Limits...
Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success.

Hiby SE, Walker JJ, O'shaughnessy KM, Redman CW, Carrington M, Trowsdale J, Moffett A - J. Exp. Med. (2004)

Bottom Line: This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, England, UK.

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

AA genotype and activating KIR frequencies in control and preeclampsia mothers. (A) There was a significant difference in the AA genotype frequencies between controls (white bar, n = 201) and preeclampsia patients (black bar, n = 200). *, P = 0.038. (B) The AA genotype frequencies in subsets of patients with preeclampsia categorized depending on the HLA-C groups 1 and 2 of mother (M) and fetus (F) (see Table III for details and patient numbers). (a) M 1 + 1/F 1 + 2. *, P 5 0.005. OR = 3.22; CI = 95%; 1.49–6.98. (b) M 2 + 2/F 1 + 2. *, P = 0.034. (c) M 1 + 2/F 1 + 1. (d) M 1 + 2/F 2 + 2. (e) M 1 + 1/F 1 + 1. (f) M 1 + 2/F 1 + 2. *, P = 0.011. (g) M 2 + 2/F 2 + 2. The subsets in which the fetus had a C2 allotype were a, b, d, f, and g. The subsets in which the fetus only had a C1 allotype were c and e. The subset in which C2 was absent from the mother, but present in the fetus, was a. The subsets with both mother and fetus having C2 were b, d, f, and g. Subset g is an exception to the increase in frequency of maternal AA genotype when the fetus had a C2 allotype but the numbers were small (n = 6). (C) The patients from Fig. 1 A have been divided into two subsets as follows: those in which the fetus presents a C2 allotype (n = 109; *, P = 0.001; OR = 2.38; 95% CI = 1.45 − 3.90) and those in which the fetus only had a C1 allotype (n = 91; NS).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2211839&req=5

fig1: AA genotype and activating KIR frequencies in control and preeclampsia mothers. (A) There was a significant difference in the AA genotype frequencies between controls (white bar, n = 201) and preeclampsia patients (black bar, n = 200). *, P = 0.038. (B) The AA genotype frequencies in subsets of patients with preeclampsia categorized depending on the HLA-C groups 1 and 2 of mother (M) and fetus (F) (see Table III for details and patient numbers). (a) M 1 + 1/F 1 + 2. *, P 5 0.005. OR = 3.22; CI = 95%; 1.49–6.98. (b) M 2 + 2/F 1 + 2. *, P = 0.034. (c) M 1 + 2/F 1 + 1. (d) M 1 + 2/F 2 + 2. (e) M 1 + 1/F 1 + 1. (f) M 1 + 2/F 1 + 2. *, P = 0.011. (g) M 2 + 2/F 2 + 2. The subsets in which the fetus had a C2 allotype were a, b, d, f, and g. The subsets in which the fetus only had a C1 allotype were c and e. The subset in which C2 was absent from the mother, but present in the fetus, was a. The subsets with both mother and fetus having C2 were b, d, f, and g. Subset g is an exception to the increase in frequency of maternal AA genotype when the fetus had a C2 allotype but the numbers were small (n = 6). (C) The patients from Fig. 1 A have been divided into two subsets as follows: those in which the fetus presents a C2 allotype (n = 109; *, P = 0.001; OR = 2.38; 95% CI = 1.45 − 3.90) and those in which the fetus only had a C1 allotype (n = 91; NS).

Mentions: All mothers were also typed for the KIR genes: inhibitory, 2DL1, 2DL2, 2DL3, 2DL5, and 3DL3; and activating, 2DS1, 2DS2, 2DS3, 2DS4, and 2DS5. On the basis of the presence of activating receptors characteristic of the B haplotypes, the mothers were designated as having either an AA genotype or an AB/BB genotype. 25% of our control population had two A haplotypes (AA genotype) in agreement with previous reports in caucasoid populations (8, 27). Considering all preeclampsia patients, there was a statistically significant increase in the frequency of the AA genotype to 35% (P = 0.038, OR = 1.59, CI = 1.03–2.45; Fig. 1 A). When individual KIR genes were analyzed, several were less frequent in preeclampsia mothers but only the KIR2DL5 gene frequency reached statistical significance (Table II). Consistent with previous reports we identified considerable variation in frequency of the KIR leading to a great diversity in genotypes (reference 8 and Table S3, available at http://www.jem.org/cgi/content/full/jem.20041214/DC1). A total of 48 genotypes could be identified, a few of which were common but most were present in only one or two individuals.


Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success.

