitative RT-PCR. Results: The cytotoxicity of peripheral blood NK cells was upregulated in PE cases. Further, we found an enhanced inflammatory cytokine mRNA response combined with a dysregulated regulatory response and a significant mRNA overexpression of NKG2D receptor and its ligands MICA/B and ULBP in PE placenta. Conclusion: The destruction of chorionic villi observed in PE placenta might be con- veyed by an enhanced local cytotoxic response through the NKG2D receptor-ligand pathway, which in turn might be promoted by an intense inflammatory response not counteracted by regulatory cytokine responses. KEYWORDS cytokines, inflammation, natural killer cells, NKG2D receptor-ligand system, pre-eclampsia, Treg