Preeclampsia (PE) is a leading cause of maternal and fetal mortality and morbidity that occurs only during pregnancy. Pregnancy is the only physiological situation where killer-cell immunoglobulin-like receptors (KIRs) may meet cognate nonself variants of human leukocyte antigen (HLA) allotypes. We previously reported that presence of fetal HLA-G*0106 was significantly associated with risk for PE in multigravid pregnancies. We have now tested the KIR2DL4 receptor gene for association with PE, as well as for its interaction with HLA-G in modulating disease risk, in a case-control study of 83 PE and 240 normotensive pregnancies. No significant association was observed between alleles of KIR2DL4 and PE in both maternal and fetal groups, either among primigravid or multigravid pregnancies. Alleles of KIR2DL4 and HLA-G were then analyzed together to determine whether particular variant ligand—receptor combinations were associated with an increased risk for PE. Gene-gene interaction analyses suggest that the presence of fetal HLA-G*0106 in combination with maternal KIR2DL4*006 is significantly associated with PE risk in multigravid pregnancies (P < .001). These data provide the first preliminary evidence suggesting that although KIR2DL4 itself is not associated with PE, it may modulate the effect of HLA-G*0106 on risk for PE.
Hauth JC, Ewell MG, Levine RJ, et al. Pregnancy outcomes in healthy nulliparas who developed hypertension . Calcium for preeclampsia prevention study group. Obstet Gynecol. 2000;95(1):24-28.
2.
Hnat MD, Sibai BM, Caritis S., et al. Perinatal outcome in women with recurrent preeclampsia compared with women who develop preeclampsia as nulliparas. Am J Obstet Gynecol. 2002;186(3):422-426.
3.
King A., Allan DS, Bowen M., et al. HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells. Eur J Immunol. 2000;30(6):1623-1631.
4.
King A., Boocock C., Sharkey AM, et al. Evidence for the expression of HLAA-C class I mRNA and protein by human first trimester trophoblast. J Immunol. 1996;156(6):2068-2076.
5.
Blaschitz A. , Hutter H., Dohr G. HLA Class I protein expression in the human placenta. Early Pregnancy. 2001;5(1):67-69.
6.
Ishitani A., Sageshima N., Lee N., et al. Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition . J Immunol. 2003;171(3):1376-1384.
7.
Yelavarthi KK , Fishback JL, Hunt JSAnalysis of HLA-G mRNA in human placental and extraplacental membrane cells by in situ hybridization . J Immunol. 1991;146(8):2847-2854.
8.
Kovats S., Main EK, Librach C., Stubblebine M., Fisher SJ, DeMars R.A class I antigen, HLA-G, expressed in human trophoblasts. Science. 1990;248(4952):220-223.
9.
McMaster MT, Librach CL, Zhou Y., et al. Human placental HLA-G expression is restricted to differentiated cytotrophoblasts. J Immunol. 1995;154(8):3771-3778.
10.
Colonna M., Navarro F., Bellon T., et al. A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J Exp Med. 1997;186(11):1809-1818.
11.
Allan DS, Colonna M., Lanier LL, et al. Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells. J Exp Med. 1999;189(7):1149-1156.
12.
Colonna M., Samaridis J., Cella M., et al. Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. J Immunol . 1998;160(7): 3096-3100.
13.
Rajagopalan S., Long EOA human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. J Exp Med. 1999;189(7):1093-1100.
14.
Shiroishi M. , Tsumoto K., Amano K., et al. Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc Natl Acad Sci U S A. 2003;100(15):8856-8861.
15.
Carreiras M. , Montagnani S., Layrisse Z.Preeclampsia: a multi-factorial disease resulting from the interaction of the fetomaternal HLA genotype and HCMV infection. Am J Reprod Immunol.2002 ;48(3):176-183.
16.
Hylenius S. , Andersen AM, Melbye M., Hviid TVAssociation between HLA-G genotype and risk of pre-eclampsia: a case-control study using family triads. Mol Hum Reprod. 2004;10(4):237-246.
