Activated NK cells cause placental dysfunction and miscarriages in fetal alloimmune thrombocytopenia

Abstract

Miscarriage and intrauterine growth restriction (IUGR) are devastating complications in fetal/neonatal alloimmune thrombocytopenia (FNAIT). We previously reported the mechanisms for bleeding diatheses, but it is unknown whether placental, decidual immune cells or other abnormalities at the maternal–fetal interface contribute to FNAIT. Here we show that maternal immune responses to fetal platelet antigens cause miscarriage and IUGR that are associated with vascular and immune pathologies in murine FNAIT models. Uterine natural killer (uNK) cell recruitment and survival beyond mid-gestation lead to elevated NKp46 and CD107 expression, perforin release and trophoblast apoptosis. Depletion of NK cells restores normal spiral artery remodeling and placental function, prevents miscarriage, and rescues hemorrhage in neonates. Blockade of NK activation receptors (NKp46, FcɣRIIIa) also rescues pregnancy loss. These findings shed light on uNK antibody-dependent cell-mediated cytotoxicity of invasive trophoblasts as a pathological mechanism in FNAIT, and suggest that anti-NK cell therapies may prevent immune-mediated pregnancy loss and ameliorate FNAIT.

Maternal obesity alters uterine NK activity through a functional KIR2DL1/S1 imbalance

“…HLA‐C, HLA‐E and HLA‐G) to generate tolerogenic signals toward the fetus . However, the tolerogenic characteristics of uNK may be disrupted in pregnancies afflicted with infection‐ or alloimmunity‐induced types of inflammation . While maternal obesity associates with elevated inflammation in early pregnancy, our findings suggest that obesity‐associated inflammation may not translate into procytotoxic uNK functions, even though our work shows that obesity correlates with enhanced uNK activity (degranulation) and links with altered NKR expression that is reflective of increased cytotoxicity (i.e.…”

“…While uNK functions are thought to be predominately noncytotoxic, recent studies show that conditions in pregnancy resulting in aberrant inflammation (i.e. infection, alloimmunity) promote uNK‐directed cytotoxicity toward fetal and placental tissue . This suggests the in utero environment is capable of shaping uNK activity and function.…”

“…infection, alloimmunity) promote uNK-directed cytotoxicity toward fetal and placental tissue. 36,37 This suggests the in utero environment is capable of shaping uNK activity and function. Because obesity associates with aberrant low-grade inflammation, and 2DS1 activation strongly triggers cytolysis in pbNK, 38 we next examined whether HLA-C2 interactions in uNK from obese women also promote 2DS1directed target cell death ( Figure 5d).…”

Immunobiology of Acute Chorioamnionitis

“…In humans, both decidua basalis and parietalis showed an increased frequency of CD56 + NK cells in women that underwent pre-term labor with acute chorioamnionitis compared to those without chorioamnionitis (134). Although NK cells perform homeostatic roles, under pathological conditions such as fetal alloimmune thrombocytopenia, dNK cells can become activated with prolonged survival, elevated NKp46 and CD107 expression, and perforin release, and can induce trophoblast apoptosis and placental pathology, leading to miscarriage (223).…”

MicroRNA-378 protects human umbilical vein endothelial cells from injuries by soluble CD226 through down-regulating the expression of soluble CD226 in natural killer cells

“…miR-378 negatively regulates the expression of CD226 in NK cells and CD226 is a target gene of miR-378 NK cells are the body's first line of defense against infections and tumours, and they are also the main effector cells of innate immunity [33]. Abnormal immunity of NK cells is closely related to abortion in pregnant women [34], suggesting that NK cells participate in the regulation of pregnancy. Bioinformatics prediction showed that activated receptor CD226 on the surface of NK cells was a potential target of miR-378 ( Figure 3(A)).…”