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

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 and Heyu Ni ()
Additional contact information
Issaka Yougbaré: Keenan Research Centre for Biomedical Science, St. Michael’s Hospital
Wei-She Tai: Keenan Research Centre for Biomedical Science, St. Michael’s Hospital
Darko Zdravic: Keenan Research Centre for Biomedical Science, St. Michael’s Hospital
Brigitta Elaine Oswald: Keenan Research Centre for Biomedical Science, St. Michael’s Hospital
Sean Lang: Keenan Research Centre for Biomedical Science, St. Michael’s Hospital
Guangheng Zhu: Keenan Research Centre for Biomedical Science, St. Michael’s Hospital
Howard Leong-Poi: University of Toronto
Dawei Qu: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Lisa Yu: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Caroline Dunk: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Jianhong Zhang: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
John G. Sled: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Stephen J. Lye: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Jelena Brkić: York University
Chun Peng: York University
Petter Höglund: Karolinska Institutet
B. Anne Croy: Queen’s University
S. Lee Adamson: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Xiao-Yan Wen: Keenan Research Centre for Biomedical Science, St. Michael’s Hospital
Duncan J. Stewart: Ottawa Hospital Research Institute
John Freedman: Keenan Research Centre for Biomedical Science, St. Michael’s Hospital
Heyu Ni: Keenan Research Centre for Biomedical Science, St. Michael’s Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00269-1

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