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Background: JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors. Methods: Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS). Results: Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry. Conclusion: JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740). [ABSTRACT FROM AUTHOR]

Objectives: To investigate the relationship between hsa_circ_0051326 and HLA-G expression in the blood of patients with pre-eclampsia. Material and methods: Real-time PCR (qRT-PCR) was used to detect the hsa_circ_0051326 expression level. Enzyme-linked immunosorbent assay (ELISA), qRT-PCR, and western blotting were used to detect HLA-G expression in blood in 50 patients with pre-eclampsia and 50 normal pregnant women. Results: HLA-G protein expression level was decreased significantly in the blood of patients with pre-eclampsia. hsa_circ_0051326 and HLA-G mRNA in blood were decreased significantly in the pre-eclampsia patients compared with normal pregnant women. There was a positive correlation between the expression of serum hsa_circ_0051326 with HLA-G mRNA. Conclusions: Serum hsa_circ_0051326 was a new diagnostic biomarker for pre-eclampsia with equivalent efficiency of HLA-G. Maternal serum hsa_circ_0051326 level may pre-diagnose potentially pre-eclampsia before delivery. [ABSTRACT FROM AUTHOR]

Objective To investigate the mechanism of human leukocyte antigen-G (HLA-G) expression and T cells activation in triple-negative breast cancer(TNBC) cells to exert immunosuppressive function. Methods From three groups of breast cancer cell lines（MDA-MB-231，HCC1937， MDA-MB-468）,real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were detected and screened that the breast cancer cell line was HCC1937,which with high expression of HLA-G, and low expression of fibrinogen-like protein 1 (FGL1), programmed death factor ligand 1 (PD-L1), as well as sialic acid-binding immunoglobulin-like lectin 15 (SIGLEC15) . HCC1937 cells were divided into NC group (control group) and KD group (knockdown group), and RNA interference (RNAi) lentiviral vectors were constructed and transfected into KD cells to knock down HLA-G gene, and the verification was carried out. HCC1937 cells were treated with HLA-G antibody blocking/nonblocking, and Jurkat cells were treated with CD3 and CD28 activation/non-activation, respectively, and the two types of cells were co-cultured into 8 groups: NC--, KD--, NC+-, KD+-, NC-+, KD-+, NC++, and KD++ groups. Cell scratch assay, MTT and ELISA method were used to detect cell migration rate, proliferation rate, and interferon (IFN)-γ and interleukin (IL)-2 levels in cell supernatants, respectively. Results RT-qPCR showed that the HLA-G gene was successfully knocked down in HCC1937 cells. Compared with the NC++ group, the migration rate of the KD++ group was significantly increased (P＜0.05), but there was no statistical difference in the cell proliferation rate between each pair of co-culture groups (P＞0.05). The concentration of IFN-γ in the KD++ group was lower than that in the NC++ group and the NC-+ group (P＜0.05), but there was no significant difference in the concentration of IL-2 between each pair of co-culture groups (P＞0.05). Conclusion HLA-G in TNBC cells may promote the secretion of IFN-γ by activing T cells, and IFN-γ can inhibit the immune function of T cells and promote tumor metastasis after HLA-G decreased."

