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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.

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Related in: MedlinePlus

KIR genotype AA and HLA-C group 2 frequencies in different populations. Most of the HLA-C and KIR data have been taken from different cohorts within each population (references 26–35). The correlation coefficient (r) was −0.82.
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fig3: KIR genotype AA and HLA-C group 2 frequencies in different populations. Most of the HLA-C and KIR data have been taken from different cohorts within each population (references 26–35). The correlation coefficient (r) was −0.82.

Mentions: Given the dramatic influence of the KIR AA/HLA-C2 combinations on reproductive success, we investigated if their effects might be detectable at the population level. According to the model we have presented, and assuming that preeclampsia is disadvantageous in any population, we would predict an inverse relationship between the population prevalence of HLA-C2 and AA genotypes. To test this, we tabulated the relative frequencies of HLA-C2 and the KIR AA genotype in populations for which data were available (Fig. 3 and references 26–35). There was an apparent inverse relationship between HLA-C2 and AA frequencies (correlation coefficient (r) = −0.82). The more frequent C2, the less frequent was the AA genotype. The most obvious association of maternal KIR AA genotype with HLA-C2 was seen in the two historically isolated populations from Japan and the Australian Aborigines who represent the extreme ends of the spectrum.


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)

KIR genotype AA and HLA-C group 2 frequencies in different populations. Most of the HLA-C and KIR data have been taken from different cohorts within each population (references 26–35). The correlation coefficient (r) was −0.82.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: KIR genotype AA and HLA-C group 2 frequencies in different populations. Most of the HLA-C and KIR data have been taken from different cohorts within each population (references 26–35). The correlation coefficient (r) was −0.82.
Mentions: Given the dramatic influence of the KIR AA/HLA-C2 combinations on reproductive success, we investigated if their effects might be detectable at the population level. According to the model we have presented, and assuming that preeclampsia is disadvantageous in any population, we would predict an inverse relationship between the population prevalence of HLA-C2 and AA genotypes. To test this, we tabulated the relative frequencies of HLA-C2 and the KIR AA genotype in populations for which data were available (Fig. 3 and references 26–35). There was an apparent inverse relationship between HLA-C2 and AA frequencies (correlation coefficient (r) = −0.82). The more frequent C2, the less frequent was the AA genotype. The most obvious association of maternal KIR AA genotype with HLA-C2 was seen in the two historically isolated populations from Japan and the Australian Aborigines who represent the extreme ends of the spectrum.

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