The Journal of Experimental Medicine
StemCell Technologies
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Published online 11 October 2004 doi:10.1084/jem.20041214
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 8, 957-965
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Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success

Susan E. Hiby1, James J. Walker2, Kevin M. O'Shaughnessy3, Christopher W.G. Redman4, Mary Carrington5, John Trowsdale1, and Ashley Moffett1

1 Department of Pathology, University of Cambridge, Cambridge CB2 1QP, England, UK
2 Department of Obstetrics and Gynecology, St. James University Hospital, Leeds LS9 7TF, England, UK
3 Department of Medicine, University of Cambridge Clinical School, Addenbrooke's Hospital, Cambridge CB2 2QQ, England, UK
4 Nuffield Department of Obstetrics and Gynecology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DZ, England, UK
5 Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702

Address correspondence to Ashley Moffett, Dept. of Pathology, Tennis Court Rd., Cambridge CB2 1QP, England, UK. Phone: 44-1223-333727; Fax: 44-1223-765065; email: am485{at}cam.ac.uk

Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.

Key Words: natural killer cells • HLA • placenta • killer immunoglobulin receptors • trophoblast

Abbreviations used in this paper: EVT, extravillous trophoblast; KIR, killer immunoglobulin receptors; uNK, uterine NK.


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