Hiby SE, Walker JJ, O'shaughnessy KM, Redman CW, Carrington M, Trowsdale J, Moffett A - J. Exp. Med. (2004)

AA genotype and activating KIR frequencies in control and preeclampsia mothers. (A) There was a significant difference in the AA genotype frequencies between controls (white bar, n = 201) and preeclampsia patients (black bar, n = 200). *, P = 0.038. (B) The AA genotype frequencies in subsets of patients with preeclampsia categorized depending on the HLA-C groups 1 and 2 of mother (M) and fetus (F) (see Table III for details and patient numbers). (a) M 1 + 1/F 1 + 2. *, P 5 0.005. OR = 3.22; CI = 95%; 1.49–6.98. (b) M 2 + 2/F 1 + 2. *, P = 0.034. (c) M 1 + 2/F 1 + 1. (d) M 1 + 2/F 2 + 2. (e) M 1 + 1/F 1 + 1. (f) M 1 + 2/F 1 + 2. *, P = 0.011. (g) M 2 + 2/F 2 + 2. The subsets in which the fetus had a C2 allotype were a, b, d, f, and g. The subsets in which the fetus only had a C1 allotype were c and e. The subset in which C2 was absent from the mother, but present in the fetus, was a. The subsets with both mother and fetus having C2 were b, d, f, and g. Subset g is an exception to the increase in frequency of maternal AA genotype when the fetus had a C2 allotype but the numbers were small (n = 6). (C) The patients from Fig. 1 A have been divided into two subsets as follows: those in which the fetus presents a C2 allotype (n = 109; *, P = 0.001; OR = 2.38; 95% CI = 1.45 − 3.90) and those in which the fetus only had a C1 allotype (n = 91; NS).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211839&req=5

fig1: AA genotype and activating KIR frequencies in control and preeclampsia mothers. (A) There was a significant difference in the AA genotype frequencies between controls (white bar, n = 201) and preeclampsia patients (black bar, n = 200). *, P = 0.038. (B) The AA genotype frequencies in subsets of patients with preeclampsia categorized depending on the HLA-C groups 1 and 2 of mother (M) and fetus (F) (see Table III for details and patient numbers). (a) M 1 + 1/F 1 + 2. *, P 5 0.005. OR = 3.22; CI = 95%; 1.49–6.98. (b) M 2 + 2/F 1 + 2. *, P = 0.034. (c) M 1 + 2/F 1 + 1. (d) M 1 + 2/F 2 + 2. (e) M 1 + 1/F 1 + 1. (f) M 1 + 2/F 1 + 2. *, P = 0.011. (g) M 2 + 2/F 2 + 2. The subsets in which the fetus had a C2 allotype were a, b, d, f, and g. The subsets in which the fetus only had a C1 allotype were c and e. The subset in which C2 was absent from the mother, but present in the fetus, was a. The subsets with both mother and fetus having C2 were b, d, f, and g. Subset g is an exception to the increase in frequency of maternal AA genotype when the fetus had a C2 allotype but the numbers were small (n = 6). (C) The patients from Fig. 1 A have been divided into two subsets as follows: those in which the fetus presents a C2 allotype (n = 109; *, P = 0.001; OR = 2.38; 95% CI = 1.45 − 3.90) and those in which the fetus only had a C1 allotype (n = 91; NS).
Mentions: All mothers were also typed for the KIR genes: inhibitory, 2DL1, 2DL2, 2DL3, 2DL5, and 3DL3; and activating, 2DS1, 2DS2, 2DS3, 2DS4, and 2DS5. On the basis of the presence of activating receptors characteristic of the B haplotypes, the mothers were designated as having either an AA genotype or an AB/BB genotype. 25% of our control population had two A haplotypes (AA genotype) in agreement with previous reports in caucasoid populations (8, 27). Considering all preeclampsia patients, there was a statistically significant increase in the frequency of the AA genotype to 35% (P = 0.038, OR = 1.59, CI = 1.03–2.45; Fig. 1 A). When individual KIR genes were analyzed, several were less frequent in preeclampsia mothers but only the KIR2DL5 gene frequency reached statistical significance (Table II). Consistent with previous reports we identified considerable variation in frequency of the KIR leading to a great diversity in genotypes (reference 8 and Table S3, available at http://www.jem.org/cgi/content/full/jem.20041214/DC1). A total of 48 genotypes could be identified, a few of which were common but most were present in only one or two individuals.

Bottom Line: This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Cambridge CB2 1QP, England, UK.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus