Manipulating CD4+ T Cell Pathways to Prevent Preeclampsia

Abstract

Preeclampsia (PreE) is a placental disorder characterized by hypertension (HTN), proteinuria, and oxidative stress. Individuals with PreE and their children are at an increased risk of serious short- and long-term complications, such as cardiovascular disease, end-organ failure, HTN, neurodevelopmental disorders, and more. Currently, delivery is the only cure for PreE, which remains a leading cause of morbidity and mortality among pregnant individuals and neonates. There is evidence that an imbalance favoring a pro-inflammatory CD4+ T cell milieu is associated with the inadequate spiral artery remodeling and subsequent oxidative stress that prime PreE’s clinical symptoms. Immunomodulatory therapies targeting CD4+ T cell mechanisms have been investigated for other immune-mediated inflammatory diseases, and the application of these prevention tactics to PreE is promising, as we review here. These immunomodulatory therapies may, among other things, decrease tumor necrosis factor alpha (TNF-α), cytolytic natural killer cells, reduce pro-inflammatory cytokine production [e.g. interleukin (IL)-17 and IL-6], stimulate regulatory T cells (Tregs), inhibit type 1 and 17 T helper cells, prevent inappropriate dendritic cell maturation, and induce anti-inflammatory cytokine action [e.g. IL-10, Interferon gamma (IFN-γ)]. We review therapies including neutralizing monoclonal antibodies against TNF-α, IL-17, IL-6, and CD28; statins; 17-hydroxyprogesterone caproate, a synthetic hormone; adoptive exogenous Treg therapy; and endothelin-1 pathway inhibitors. Rebalancing the maternal inflammatory milieu may allow for proper spiral artery invasion, placentation, and maternal tolerance of foreign fetal/paternal antigens, thereby combatting early PreE pathogenesis.

Increased fetal microchimerism in immune and stem cell subsets in preeclampsia

“…Previous studies have demonstrated decreased NK cell and Treg frequency in the peripheral blood and decidua, which may be associated with the pathophysiology of PE 63–70 . We similarly found decreased maternal peripheral NK cells and Tregs in PE cases compared to controls.…”

“…Previous studies have demonstrated decreased NK cell and Treg frequency in the peripheral blood and decidua, which may be associated with the pathophysiology of PE. [63][64][65][66][67][68][69][70] We similarly found decreased maternal peripheral NK cells and Tregs in PE cases compared to controls. We also found decreased NK cell and Treg frequency with advancing gestational age in controls, similar to prior findings.…”

New immune horizons in therapeutics and diagnostic approaches to Preeclampsia

“…Recently, evidence from studies has emerged supporting the idea that mesenchymal stem cells might be part of the fetomaternal tolerance environment. CD4+ T cells can regulate antigen‐presenting cell maturation, cytotoxic behavior of NK cells, placental trophoblasts cells, and maternal vascular endothelium, thereby immune‐modulating at the maternal‐fetal interface 134 …”

An Update Review of the Pathogenesis Hypothesis in Preeclampsia

“…In preeclampsia women, the maternal immune response, against the fetus, interferes with trophoblast invasion and angiogenesis, resulting in oxidative stress and a maternal systemic inflammatory response [68]. Immunity imbalance of Th1/Th2 cells, Th17/Treg cells and abnormal regulation of decidual NK cells will lead to the failure of trophoblast invasion and the reduction of placental perfusion, which would generate of reactive oxygen species, and the aggravate of oxidative stress Autoreactive antibodies to the angiotensin receptor AT1 are elevated in preeclamptic mothers and inhibit trophoblast invasion, thereby promoting oxidative stress [69]. Complement system also plays a crucial role in maintaining a healthy pregnancy, and abnormal activation of the complement system would cause maternal systemic inflammatory response, leading to the occurrence of preeclampsia.…”