Adoptive transfer of placental ischemia‐stimulated natural killer cells causes a preeclampsia‐like phenotype in pregnant rats

Travis, Olivia K.; Baik, Cedar; Tardo, Geilda A.; Amaral, Lorena M.; Jackson, Carmilya; Greer, Mallory; Giachelli, Chelsea; Ibrahim, Tarek; Herrock, Owen; Cornelius, Denise C.

doi:10.1111/aji.13386

Cited by 17 publications

(11 citation statements)

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“…[53][54][55] Activated NK cells can induce production of anti-angiogenic factors, resulting in decreased placental vascularization and contributing to FGR. [56][57][58] While AT1-AA can activate the AT1 receptor, 59 they can also target cells for destruction through antibody dependent cellular cytotoxicity (ADCC), which involves activated NK cells. In ADCC, an antigen is bound by an antibody's binding region, while the constant region of the antibody can be recognized by NK cells, which induce apoptosis of the targeted cell.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting B cell activating factor attenuates preeclamptic symptoms in placental ischemic rats

Herrock

Deer

Amaral

et al. 2023

American J Rep Immunol

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Problem Preeclampsia (PE), new‐onset hypertension during pregnancy, is associated with a pro‐inflammatory state with activated T cells, cytolytic natural killer (NK) cells, dysregulated complement proteins, and B cells secreting agonistic autoantibodies to the angiotensin II type‐1 receptor (AT1‐AA). The reduced uterine perfusion pressure (RUPP) model of placental ischemia recapitulates these features of PE. Blocking CD40L‐CD40 communication between T and B cells or B cell depletion with Rituximab prevents hypertension and AT1‐AA production in RUPP rats. This suggests that T cell‐dependent B cell activation contributes to the hypertension and AT1‐AA associated with PE. B2 cells maturing into antibody producing plasma cells are the product of T cell‐dependent B cell‐interactions and B cell Activating Factor (BAFF) is an integral cytokine in the development of B2 cells specifically. Thus, we hypothesize that BAFF blockade will selectively deplete B2 cells, therefore reducing blood pressure, AT1‐AA, activated NK Cells, and complement in the RUPP rat model of PE. Method of study Gestational Day (GD) 14 pregnant rats underwent the RUPP procedure, and a subset were treated with 1 mg/kg Anti‐BAFF antibodies via jugular catheters. On GD19, blood pressure was measured, B cells and NK cells were measured by flow cytometry, AT1‐AA was measured by cardiomyocyte bioassay, and complement activation was measured by ELISA. Results Anti‐BAFF therapy attenuated hypertension, AT1‐AA, NK cell activation, and APRIL levels in RUPP rats without negatively impacting fetal outcomes. Conclusions This study demonstrates that B2 cells contribute to hypertension, AT1‐AA, and NK cell activation in response to placental ischemia during pregnancy.

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Section: Discussionmentioning

confidence: 99%

Inhibiting B cell activating factor attenuates preeclamptic symptoms in placental ischemic rats

Herrock

Deer

Amaral

et al. 2023

American J Rep Immunol

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“…This study demonstrated that Reduced Uterine Perfusion Pressure (RUPP) promoted the activation and proliferation of cNK cells, and that NK cell removal ameliorated hypertension, fetal growth restriction, and inflammation ( 127 ). Adoptive transfer of NK cells from RUPP to normal pregnant rats resulted in NK cell stimulation, increased uterine artery resistance index (UARI) and oxidative stress reaction in the placenta, which ultimately caused PE and IUGR ( 128 ). RUPP acceptors of NK cells from normal pregnant rats exhibited normal NK activation, plasma soluble fms-like tyrosine kinase receptor-1 (sFlt1), plasma and decidual VEGF, and normal UARI, thereby compromising hypertension and fetal growth restriction ( 128 ).…”

Section: Dnk Cells In Pementioning

confidence: 99%

“…Adoptive transfer of NK cells from RUPP to normal pregnant rats resulted in NK cell stimulation, increased uterine artery resistance index (UARI) and oxidative stress reaction in the placenta, which ultimately caused PE and IUGR ( 128 ). RUPP acceptors of NK cells from normal pregnant rats exhibited normal NK activation, plasma soluble fms-like tyrosine kinase receptor-1 (sFlt1), plasma and decidual VEGF, and normal UARI, thereby compromising hypertension and fetal growth restriction ( 128 ). The studies point out that cNK cells matter in the pathogenesis of PE, while normal NK cells alleviate hypertension and promote fetal development ( 128 ).…”

Section: Dnk Cells In Pementioning

confidence: 99%

“…RUPP acceptors of NK cells from normal pregnant rats exhibited normal NK activation, plasma soluble fms-like tyrosine kinase receptor-1 (sFlt1), plasma and decidual VEGF, and normal UARI, thereby compromising hypertension and fetal growth restriction ( 128 ). The studies point out that cNK cells matter in the pathogenesis of PE, while normal NK cells alleviate hypertension and promote fetal development ( 128 ). Compared to removing NK cells from healthy pregnant rats, removing NK cells from PE rats decreased trophoblast cell invasion, but did not affect spiral artery recasting ( 129 ).…”

Section: Dnk Cells In Pementioning

confidence: 99%

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The central role of natural killer cells in preeclampsia

Wei

Yang

2023

Front. Immunol.

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Preeclampsia (PE) is a disease that is unique to pregnancy and affects multiple systems. It can lead to maternal and perinatal mortality. The precise etiology of PE is unclear. Patients with PE may have systemic or local immune abnormalities. A group of researchers has proposed that the immune communication between the fetus and mother is primarily moderated by natural killer (NK) cells as opposed to T cells, since NK cells are the most abundant immune cells in the uterus. This review examines the immunological roles of NK cells in the pathogenesis of PE. Our aim is to provide obstetricians with a comprehensive and updated research progress report on NK cells in PE patients. It has been reported that decidual NK (dNK) cells contribute to the process of uterine spiral artery remodeling and can modulate trophoblast invasion. Additionally, dNK cells can stimulate fetal growth and regulate delivery. It appears that the count or proportion of circulating NK cells is elevated in patients with or at risk for PE. Changes in the number or function of dNK cells may be the cause of PE. The Th1/Th2 equilibrium in PE has gradually shifted to an NK1/NK2 equilibrium based on cytokine production. An improper combination of killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA)-C may lead to insufficient activation of dNK cells, thereby causing PE. In the etiology of PE, NK cells appear to exert a central effect in both peripheral blood and the maternal-fetal interface. To maintain immune equilibrium both locally and systemically, it is necessary to take therapeutic measures directed at NK cells.

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“…These activated NK cells also produce TNF-α and INF-γ further contributing to the chronic inflammation in PE [42,97]. Recent studies from Travis et al [57,98] show that NK cells stimulated from the RUPP rat model of PE can cause preeclamptic symptoms in healthy pregnant rats and that NK cells from PE rats have a 5-fold increase in cytolytic activity compared to normal controls. Furthermore, B cells secrete AT1-AA which directly activate the AT1R resulting in increased vascular resistance but also producing anti-angiogenic factors downstream of AT1R activation.…”

Section: Nk Cells In Preeclampsiamentioning

confidence: 99%

The Role of Different Lymphoid Cell Populations in Preeclampsia Pathophysiology

et al. 2022

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Preeclampsia (PE), new-onset hypertension during pregnancy, affects up to 10% of pregnancies worldwide. Despite being the leading cause of maternal and fetal morbidity and mortality, there is no cure for PE beyond the delivery of the fetal-placental unit. Although the exact pathogenesis of PE is unclear, there is a strong correlation between chronic immune activation, intrauterine growth restriction, uterine artery resistance, dysregulation of the renin angiotensin system which contributes to renal dysfunction, and the resulting hypertension during pregnancy. The genesis of PE is thought to begin with insufficient trophoblast invasion leading to reduced spiral artery remodeling resulting in decreased placental perfusion thereby causing placental ischemia. The ischemic placenta releases factors that shower the endothelium and contribute to peripheral vasoconstriction and chronic immune activation and oxidative stress. Studies have shown imbalances in pro-inflammatory and anti-inflammatory cell types in women with PE and in animal models utilized to examine mediators of a PE phenotype during pregnancy. T cells, B cells, and natural killer cells have all emerged as potential mediators contributing to the production of vasoactive factors, renal and endothelial dysfunction, mitochondrial dysfunction, and hypertension during pregnancy. The chronic immune activation seen in PE leads to a higher risk for other diseases such as cardiovascular disease, chronic kidney disease, dementia during their postpartum period, and PE during a subsequent pregnancy. The purpose of this review is to highlight studies demonstrating the role that different lymphoid cell populations play in the pathophysiology of PE. Moreover, we will discuss treatments focused on restoring immune balance or targeting specific immune mediators that may be potential strategies to improve maternal and fetal outcomes associated with PE.

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Adoptive transfer of placental ischemia‐stimulated natural killer cells causes a preeclampsia‐like phenotype in pregnant rats

Cited by 17 publications

References 95 publications

Inhibiting B cell activating factor attenuates preeclamptic symptoms in placental ischemic rats

Inhibiting B cell activating factor attenuates preeclamptic symptoms in placental ischemic rats

The central role of natural killer cells in preeclampsia

The Role of Different Lymphoid Cell Populations in Preeclampsia Pathophysiology

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