• 14 bp deletion/insertion polymorphism
• 3′-untranslated region (3′-UTR)
• 5′-upstream regulatory region (URR)
• maternal tolerance
• semiallogenic fetus
• single nucleotide polymorphism

• All India Institute of Medical Sciences, New Delhi
• Department of Biotechnology-Ministry of Science and Technology, Government of India

During the 2015–2016 epidemic, Brazil was the country with the highest rate of Zika virus (ZIKV) infection in the Americas. Twenty-nine percent of pregnant women positive for ZIKV exhibited ultrasound scans with fetus anomalies. Human leukocyte antigen-G (HLA-G) exerts immunoregulatory effects by binding to inhibitory receptors, namely LILRB1 and LILRB2, thus preventing mother–fetus rejection and vertical pathogen transmission. The binding of HLA-G to one of its receptors modulates both innate and adaptive immunity. However, in a viral infection, these molecules may behave as pathogenic mediators shifting the pregnancy environment from an anti-inflammatory profile to a pro-inflammatory phenotype. Genetic mutations might be associated with the change in phenotype. This study aimed to explore the possible role of polymorphic sites in HLA-G, LILRB1 and LILRB2 in mother–fetus ZIKV transmission. Polymorphisms were detected by direct sequencing. Differences in allele and/or genotype frequencies for each SNP analyzed among ZIKV non-transmitting and transmitting mother–child pairs, among ZIKV-transmitting and non-transmitting mothers and between ZIKV-infected and non-infected children were compared by Mid-P exact test or Yates’ correction. Significant susceptibility of ZIKV vertical transmission is suggested in ZIKV-transmitting and non-transmitting mothers and ZIKV-infected and non-infected children for LILRB1_rs1061684 T/T (p = 0.03, Pc = 0.06, OR = 12.4; p = 0.008, Pc = 0.016, OR = 16.4) and LILRB1_rs16985478 A/A (p = 0.01, Pc = 0.02, OR = 19.2; p = 0.008, Pc = 0.016, OR = 16.4). HLA-G_rs1710 (p = 0.04, Pc = 0.52, OR = 4.30) was also a susceptibility factor. LILRB2_rs386056 G/A (p = 0.02, Pc = 0.08, OR = 0.07), LILRB2_rs7247451 G/G (p = 0.01, Pc = 0.04, OR = 0.04) and HLAG_rs9380142 T/T (p = 0.04, Pc = 0.52, OR = 0.14) were suggested as protective factors against vertical transmission. The current study suggests that polymorphic sites in the LILRB1 and HLA-G genes might be associated with mother-to-child ZIKV transmission while LILRB2 might be associated with protection against ZIKV transmission in the womb in a population from the south and southeast of Brazil.

• HLA
• LILRB
• SNPs
• ZIKV
• flavivirus
• vertical transmission

Maternal-fetal immune-tolerance occurs throughout the whole gestational trimester, thus a mother can accept a genetically distinct fetus without immunological aggressive behavior. HLA-G, one of the non-classical HLA class I molecules, is restricted-expression at extravillous trophoblast. It can concordantly interact with various kinds of receptors mounted on maternally immune cells residing in the uterus (e.g. CD4+ T cells, CD8+ T cells, natural killer cells, macrophages, and dendritic cells) for maintaining immune homeostasis of the maternal-fetus interface. HLA-G is widely regarded as the pivotal protective factor for successful pregnancies. In the past 20 years, researches associated with HLA-G have been continually published. Indeed, HLA-G plays a mysterious role in the mechanism of maternal-fetal immune-tolerance. It can also be ectopically expressed on tumor cells, infected sites and other pathologic microenvironments to confer a significant local tolerance. Understanding the characteristics of HLA-G in immunologic tolerance is not only beneficial for pathological pregnancy, but also helpful to the therapy of other immune-related diseases, such as organ transplant rejection, tumor migration, and autoimmune disease. In this review, we describe the biological properties of HLA-G, then summarize our understanding of the mechanisms of fetomaternal immunologic tolerance and the difference from transplant tolerance. Furthermore, we will discuss how HLA-G contributes to the tolerogenic microenvironment during pregnancy. Finally, we hope to find some new aspects of HLA-G in fundamental research or clinical application for the future.

• HLA-G
• KIR receptor
• maternal-fetal immune-tolerance
• pregnancy
• reproductive immunology

Natural killer (NK) cells are innate lymphocytes that can kill diseased- or virally-infected cells, mediate antibody dependent cytotoxicity and produce type I immune-associated cytokines upon activation. NK cells also contribute to the allo-immune response upon kidney transplantation either by promoting allograft rejection through lysis of cells of the transplanted organ or by promoting alloreactive T cells. In addition, they protect against viral infections upon transplantation which may be especially relevant in patients receiving high dose immune suppression. NK cell activation is tightly regulated through the integrated balance of signaling via inhibitory- and activating receptors. HLA class I molecules are critical regulators of NK cell activation through the interaction with inhibitory- as well as activating NK cell receptors, hence, HLA molecules act as critical immune checkpoints for NK cells. In the current review, we evaluate how NK cell alloreactivity and anti-viral immunity are regulated by NK cell receptors belonging to the KIR family and interacting with classical HLA class I molecules, or by NKG2A/C and LILRB1/KIR2DL4 engaging non-classical HLA-E or -G. In addition, we provide an overview of the methods to determine genetic variation in these receptors and their HLA ligands.

• HLA class I
• KIR
• NK cell
• NKG2A
• solid organ transplantation

• HLA-G
• allele
• isoform
• pre-eclampsia
• pregnancy
• reproductive immunology

• Acute rejection
• Chronic rejection
• HLA-G 3'UTR 14 bp polymorphism
• Kidney transplantation
• sHLA-G level

• 3' Untranslated Regions
• Adolescent
• Adult
• Aged
• Biomarkers/analysis
• Case-Control Studies
• Female
• Graft Rejection/diagnosis
• Graft Rejection/etiology
• HLA-G Antigens/genetics
• Humans
• Kidney Transplantation/adverse effects
• Male
• Middle Aged
• Polymorphism, Genetic
• Renal Insufficiency, Chronic/pathology
• Renal Insufficiency, Chronic/surgery
• Young Adult

• Acute atherosis
• Decidua basalis
• Extravillous trophoblasts
• HLA-G
• HLA-G 3’UTR polymorphisms
• Preeclampsia

During pregnancy, the maternal uterus and fetus form a special microenvironment at the maternal-fetal interface to support fetal development. Extravillous trophoblasts (EVTs), differentiated from the fetus, invade into the decidua and interact with maternal cells. Human leukocyte antigen (HLA)-G is a non-classical MHC-I molecule that is expressed abundantly and specifically on EVTs in physiological conditions. Soluble HLA-G (sHLA-G) is also found in maternal blood, amniotic fluid, and cord blood. The abnormal expression and polymorphisms of HLA-G are related to adverse pregnancy outcomes such as preeclampsia (PE) and recurrent spontaneous abortion (RSA). Here we summarize current findings about three main roles of HLA-G during pregnancy, namely its promotion of spiral artery remodeling, immune tolerance, and fetal growth, all resulting from its interaction with immune cells. These findings are not only of great significance for the treatment of pregnancy-related diseases but also provide clues to tumor immunology research since HLA-G functions as a checkpoint in tumors.

• extravillous trophoblasts
• fetal development
• human leukocyte antigen G
• immunology
• natural killer cells
• pregnancy
• spiral artery remodeling

• Adult
• Black People/genetics
• Black People/statistics & numerical data
• Female
• Gene Frequency/genetics
• Genetic Predisposition to Disease/epidemiology
• Genetic Predisposition to Disease/genetics
• HIV Infections/complications
• HIV Infections/epidemiology
• HIV Infections/genetics
• HLA-G Antigens/genetics
• Humans
• Polymorphism, Single Nucleotide/genetics
• Pre-Eclampsia/epidemiology
• Pre-Eclampsia/genetics
• Pregnancy
• Pregnancy Complications, Infectious/epidemiology
• Pregnancy Complications, Infectious/genetics
• Retrospective Studies
• South Africa
• Young Adult

• immune tolerance
• placenta
• pre-eclampsia
• pregnancy
• trophoblast

• HLA-G
• Host genetics
• Leishmaniosis
• Resistance
• Susceptibility

Purpose: Although it has been frequently confirmed that HLA-G plays an important role in the reproduction and pregnancy, the pattern of HLA-G gene and its protein expression are rarely addressed in studies. Therefore we conducted this study in regard to evaluate the HLA-G gene and its protein expression in the women’s placenta with recurrent miscarriage.