17.
Moreau P., Contu L., Alba F., et al. HLA-G gene polymorphism in human placentas: possible association of G*0106 allele with preeclampsia and miscarriage. Biol Reprod . 2008;79(3):459-467.
18.
O’Brien M., McCarthy T., Jenkins D., et al. Altered HLA-G transcription in pre-eclampsia is associated with allele specific inheritance: possible role of the HLA-G gene in susceptibility to the disease. Cell Mol Life Sci.2001;58(12-13):1943-1949.
19.
Witt CS, Whiteway JM, Warren HS, et al. Alleles of the KIR2DL4 receptor and their lack of association with preeclampsia. Eur J Immunol. 2002;32(1):18-29.
20.
Tan CY, Ho JF, Chong YS, et al. Paternal contribution of HLA-G*0106 significantly increases risk for pre-eclampsia in multigravid pregnancies. Mol Hum Reprod. 2008;14(5):317-324.
21.
Clayton D.SNPhap: a program for estimating frequencies of large haplotypes of SNPs (version 1.2). http://www.-gene.cimr.cam.ac.uk/clayton/software/snphap.txt . May 1, 2007.
22.
Martin AM, Freitas EM, Witt CS, Christiansen FTThe genomic organization and evolution of the natural killer immunoglobulin-like receptor (KIR) gene cluster. Immunogenetics. 2000;51(4-5):268-280.
23.
Wilson MJ, Torkar M., Haude A., et al. Plasticity in the organization and sequences of human KIR/ILT gene families. Proc Natl Acad Sci U S A. 2000 ;97(9):4778-4783.
24.
Barten R., Torkar M., Haude A., Trowsdale J., Wilson MJDivergent and convergent evolution of NK-cell receptors. Trends Immunol. 2001;22(1):52-57.
25.
Goodridge JP , Witt CS, Christiansen FT, Warren HSKIR2DL4 (CD158d) genotype influences expression and function in NK cells. J Immunol. 2003;171(4):1768-1774.
26.
Valiante NM , Uhrberg M., Shilling HG, et al. Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity. 1997;7(6):739-751.
27.
Ponte M., Cantoni C., Biassoni R., et al. Inhibitory receptors sensing HLA-G1 molecules in pregnancy: deciduaassociated natural killer cells express LIR-1 and CD94/ NKG2a and acquire p49, an HLA-G1-specific receptor. Proc Natl Acad Sci U S A . 1999;96(10):5674-5679.
28.
Faure M., Long EOKIR2DL4 (CD158d), an NK cell-activating receptor with inhibitory potential . J Immunol. 2002;168(12):6208-6214.
29.
Kikuchi-Maki A., Yusa S., Catina TL, Campbell KSKIR2DL4 is an IL-2-regulated NK cell receptor that exhibits limited expression in humans but triggers strong IFN-gamma production . J Immunol.2003;171(7):3415-3425.
30.
Rajagopalan S., Fu J., Long EOCutting edge: induction of IFN-gamma production but not cytotoxicity by the killer cell Ig-like receptor KIR2DL4 (CD158d) in resting NK cells. J Immunol. 2001;167(4):1877-1881.
31.
Riteau B., Menier C., Khalil-Daher I., et al. HLA-G1 co-expression boosts the HLA class I-mediated NK lysis inhibition. Int Immunol.2001;13(2):193-201.
32.
Choi SJ, Park JY, Lee YK, et al. Effects of cytokines on VEGF expression and secretion by human first trimester trophoblast cell line. Am J Reprod Immunol . 2002;48(2):70-76.
33.
Fujii T., Ishitani A., Geraghty DEA soluble form of the HLA-G antigen is encoded by a messenger ribonucleic acid containing intron 4. J Immunol. 1994;153(12):5516-5524.
34.
