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The Differential Expression of ERAP1/ERAP2 and Immune Cell Activation in Pre-eclampsia

Stratikos, Efstratios; Warthan, Michelle; Strauss, Jerome F.; Kurlak, Lesia O.; Seamon, Kimberly; Lee, Eun D.; Mistry, Hiten D.

The Differential Expression of ERAP1/ERAP2 and Immune Cell Activation in Pre-eclampsia Thumbnail


Efstratios Stratikos

Michelle Warthan

Jerome F. Strauss

Lesia O. Kurlak

Kimberly Seamon

Eun D. Lee

Hiten D. Mistry


Pre-eclampsia (PE) is a disorder of pregnancy, often leading to serious and fatal complications. Endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1/ERAP2) are present in the placenta. They are involved in processes regulating blood pressure, angiogenesis, cytokine receptor shedding, and immune recognition. Previous studies have associated both ERAP1/ERAP2 genetic variants with PE, although the underlying mechanisms remain unknown. Less is known about the roles for these enzymes in early placentation, which could be a contributory factor to PE. To ascertain whether ERAP1/ERAP2 change in PE and whether such a change is present before PE is clinically diagnosed, we analyzed mRNA and ERAP1/2 protein expression in the placenta in the early first trimester (8–14 weeks) and at delivery in normotensive or PE women (n = 12/group). Gene expression was analyzed using qPCR, and protein expression and localization were assessed by immunohistochemistry. Additionally, we profiled peripheral immune cells from normotensive and PE (n = 5/group) women for activation and expression of cytotoxic markers using flow cytometry to investigate a possible correlation with placental expression of ERAP1/2. Finally, we characterized the cytokines released from immune cells isolated from normotensive women and those with PE, stimulated ex vivo by JEG-3 trophoblast cells. The ERAP1 protein was significantly upregulated in first trimester placentae compared to placentae at delivery from both normotensive and PE women (p [less than] 0.05): expression of placental ERAP1 protein was also relatively higher in normotensive than PE women. Although the protein expression of both ERAP1/ERAP2 was significantly lower in women with PE compared to normotensive controls (p [less than] 0.05), ERAP2 protein expression remained unchanged in normotensive women at delivery compared to expression in the first trimester. Flow cytometry analysis revealed an increase in activation and cytotoxic natural killer (NK) cells in peripheral blood of PE compared to normotensive women. Intriguingly, there was a notable difference in cytokine release from the activated immune cells when further stimulated by trophoblast cells. The immune cells from PE released elevated expressions of interleukin (IL)-2, IL-4, and most notably, pro-inflammatory IL-13 and IL-17α, inflammatory cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF) compared to normal peripheral blood mononuclear cells (PBMCs). Taken together, these findings suggest that differential lymphocyte activation could be associated with altered ERAP1/ERAP2 expression.


Stratikos, E., Warthan, M., Strauss, J. F., Kurlak, L. O., Seamon, K., Lee, E. D., & Mistry, H. D. (2020). The Differential Expression of ERAP1/ERAP2 and Immune Cell Activation in Pre-eclampsia. Frontiers in Immunology, 11, Article 396.

Journal Article Type Article
Acceptance Date Feb 19, 2020
Online Publication Date Mar 10, 2020
Publication Date Mar 10, 2020
Deposit Date Feb 25, 2020
Publicly Available Date Mar 12, 2020
Journal Frontiers in Immunology
Electronic ISSN 1664-3224
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 11
Article Number 396
Public URL
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