Methods: Placental samples were obtained from the women who were admitted for delivery or abortion in Al Zahra and Taleghani hospitals, Tabriz, Iran. HLA-G gene expression was determined by real-time polymerase chain reaction (PCR) and HLA-G protein expression was assessed by western blotting and immunofluorescence staining in the tissue samples.

Results: The results showed a significant decrease in the expression of gene and proteins of HLA-G in the women with recurrent miscarriage compared to the control placental tissues.

Conclusion: According to the obtained results, it was concluded that the decrement of HLA-G gene and protein expressions are associated with recurrent miscarriage. Since there are conflicting results from other studies, it is suggested to conduct a more comprehensive similar study with greater sample size.

• HLA-G
• Miscarriage
• Real-Time PCR
• placenta

• GATA2
• HLA-F
• decidualization
• endometrium
• pregnancy

• 14-bp polymorphism
• 3′UTR
• HLA-G
• Indel
• Non-classical MHC

• 3' Untranslated Regions
• Alleles
• Genetic Association Studies
• Genetic Predisposition to Disease
• HLA-G Antigens/genetics
• Humans
• INDEL Mutation
• Lupus Erythematosus, Systemic/genetics
• Odds Ratio
• Open Reading Frames
• Polymorphism, Genetic
• Promoter Regions, Genetic
• Regulatory Sequences, Nucleic Acid

• Apol-1 gene polymorphisms
• Bioinformatic studies
• Candidate gene studies
• Genome-wide association studies
• Pre-eclampsia

• Female
• Genetic Linkage
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Polymorphism, Genetic
• Pre-Eclampsia/genetics
• Pregnancy

• HLA-G
• polymorphism
• preeclampsia
• soluble HLA-G

• HLA-G
• Placenta
• Preeclampsia
• Preterm births
• Single nucleotide polymorphism

Congenital CMV infection (cCMV) is the most common congenital infection causing permanent long-term impairments (LTI). cCMV immunopathogenesis is largely unknown due to the complex interplay between viral, maternal, placental, and child factors. In this study, a large retrospective nationwide cohort of children with cCMV and their mothers was used. HLA-C, HLA-E, and HLA-G were assessed in 96 mother–child pairs in relation to symptoms at birth and LTI at 6 years of age. The mothers were additionally typed for killer cell immunoglobulin-like receptors. The maternal HLA-G 14 bp deletion/deletion polymorphism was associated with a worse outcome, as the immunomodulation effect of higher protein levels may induce less CMV control, with a direct impact on placenta and fetus. The absence of maternal HLA-C belonging to the C2 group was associated with symptoms at birth, as activating signals on decidual NK may override inhibitory signals, contributing to a placental pro-inflammatory environment. Here, the increased HLA-E*0101 and HLA-C mismatches, which were associated with symptoms at birth, may enhance maternal allo-reactivity to fetal Ags, and cause suboptimal viral clearance. Finally, HLA-C non-inherited maternal antigens (NIMAs) were associated with LTI. The tolerance induced in the fetus toward NIMAs may indirectly induce a suboptimal CMV antiviral response throughout childhood. In light of our findings, the potential role of maternal–child HLA in controlling CMV infection and cCMV-related disease, and the clinical value as predictor for long-term outcome certainly deserve further evaluation.

• NIMA effect
• allo-reactivity
• biomarkers
• congenital CMV infection
• dried blood spots
• immunopathology
• mother–child HLA
• suboptimal viral clearance

• Assisted reproduction
• HLA class Ib genes
• Pre-eclampsia
• Pregnancy
• Pregnancy complications

• Abortion, Habitual/etiology
• Abortion, Habitual/immunology
• Female
• Fertility
• HLA-G Antigens/genetics
• HLA-G Antigens/physiology
• Histocompatibility Antigens Class I/genetics
• Histocompatibility Antigens Class I/physiology
• Humans
• Pre-Eclampsia/etiology
• Pre-Eclampsia/immunology
• Pregnancy/immunology
• Reproductive Techniques, Assisted
• HLA-E Antigens

