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.Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a gestational disease caused by maternal immune responses against fetal platelets. Using a FNAIT mouse model and human trophoblast cell lines, here the authors show that uterine natural killer cell-mediated trophoblast apoptosis contributes to FNAIT pathogenesis.

• Authors: Issaka Yougbaré, Wei-She Tai, Darko Zdravic, Brigitta Elaine Oswald, Sean Lang, Guangheng Zhu, Howard Leong-Poi, Dawei Qu, Lisa Yu, Caroline Dunk, Jianhong Zhang, John G Sled, Stephen J Lye, Jelena Brkić, Chun Peng, Petter Höglund, B Anne Croy, S Lee Adamson, Xiao-Yan Wen, Duncan J Stewart, John Freedman, Heyu Ni
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 224 (08 09 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28794456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin beta3
• Natural Cytotoxicity Triggering Receptor 1

Topics

• Abortion, Spontaneous (immunology)
• Animals
• Apoptosis
• Cell Line
• Disease Models, Animal
• Female
• Fetal Growth Retardation (immunology)
• Humans
• Integrin beta3 (immunology)
• Killer Cells, Natural (physiology)
• Male
• Mice
• Natural Cytotoxicity Triggering Receptor 1 (metabolism)
• Placenta (immunology, physiopathology)
• Pregnancy
• Thrombocytopenia, Neonatal Alloimmune (immunology, physiopathology)