Why natural killer cells are not enough: a further understanding of killer immunoglobulin-like receptor and human leukocyte antigen

The uterine immune system uses natural killer cell allorecognition to regulate placentation and to control the maternofetal interface. In assisted reproductive technology, these insights affect elective single-embryo transfer selection in killer immunoglobulin-like receptor haplotype AA patients.

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Volume 107, Issue 6, Pages 1273–1278


Diana Alecsandru, M.D., Ph.D., Juan A. García-Velasco, M.D., Ph.D.


The immune system's role in recurrent reproductive failure is a controversial issue in assisted reproduction. Most studies into immune system implication in reproduction have focused on finding markers of peripheral blood and less on the uterine environment. Peripheral blood natural killer cells have become an “immune study core” for women with recurrent miscarriage or recurrent implantation failure, based on the mistaken notion that they cause reproductive failure by killing or “rejecting” the embryo. Maternal-fetal tolerance begins at the uterine level, so successful adaptation to the fetus occurs after a complicated process. Insufficient uterine lining invasion by an invading extravillous trophoblast is the primary defect in pregnancy disorders such as recurrent miscarriage. This process is regulated by the interaction between maternal killer immunoglobulin-like receptors (KIRs), expressed by uterine natural killer cells (uNK), and their ligand human leukocyte antigen (HLA) C, expressed by the extravillous trophoblast. Pregnancies are an increased risk of disorders in mothers with KIR AA when the fetus has paternal HLA-C2. A recent report has indicated that the expression of more than one paternal HLA-C by the extravillous trophoblast in assisted reproduction may affect placentation in mothers with KIR AA. This review provides insight into the immune system's role in assisted reproductive treatments. These insights can have an impact on the selection of single-embryo transfer and/or oocyte/sperm donor according to HLA-C in patients with recurrent implantation failure and recurrent miscarriage depending on their KIR haplotype.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. 


Go to the profile of Evelin Lara-Molina
over 4 years ago
Thank you for this comprehensive contribution which actually enhances the "immunological matching" in the egg donation cycles. Congrats and looking forward to finding more results from clinical practice in ART.