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HLA-C and KIR Interactions on Pregnancy: Research Review

A short overview of the role of fetal HLA-C and maternal KIR in fertility and the science behind it.

April 22, 2022 Pregmune Team
Spiral Artery Remodeling

Fetal HLA-C and maternal KIR interactions are assessed as part of the parental histocompatibility section of the IRMA report. Parental histocompatibility examines the impact of human leukocyte antigens (HLAs) on pregnancy.

HLAs are diverse proteins displayed on human cells like a barcode – unique for everyone. The immune system uses HLAs to differentiate “self” from “non-self.” Half of a developing embryo’s HLAs come from the father, and a certain amount of mismatch between parental HLAs is a good thing.

A developing embryo’s unique HLAs are recognized by the mother’s uterine natural killer cells using receptors called killer immunoglobulin-like receptors (KIRs). Some maternal KIRs respond better than others to embryos displaying HLA-C2, which influences how much oxygen and nutrition is sent through the placenta (through spiral artery remodeling). Additionally, if the embryo has more (or in some cases the same number of) HLA-C2 alleles than the mother, this could also pose a risk. This test examines the patient’s HLA-C2 content, the predicted embryo’s HLA-C2 content, and whether the maternal KIRs are a good match for HLA-C2.

Physiology

Uterine natural killer cells (uNK) secrete a unique repertoire of cytokines and growth factors that regulate blood vessel growth and development (also known as spiral artery remodeling) leading to a healthy placentation that supports embryo growth1. Killer immunoglobulin-like receptors (KIRs) present on the surface of uNK interact with HLA-C on the trophoblast to promote (activating KIR) or suppress (inhibiting KIR) vascular remodeling2.

HLA-C genotypes of both the father and the mother have a significant impact on the risk for defective placentation which can manifest as recurrent miscarriage, intrauterine growth restriction and/or preeclampsia3.

Published clinical data

Clinical studies found that the combination of maternal KIR-AA and fetal HLA-C2, but not fetal HLA-C1, lead to increased risk of recurrent losses4, preeclampsia3 and low birth weight5.

Indeed, maternal KIR AA frequency is increased in pregnancies ending with a loss or affected pre-eclampsia compared with control pregnancies when the fetus has more C2 genes than the mother or when fetal C2 is inherited paternally4.

Further, a study comparing HLA-C and KIR haplotypes of both partners in couples with three or more spontaneous miscarriages (RPL) versus couples with no fertility issues showed a significant association of the lack of activating KIR in the affected woman (KIR AA genotype) and an increased HLA-C2 group frequency in the RPL couples6.

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About Pregmune: We’re an innovative reproductive health technology company, built on a solid foundation of data gained from decades of experience and thousands of successful pregnancies. Our team of fertility specialists and scientists are using artificial intelligence to decipher the complexity of the immune system and help patients grow the families of their dreams.

Our first product, IRMA, provides patients and their doctors with a personalized report and evidence-based treatment plan that addresses immunological sources of unexplained infertility, recurrent pregnancy loss, and recurrent implantation failure.

References

  1. Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol (2002) 2(9):656–63.
  2. Chazara O, Xiong S, Moffett A. Maternal KIR and fetal HLA-C: a fine balance. J Leukoc Biol. 2011 Oct;90(4):703-16. doi: 10.1189/jlb.0511227. Epub 2011 Aug 26. Review.
  3. Hiby SE,Walker JJ, O’Shaughnessy KM, Redman CW, Carrington M, Trowsdale J, 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):957–65.
  4. Hiby SE, Apps R, Sharkey AM, Farrell LE, Gardner L, Mulder A, Claas FH, Walker JJ, Redman CW, Morgan L, Tower C, Regan L, Moore GE, Carrington M, Moffett A. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J Clin Invest. 2010 Nov;120(11):4102-10.
  5. Hiby SE, Apps R, Chazara O, Farrell LE, Magnus P, Trogstad L, Gjessing HK, Carrington M, Moffett A. Maternal KIR in combination with paternal HLA-C2 regulate human birth weight. J Immunol. 2014 Jun 1;192(11):5069-73.
  6. Hiby SE, Regan L, Lo W, Farrell L, Carrington M, Moffett A. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum Reprod. 2008 Apr;23(4):972-6.