Recurrent Pregnancy Loss in Women with Killer Cell Immunoglobulin-Like Receptor KIR2DS1 is Associated with an Increased HLA-C2 Allelic Frequency

Dambaeva, Svetlana; Lee, Dong‐Hyung; Sung, Nak‐Ju; Chen, Chi-Yao; Bao, Shihua; Gilman‐Sachs, Alice; Kwak‐Kim, Joanne; Beaman, Kenneth D.

doi:10.1111/aji.12453

Cited by 27 publications

(18 citation statements)

References 53 publications

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“…Our focus on KIR2D(L1/S1) stems from research showing the importance of these two receptors in controlling aspects of placental development and in their association with poor pregnancy outcomes. 9,10,28 Notably, HLA-C2 directed activation of KIR2DS1 41 and the resulting expression of GM-CSF in KIR2DS1 + uNK promotes trophoblast invasion. 28 Moreover, a KIR2DS1containing genotype (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Inadequate (not enough) or inappropriate (too much) uNK activation may contribute to preterm birth, recurrent miscarriage and pre-eclampsia by limiting angiogenesis/artery remodeling or oversensitizing uNK to being cytotoxic. [9][10][11][12] Obesity, with a prevalence between 13% and 18% in women of reproductive age, 13 correlates with higher incidences of poor pregnancy outcomes. 14 For example, pre-existing obesity associates with recurrent miscarriage, 15 gestational diabetes, 16 preterm birth 17 and pre-eclampsia.…”

Section: Introductionmentioning

confidence: 99%

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Maternal obesity alters uterine NK activity through a functional KIR2DL1/S1 imbalance

et al. 2018

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In pregnancy, uterine natural killer cells (uNK) play essential roles in coordinating uterine angiogenesis, blood vessel remodeling and promoting maternal tolerance to fetal tissue. Deviances from a normal uterine microenvironment are thought to modify uNK function(s) by limiting their ability to establish a healthy pregnancy. While maternal obesity has become a major health concern due to associations with adverse effects on fetal and maternal health, our understanding into how obesity contributes to poor pregnancy disorders is unknown. Given the importance of uNK in pregnancy, this study examines the impact of obesity on uNK function in women in early pregnancy. We identify that uNK from obese women show a greater propensity for cellular activation, but this difference does not translate into increased effector killing potential. Instead, uNK from obese women express an altered repertoire of natural killer receptors, including an imbalance in inhibitory KIR2DL1 and activating KIR2DS1 receptors that favors HLA-C2-directed uNK activation. Notably, we show that obesity-related KIR2DS1 skewing potentiates TNFα production upon receptor crosslinking. Together, these findings suggest that maternal obesity modifies uNK activity by altering the response toward HLA-C2 antigen and KIR2DL1/2DS1-controlled TNFα release. Furthermore, this work identifies alterations in uNK function resulting from maternal obesity that may impact early developmental processes important in pregnancy health.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Maternal obesity alters uterine NK activity through a functional KIR2DL1/S1 imbalance

et al. 2018

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“…Indeed, population genetic studies have revealed associations between KIRs and KIR ligands, and pregnancy disorders such as recurrent miscarriage and preeclampsia. [12][13][14][15][16] However, difficulties in accessing primary uterine tissue have hampered efforts to understand uterine NK cell KIR repertoire composition.…”

Section: Introductionmentioning

confidence: 99%

Composition and dynamics of the uterine NK cell KIR repertoire in menstrual blood

et al. 2017

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Uterine natural killer (NK) cells are abundantly present in endometrium and decidua. Their function is governed by interactions between killer cell immunoglobulin-like receptors (KIRs) and cognate human leukocyte antigen (HLA) class I ligands. These interactions have implications for reproductive success. Whereas most uterine NK cells are known to express KIRs, little information is available about KIR repertoire formation and stability over time. This is primarily due to inherent difficulties in gaining access to human uterine tissue. As endometrial immune cells are shed during menstruation, menstrual blood may serve as a source for studies of KIRs on uterine NK cells. Here, we performed a combined assessment of six inhibitory and activating KIRs on uterine NK cells from paired menstrual and peripheral blood. Menstrual blood contained a high frequency of uterine NK cells expressing KIRs. The uterine NK cell KIR repertoires were markedly different from those in peripheral blood NK cells, biased toward KIR2D-receptor expression, and formed independently of selection conferred by cognate HLA class I molecules. Moreover, uterine NKG2Cself-KIR NK cell expansions were detected. Finally, the distinct KIR repertoires of uterine NK cells were stable over multiple menstrual cycles. Our results provide novel insight into KIR repertoire formation on human uterine NK cells.

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“…However, HLA-C was not analysed in this study. Although Dambaeva et al did not confirm the association of RM with increased KIR AA genotype or decreased KIR2DS1 frequency, they did find increased C2 + HLA-C partners among the RM cases with KIR AA genotype (Dambaeva et al 2016 ). The scenario that emerges from these three studies suggests that excessive inhibition of uNK cells may be detrimental.…”

Section: Kir and Hla Association With Recurrent Miscarriagementioning

confidence: 97%

The role of KIR and HLA interactions in pregnancy complications

Colucci

2017

Immunogenetics

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Combinations of KIR and HLA genes associate with pregnancy complications as well as with many other clinical scenarios. Understanding how certain KIR and HLA genes influence the biology of a disease is, however, a formidable challenge. These are the two most variable gene families in the human genome. Moreover, the biology of a disease is best understood by studying the cells of the affected tissue. Natural Killer (NK) cells express KIR and are the most abundant leukocytes in the uterus. Most of our knowledge of NK cells is based on what we have learned from cells isolated from blood, but these are different from their tissue resident counterparts, including uterine NK (uNK) cells. Reproductive immunology faces an additional challenge: Two genotypes must be considered because both maternal and foetal HLA class I molecules may influence the outcome of pregnancy, most likely through interactions with maternal KIR expressed on uNK cells. Maternal uNK cells are not spontaneously cytotoxic and instead engage in interactions with trophoblast. We hypothesise that these interactions regulate allocation of resources between the foetus and the mother and may go wrong in diseases of pregnancy.

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Recurrent Pregnancy Loss in Women with Killer Cell Immunoglobulin-Like Receptor KIR2DS1 is Associated with an Increased HLA-C2 Allelic Frequency

Abstract: Our results indicate that among KIR2DS1 pos women, the co-expression of HLA-C2 is associated with RPL.

Cited by 27 publications

References 53 publications

Maternal obesity alters uterine NK activity through a functional KIR2DL1/S1 imbalance

Maternal obesity alters uterine NK activity through a functional KIR2DL1/S1 imbalance

Composition and dynamics of the uterine NK cell KIR repertoire in menstrual blood

The role of KIR and HLA interactions in pregnancy complications

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