Hiby SE, King A., Sharkey A., Loke YWMolecular studies of trophoblast HLA-G: polymorphism, isoforms, imprinting and expression in preimplantation embryo. Tissue Antigens . 1999;53(1):1-13.
35.
Rousseau P. , Le Discorde M., Mouillot G., Marcou C., Carosella ED, Moreau P.The 14 bp deletion-insertion polymorphism in the 3’ UT region of the HLA-G gene influences HLA-G mRNA stability . Hum Immunol. 2003;64(11): 1005-1010.
36.
Hviid TV, Hylenius S., Rorbye C., Nielsen LGHLA-G allelic variants are associated with differences in the HLA-G mRNA isoform profile and HLA-G mRNA levels. Immunogenetics . 2003;55(2):63-79.
37.
Shiroishi M. , Kuroki K., Ose T., et al. Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA-G dimer. J Biol Chem. 2006;281(15): 10439-10447.
38.
Gomez-Lozano N., de Pablo R., Puente S., Vilches C.Recognition of HLA-G by the NK cell receptor KIR2DL4 is not essential for human reproduction . Eur J Immunol.2003; 33(3):639-644.
39.
Norman PJ, Carrington CV, Byng M., et al. Natural killer cell immunoglobulin-like receptor (KIR) locus profiles in African and South Asian populations. Genes Immun . 2002;3(2):86-95.
40.
LeMaoult J. , Zafaranloo K., Le Danff C., Carosella EDHLA-G up-regulates ILT2, ILT3, ILT4, and KIR2DL4 in antigen presenting cells, NK cells, and T cells. FASEB J.2005;19(6):662-664.
41.
Yan WH, Fan LAResidues Met76 and Gln79 in HLA-G alpha1 domain involve in KIR2DL4 recognition . Cell Res. 2005;15(3):176-182.
42.
Boyson JE, Erskine R., Whitman MC, et al. Disulfide bond-mediated dimerization of HLA-G on the cell surface . Proc Natl Acad Sci U S A. 2002;99(25):16180-16185.
43.
Cantoni C., Verdiani S., Falco M., et al. P49, a putative HLA class I-specific inhibitory NK receptor belonging to the immunoglobulin superfamily. Eur J Immunol . 1998;28(6): 1980-1990.
44.
Gedil MA, Steiner NK, Hurley CKGenomic characterization of KIR2DL4 in families and unrelated individuals reveals extensive diversity in exon and intron sequences including a common frameshift variation occurring in several alleles. Tissue Antigens. 2005;65(5):402-418.
45.
Rajalingam R., Gardiner CM, Canavez F., Vilches C., Parham P.Identification of seventeen novel KIR variants: fourteen of them from two non-caucasian donors . Tissue Antigens . 2001;57(1):22-31.
46.
Selvakumar A., Steffens U., Dupont B.NK cell receptor gene of the KIR family with two Ig domains but highest homology to KIR receptors with three Ig domains . Tissue Antigens.1996;48(4 pt 1):285-294.
47.
Selvakumar A., Steffens U., Palanisamy N., Chaganti RS, Dupont B.Genomic organization and allelic polymorphism of the human killer cell inhibitory receptor gene KIR103. Tissue Antigens. 1997;49(6):564-573.
Li Y., Zhao YH, Zhang WY, Cui MHCorrelation between killer cell immunoglobulin-like receptors genes and pre-eclampsia . Zhonghua Fu Chan Ke Za Zhi.2008;43(12): 909-912.
51.
Witt CS, Martin A., Christiansen FTDetection of KIR2DL4 alleles by sequencing and SSCP reveals a common allele with a shortened cytoplasmic tail. Tissue Antigens . 2000;56(3): 248-257.
52.
Trundley A. , Moffett A.Human uterine leukocytes and pregnancy . Tissue Antigens. 2004;63(1):1-12.
53.
Hiby SE, Walker JJ, O’Shaughnessy KM, et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med.2004;200(8):957-965.