• HLA-G
• abruptio placentae
• placentation
• pre-eclampsia
• pregnancy

• HLA-E
• HLA-G
• haplotypes
• preeclampsia
• pregnancy

• 3' Untranslated Regions
• Case-Control Studies
• Child
• Eclampsia/diagnosis
• Eclampsia/genetics
• Eclampsia/immunology
• Eclampsia/pathology
• Female
• Gene Expression
• HLA-G Antigens/genetics
• HLA-G Antigens/immunology
• Haplotypes
• Histocompatibility Antigens Class I/genetics
• Histocompatibility Antigens Class I/immunology
• Histocompatibility Testing
• Humans
• INDEL Mutation
• Infant, Newborn
• Male
• Placenta/immunology
• Placenta/pathology
• Polymorphism, Single Nucleotide
• Pre-Eclampsia/diagnosis
• Pre-Eclampsia/genetics
• Pre-Eclampsia/immunology
• Pre-Eclampsia/pathology
• Pregnancy
• Sequence Analysis, DNA
• Severity of Illness Index
• HLA-E Antigens

Fertility traits in humans are heritable, however, little is known about the genes that influence reproductive outcomes or the genetic variants that contribute to differences in these traits between individuals, particularly women. To address this gap in knowledge, we performed an unbiased genome-wide expression quantitative trait locus (eQTL) mapping study to identify common regulatory (expression) single nucleotide polymorphisms (eSNPs) in mid-secretory endometrium. We identified 423 cis-eQTLs for 132 genes that were significant at a false discovery rate (FDR) of 1%. After pruning for strong LD (r² >0.95), we tested for associations between eSNPs and fecundability (the ability to get pregnant), measured as the length of the interval to pregnancy, in 117 women. Two eSNPs were associated with fecundability at a FDR of 5%; both were in the HLA region and were eQTLs for the TAP2 gene (P = 1.3x10^-4) and the HLA-F gene (P = 4.0x10^-4), respectively. The effects of these SNPs on fecundability were replicated in an independent sample. The two eSNPs reside within or near regulatory elements in decidualized human endometrial stromal cells. Our study integrating eQTL mapping in a primary tissue with association studies of a related phenotype revealed novel genes and associated alleles with independent effects on fecundability, and identified a central role for two HLA region genes in human implantation success.

Little is known about the genetics of female fertility. In this study, we addressed this gap in knowledge by first searching for genetic variants that regulate gene expression in uterine endometrial cells, and then testing those functional variants for associations with the length of time to pregnancy in fertile women. Two functional genetic variants were associated with time to pregnancy in women after correcting for multiple testing. Those variants were each associated with the expression of genes in the HLA region, HLA-F and TAP2, which are have not previously been implicated female fertility. The association between HLA-F and TAP2 genotypes on the length of time to pregnancy was replicated in an independent cohort of women. Because HLA-F and TAP2 are involved in immune processes, these results suggest their role in specific immune regulation in the endometrium during implantation. Future studies will characterize these molecules in the implantation process and their potential as drug targets for treatment of conditions related to implantation failure.

• ATP Binding Cassette Transporter, Subfamily B, Member 3/biosynthesis
• ATP Binding Cassette Transporter, Subfamily B, Member 3/genetics
• Adult
• Chromosome Mapping
• Endometrium/metabolism
• Endometrium/pathology
• Female
• Fertility/genetics
• Fertility/physiology
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Histocompatibility Antigens Class I/biosynthesis
• Histocompatibility Antigens Class I/genetics
• Humans
• Phenotype
• Polymorphism, Single Nucleotide
• Pregnancy
• Quantitative Trait Loci/genetics
• Regulatory Sequences, Nucleic Acid

• UL1 TR000445 NCATS NIH HHS
• R01 HD021244 NICHD NIH HHS
• R01 HD049675 NICHD NIH HHS
• R01 HD043883 NICHD NIH HHS
• R01 HL085197 NHLBI NIH HHS
• National Institutes of Health
• American Water Works Association Research Foundation
• National Center for Advancing Translational Sciences

• Endothelium
• Extracellular matrix
• Hypertension
• Preeclampsia
• Pregnancy
• Vascular smooth muscle

• Autistic spectrum disorder
• Genetic polymorphism
• HLA
• HLA-G
• Immune activation
• Immune system
• In utero immunology
• KIR
• NK cells

• 3' Untranslated Regions
• Adolescent
• Adult
• Child
• Child Development Disorders, Pervasive/genetics
• Cohort Studies
• Female
• Genotype
• HLA-G Antigens/genetics
• Humans
• INDEL Mutation
• Italy
• Male
• Middle Aged
• Polymorphism, Genetic