Background: Human leukocyte antigen (HLA-G) plays a role in inflammation and autoimmune disorders. Variations in the HLA-G gene may have an effect on rheumatoid arthritis (RA). This study examined the impact of the polymorphisms +3142G>C and 14 bp ins/del on disease susceptibility, activity, severity, and responsiveness to therapy in a cohort of Egyptian RA patients. Methods: This case-control study was done on 75 patients with RA and 75 healthy people. The HLA-G rs1063320 (+3142G>C) and rs66554220 14 bp insertion (ins)/deletion (del) variants were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFP) and PCR technique, respectively. Results: Our finding didn't support an association between HLA-G 14 bp ins/del or the HLA-G +3142G>C variants and RA susceptibility. Subcutaneous nodules and prolonged morning stiffness were substantially related with the G allele of HLA-G +3142G>C. We used the disease activity score 28 (DAS-28) to look for a correlation between the HLA-G gene variations and disease activity, but we were unable to find one. Higher levels of C-reactive protein (CRP) and autoantibodies (anti-citrullinated protein antibodies (ACPA) and ACPA+ rheumatoid factor (RF)) have been linked to the GG genotype and the G allele of HLA-G +3142G>C. Higher rheumatoid arthritis severity scale (RASS) was found to be related to the HLAG+3142G>C polymorphism and RA severity. The 14 bp ins/del polymorphism and treatment response were found to be significantly correlated. Patients with the del/del genotype and the del allele had a significantly higher percentage of satisfactory response to therapy. Conclusion: The 14 bp ins/del and the +3142G>C of HLA-G gene didn’t appear to be associated with RA susceptibility in this studied group of RA patients. But in terms of autoantibody production, severity, clinical phenotype, and treatment responsiveness, it may operate as a genetic modulator of disease phenotype. In this regard, we propose that rather than serving as a risk factor for the onset of RA, these polymorphisms serve as disease modifiers. Treatment response and polymorphism were discovered. Patients with the del/del genotype and the del allele had a significantly higher percentage of satisfactory response to therapy [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA)-G plays a role in various physiological immunomodulatory functions. Aberrant HLA-G expression is observed in various disease states, including tumors, autoimmune disorders, and viral infections. The present study investigated the association between HLA-G functional gene polymorphisms (rs1736933 [-486 C > A], rs1049033 [+2018 C > T], 14 bp Insertion [Ins]/Deletion [Del] [+2961 Del > Ins], and rs1063320 [+3142 C > G]) and disease susceptibility, hepatocellular carcinoma (HCC) development, and hepatitis B surface antigen (HBsAg) clearance. Allele discrimination of the 3 SNPs (-486 C > A, +2018 C > T, +3142 C > G) was determined by a TaqMan 5′ exonuclease assay, while the 14 bp Ins/Del polymorphism was typed by fragment analysis using Genetic Analyzer and GeneMapper software. The above polymorphisms were analyzed for 325 Japanese hepatitis B virus (HBV) patients, 355 Japanese healthy subjects (Controls) as healthy controls, and 799 Japanese hepatitis C virus (HCV) patients as disease controls, respectively. The 14 bp Insertion allele was significantly more frequent in HBV patients than Controls (27.1 % vs 20.6 %, odds ratio [OR] 1.43, P = 0.005) but did not differ between HCV patients and Controls. Similar results were found for the rs1063320 G allele (38.9 % vs 26.3 %, OR 1.78, P < 0.001) and the rs1736933 T allele (32.2 % vs 26.9 %, OR 1.29, P = 0.034) between HBV and Controls. The rs1049033 T allele showed a weak but significant association with HCC development in the dominant model (OR 1.95, P = 0.04). Regarding HBsAg clearance, the A allele at rs1736933 was significantly correlated in the recessive model (OR 3.23, P = 0.003). This study revealed significant associations of HLA-G gene polymorphisms with disease susceptibility, HCC development, and HBsAg clearance in HBV patients. [ABSTRACT FROM AUTHOR]

Adenomyosis is a benign gynaecological disease caused by the growth of endometrial tissue in the myometrium that affects approximately 30 % of child-bearing-age women. We evaluated the levels of soluble human leukocyte antigen G (sHLA-G) in the serum of patients with adenomyosis before and after treatment. Serum samples of 34 patients with adenomyosis and 31 patients with uterine fibroids were collected before and after the operation and were analysed for sHLA-G levels by ELISA assay. The preoperative levels of serum sHLA-G in the adenomyosis group (28.05 ± 2.466 ng/ml) were significantly higher than those in the uterine fibroid group (18.53 ± 1.435 ng/ml) (P < 0.05). Serum sHLA-G levels in the adenomyosis group showed a decreasing trend at different time points after surgery (28.05 ± 14.38 ng/ml, 18.41 ± 8.34 ng/ml, and 14.45 ± 5.77 ng/ml). Adenomyosis patients who underwent total hysterectomy (n = 20) had a more significant decrease in sHLA-G levels in the early postoperative period (2 days post-operative) than those who underwent partial hysterectomy (n = 14). These results suggest that immunologic dysfunctions may be detected in patients with adenomyosis. [ABSTRACT FROM AUTHOR]

