Definitive class I human leukocyte antigen expression in gestational placentation: <scp>HLA</scp>‐F, <scp>HLA</scp>‐E, <scp>HLA</scp>‐C, and <scp>HLA</scp>‐G in extravillous trophoblast invasion on placentation, pregnancy, and parturition

Hackmon, Rinat; Pinnaduwage, Lakmini; Zhang, Jianhong; Lye, Stephen J.; Geraghty, Daniel E.; Dunk, Caroline

doi:10.1111/aji.12643

Cited by 115 publications

(106 citation statements)

References 34 publications

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“…Furthermore, Hackmon et al confirmed the distinct expression of HLA-F, HLA-G, HLA-E, and HLA-C in placental tissue, especially on extravillous trophblast cells (EVT). This study provided the first evidence of increased HLA-C expression in parturition that may indicate modulation of the immune-inflammatory role of HLA-C [39]. These combined studies raise the possibility of the deleterious allogeneic effect stemming from paternal HLA-C, specifically C2 group.…”

Section: Introductionmentioning

confidence: 83%

Endoplasmic Reticulum Aminopeptidase 2, a common immunological link to adverse pregnancy outcomes and cancer clearance?

Lee

2017

Placenta

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Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) trims HLA class I-binding peptides, determining the peptide repertoire presented for immune recognition. Variation in the ERAP2 amino acid sequence could affect the ability of some fetuses and tumors to achieve immune evasion. For example, homozygosity for an ERAP2 variant that has increased trimming efficiency for hydrophobic molecules has never been detected in mothers and fetuses. Thus, it is possible that this single nucleotide polymorphism (SNP) in the ERAP2 gene has been selected against in order to prevent alteration of the immune privileged uterine environment, and to allow tumors to escape immune recognition. Currently, there are no immunological treatments or prophylactic approaches to ensure a healthy pregnancy outcome, and the success of cancer immunotherapies is variable. Understanding the role of ERAP2 in immune evasion mechanisms in pregnancy and cancer may improve fetal survival and tumor clearance. This review summarizes current knowledge about ERAP2 and its N392 variant, and their relationship to pregnancy outcomes and cancer immune evasion/recognition.

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Section: Introductionmentioning

confidence: 83%

Endoplasmic Reticulum Aminopeptidase 2, a common immunological link to adverse pregnancy outcomes and cancer clearance?

Lee

2017

Placenta

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“…Throughout primate evolution, pregnancy has progressively become more invasive and immunologically complex (Coe and Lubach, 2014; Carter et al, 2015). The distinct expression pattern of HLA-F (Shobu et al, 2006; Hackmon et al, 2017) and its ability to regulate NK cells which govern the remodeling of the fetal-maternal interface during pregnancy, indicate a role for HLA-F during gestation. Future studies will supplement the abundant observational evidence that HLA-F plays a critical role in pregnancy by providing mechanistic insight into how and through which NKRs HLA-F regulates gestational immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is generally thought that HLA-F does not present antigen (Goodridge et al, 2010; Wainwright et al, 2000) and instead may function as an empty, open conformer (OC) that heterodimerizes with other MHC-I molecules and lacks association with beta-2 microglobulin (β 2 m) (Goodridge et al, 2013). However, there is evidence for dimerized HLA-F complexed with β 2 m on the cell surface of placental tissues during pregnancy (Hackmon et al, 2017) and small amounts of β 2 m-HLA-F have been extracted from cells (Goodridge et al, 2010). Furthermore, HLA-F interacts with components of the transporter associated with antigen processing (TAP) peptide-loading complex (Lepin et al, 2000; Wainwright et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors

et al. 2017

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Summary Evidence is mounting that the major histocompatibility complex (MHC) molecule HLA-F regulates the immune system in pregnancy, infection, and autoimmunity by signaling through NK-cell receptors (NKRs). We present structural, biochemical and evolutionary analyses demonstrating that HLA-F presents peptides of unconventional length dictated by a newly arisen mutation (R62W) that has produced an open-ended groove accommodating particularly long peptides. Compared to empty HLA-F open conformers (OC), HLA-F tetramers bound with human-derived peptides differentially stained leukocytes suggesting peptide-dependent engagement. Our in vitro studies confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F. The complex structure of peptide-loaded β2m-HLA-F bound to the inhibitory LIR1 revealed similarities to high-affinity recognition of the viral MHC-I mimic UL18 and a docking strategy that relies on contacts with HLA-F as well as β2m, thus precluding binding to HLA-F OC. These findings provide a biochemical framework to understand how HLA-F could regulate immunity via interactions with NKRs.

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“…To ensure equal loading, the gel membranes were stripped and reprobed using a rabbit polyclonal antibody to 14,3,3 zeta dilution of 1:2000. We have previously shown that this protein is stably expressed in the human placenta across gestation and in all pathologies . Band intensity and area were analysed using Quantity One 4.6.7 software (Bio‐Rad).…”

Section: Methodsmentioning

confidence: 99%

P‐Glycoprotein (P‐gp)/ABCB1 plays a functional role in extravillous trophoblast (EVT) invasion and is decreased in the pre‐eclamptic placenta

Dunk

Pappas

Lye

et al. 2018

J Cellular Molecular Medi

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Dysregulation of trophoblast differentiation is implicated in the placental pathologies of intrauterine growth restriction and pre‐eclampsia. P‐glycoprotein (P‐gp encoded by ABCB1) is an ATP‐binding cassette transporter present in the syncytiotrophoblast layer of the placenta where it acts as a molecular sieve. In this study, we show that P‐gp is also expressed in the proliferating cytotrophoblast (CT), the syncytiotrophoblast (ST) and the extravillous trophoblast (EVT), suggesting our hypothesis of a functional role for P‐gp in placental development. Silencing of ABCB1, via siRNA duplex, results in dramatically reduced invasion and migration, and increased tube formation and fusion in the EVT‐like HTR8/SV neo cell line. In both EVT and CT explant differentiation experiments, silencing of ABCB1 leads to induction of the fusion markers human hCG, ERVW‐1 and GJA1 and terminal differentiation of both trophoblast subtypes. Moreover, P‐gp protein levels are decreased in both the villous and the EVT of severe early‐onset pre‐eclamptic placentas. We conclude that, in addition to its role as a syncytial transporter, P‐gp is a key factor in the maintenance of both CT and EVT lineages and that its decrease in severe pre‐eclampsia may contribute to the syncytial and EVT placental pathologies associated with this disease.

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Definitive class I human leukocyte antigen expression in gestational placentation: HLA‐F, HLA‐E, HLA‐C, and HLA‐G in extravillous trophoblast invasion on placentation, pregnancy, and parturition

Cited by 115 publications

References 34 publications

Endoplasmic Reticulum Aminopeptidase 2, a common immunological link to adverse pregnancy outcomes and cancer clearance?

Endoplasmic Reticulum Aminopeptidase 2, a common immunological link to adverse pregnancy outcomes and cancer clearance?

Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors

P‐Glycoprotein (P‐gp)/ABCB1 plays a functional role in extravillous trophoblast (EVT) invasion and is decreased in the pre‐eclamptic placenta

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