Despite decades of research, the highly prevalent pregnancy complication preeclampsia, “the disease of theories,” has remained an enigma. Indeed, the etiology of preeclampsia is largely unknown. A compiling amount of studies indicates that the pathological basis involves a complex array of genetic predisposition and immunological maladaptation, and that a contribution from the mother, the father, and the fetus is likely to be important. The Human Leukocyte Antigen (HLA)-G is an increasing focus of research in relation to preeclampsia. The HLA-G molecule is primarily expressed by the extravillous trophoblast cells lining the placenta together with the two other HLA class Ib molecules, HLA-E and HLA-F. Soluble isoforms of HLA-G have been detected in the early endometrium, the matured cumulus–oocyte complex, maternal blood of pregnant women, in umbilical cord blood, and lately, in seminal plasma. HLA-G is believed to be involved in modulating immune responses in the context of vascular remodeling during pregnancy as well as in dampening potential harmful immune attacks raised against the semi-allogeneic fetus. In addition, HLA-G genetic variants are associated with both membrane-bound and soluble forms of HLA-G, and, in some studies, with preeclampsia. In this review, a genetic contribution from the mother, the father, and the fetus, together with the presence and function of various immune cells of relevance in pregnancy are reviewed in relation to HLA-G and preeclampsia.

• HLA class Ib
• HLA-E
• HLA-F
• HLA-G
• immune cells
• preeclampsia

• +3187A/G
• 3′UTR
• HLA-G
• Preeclampsia
• SNP

Human leukocyte antigen G (HLA-G) belongs to the family of non-classical HLA class I genes, located within the major histocompatibility complex (MHC). HLA-G has been the target of most recent research regarding the function of class I non-classical genes. The main features that distinguish HLA-G from classical class I genes are (a) limited protein variability, (b) alternative splicing generating several membrane bound and soluble isoforms, (c) short cytoplasmic tail, (d) modulation of immune response (immune tolerance), and (e) restricted expression to certain tissues. In the present work, we describe the HLA-G gene structure and address the HLA-G variability and haplotype diversity among several populations around the world, considering each of its major segments [promoter, coding, and 3′ untranslated region (UTR)]. For this purpose, we developed a pipeline to reevaluate the 1000Genomes data and recover miscalled or missing genotypes and haplotypes. It became clear that the overall structure of the HLA-G molecule has been maintained during the evolutionary process and that most of the variation sites found in the HLA-G coding region are either coding synonymous or intronic mutations. In addition, only a few frequent and divergent extended haplotypes are found when the promoter, coding, and 3′UTRs are evaluated together. The divergence is particularly evident for the regulatory regions. The population comparisons confirmed that most of the HLA-G variability has originated before human dispersion from Africa and that the allele and haplotype frequencies have probably been shaped by strong selective pressures.

• 1000Genomes Project
• HLA-G
• gene structure and diversity
• haplotypes
• non-classical HLA
• polymorphisms
• selective pressure
• variability

• HLA class Ib
• HLA-G
• MHC
• human reproduction
• pregnancy complications

• Animals
• Gene Expression Regulation
• HLA-G Antigens/genetics
• HLA-G Antigens/immunology
• HLA-G Antigens/metabolism
• Humans
• Immune Tolerance
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/metabolism
• Receptors, Immunologic/metabolism

Human leukocyte antigen-G (HLA-G) is a non-classical HLA class I molecule that differs from classical HLA class I molecules by low polymorphism and tissue distribution. HLA-G is a tolerogenic molecule with an immune-modulatory and anti-inflammatory function on both innate and adaptative immunity. This peculiar characteristic of HLA-G has led to investigations of its role in pathological conditions in order to define possible uses in diagnosis, prevention and treatment. In recent years, HLA-G has been shown to have an important implication in different inflammatory and autoimmune diseases, pregnancy complications, tumor development and aggressiveness, and susceptibility to viral infections. In fact, HLA-G molecules have been reported to alternate at both genetic and protein level in different disease situations, supporting its crucial role in pathological conditions. Specific pathologies show altered levels of soluble (s)HLA-G and different HLA-G gene polymorphisms seem to correlate with disease. This review aims to update scientific knowledge on the contribution of HLA-G in managing pathological conditions.

• Human leukocyte antigen-G
• Pathology
• Prognosis
• Diagnosis
• Treatment
• Marker