Gynaecological tumours that threaten the health of women, especially when advanced and recurrent, have remained mostly intractable to existing treatments. Therefore, new therapeutic targets are urgently needed. Human leukocyte antigen‐G (HLA‐G) is a nonclassical major histocompatibility complex class I molecule typically expressed in foetuses for protection against destruction by the maternal immune system. HLA‐G is also expressed under pathological conditions, such as in solid tumours, and may participate in tumour development and serve as a novel immune checkpoint in cancer. Furthermore, it is expressed in most gynaecological tumours. Therefore, inhibiting HLA‐G and its receptors to block the immune escape pathway could represent a new strategy in cancer immunotherapy. To the best of our knowledge, this review is the first to summarize recent research findings on HLA‐G in gynaecological oncology. We highlight the fact that HLA‐G is expressed in gynaecological tumour tissues, wherein it inactivates immune effectors involved in tumour progression. Further studies on HLA‐G in gynaecological oncology are needed to incorporate HLA‐G into the design and evaluation of immunotherapy for malignant gynaecological diseases. [ABSTRACT FROM AUTHOR]

This meta-analysis investigated the significant association between human leukocyte antigen (HLA)-G 14-bp insertion/deletion and +3142G>C polymorphisms with susceptibility to rheumatoid arthritis (RA). This relationship has been scrutinized in several studies, and the findings are controversial. The association studies related to HLA-G gene polymorphisms and RA were extracted from PubMed, Mendeley, ScienceDirect, and Google Scholar databases up to December 31, 2020. Finally, a total of 1516 cases and 1683 control samples were chosen from 7 published research articles for this meta-analysis. A significant association was evaluated using the pooled odds ratios (ORs) and 95% confidence intervals (CIs) under allelic, dominant, recessive, and additive models. Overall, there is absence of significant association between 14-bp ins/del polymorphism and RA (recessive model: OR = 1.012, 95% CI = 0.841–1.217, P = 0.900; dominant model: OR = 1.068, 95% CI = 0.919–1.241, P = 0.393; ins/ins vs. del/del: OR = 1.059, 95% CI = 0.861–1.303, P = 0.587). In the case of +3142G>C polymorphism, the recessive model (OR = 1.332, 95% CI = 1.083–1.640, P = 0.007) showed a significant association with RA susceptibility. When subgroup analysis was done by ethnicity, +3142G>C polymorphism was found to be significantly associated with RA susceptibility in the Asian population under the recessive model (OR = 1.450, 95% CI = 1.048–2.006, P = 0.025). This meta-analysis brings to light that there was no significant association between 14-bp ins/del polymorphism and RA susceptibility. Whereas, +3142G>C polymorphism was found to be significantly associated with susceptibility to RA.

This meta-analysis investigated the significant association between human leukocyte antigen (HLA)-G 14-bp insertion/deletion and +3142G>C polymorphisms with susceptibility to rheumatoid arthritis (RA). This relationship has been scrutinized in several studies, and the findings are controversial. The association studies related to HLA-G gene polymorphisms and RA were extracted from PubMed, Mendeley, ScienceDirect, and Google Scholar databases up to December 31, 2020. Finally, a total of 1516 cases and 1683 control samples were chosen from 7 published research articles for this meta-analysis. A significant association was evaluated using the pooled odds ratios (ORs) and 95% confidence intervals (CIs) under allelic, dominant, recessive, and additive models. Overall, there is absence of significant association between 14-bp ins/del polymorphism and RA (recessive model: OR = 1.012, 95% CI = 0.841-1.217, P = 0.900; dominant model: OR = 1.068, 95% CI = 0.919-1.241, P = 0.393; ins/ins vs. del/del: OR = 1.059, 95% CI = 0.861-1.303, P = 0.587). In the case of +3142G>C polymorphism, the recessive model (OR = 1.332, 95% CI = 1.083-1.640, P = 0.007) showed a significant association with RA susceptibility. When subgroup analysis was done by ethnicity, +3142G>C polymorphism was found to be significantly associated with RA susceptibility in the Asian population under the recessive model (OR = 1.450, 95% CI = 1.048-2.006, P = 0.025). This meta-analysis brings to light that there was no significant association between 14-bp ins/del polymorphism and RA susceptibility. Whereas, +3142G>C polymorphism was found to be significantly associated with susceptibility to RA. [ABSTRACT FROM AUTHOR]

Background Recurrent Pregnancy Loss (RPL) is a multifactorial disease that affects 1%-3% of couples. Since Human Leukocyte Antigen-G (HLA-G) gene is involved in fetal maternal immune tolerance, mutations in the HLA-G gene can affect the success rate of pregnancy. Objective The present study aims to investigate the haplotype effect of rs1736933 and rs2735022 polymorphisms found in the HLA-G gene on the RPL. Methods In this case-control study, participants were 100 women with RPL and 80 women with normal fertility in northwestern Iran. The HLA-G gene promoter was amplified by Polymerase Chain Reaction (PCR) method and sequenced. The genotype and allele frequencies of the two polymorphisms were compared between the two groups by using t-test in SPSS software version 22. Haplotype analysis was performed using PHASE 2.1 and Haploview 4.2 applications Findings C allele and CC genotype in rs2735022 polymorphism and the G allele and GG genotype in rs1736933 polymorphism showed a significant association with the RPL (P

Hepatitis C virus (HCV) infection is a global health problem. Several previous studies have addressed the role of host single-nucleotide polymorphisms (SNPs) in HCV infection. SNPs in the regulatory region of the human leukocyte antigen G (HLA-G) gene play an important role in several diseases. The objective of this study is to determine the association of HLA-G 3′untranslated region (UTR) polymorphisms with the susceptibility to chronic hepatitis C infection in the Chinese population. HLA-G 3′ UTR polymorphisms, which include 14-bp Ins/Del (rs371194629), +3003T/C (rs1707), +3010C/G (rs1710), +3027 A/C (rs17179101), +3035C/T (rs17179108), +3142 G/C (rs1063320), +3187 A/G (rs9380142) and + 3196C/G (rs1610696), were analyzed in 246 patients with chronic hepatitis C infection and 294 healthy individuals. The alleles, genotypes, and haplotypes were compared between chronic hepatitis C-infected subjects and controls using chi-square tests and logistic regression models. After a correction of multiple comparisons by the false discovery rate (FDR), the allele frequency of + 3196C, genotype frequencies of + 3187 AA and + 3196CC and frequency of the UTR-3 haplotype were significantly higher in the patients than in the control group (P < 0.05), whereas the frequencies of UTR-1 and UTR-2 haplotypes were significantly lower in the patients than in the control group (P < 0.05). After a correction of multiple comparisons by FDR, UTR-2 and UTR-3 maintained significant associations with chronic hepatitis C. This study indicates that HLA-G 3′UTR polymorphisms are associated with the susceptibility to chronic hepatitis C infection in the Chinese population. HLA-G 3′UTR may play an important role in risk modulation toward HCV infection. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic strategy to treat several hematological malignancies and non-hematological malignancies. However, graft-versus-host disease (GVHD) is a frequent and serious transplant-related complication which dramatically restrains the curative effect of allo-HSCT and a significant cause of morbidity and mortality in allogeneic HCT recipients. Effective prevention of GVHD mainly depends on the induction of peripheral immune tolerance. Human leukocyte antigen-G (HLA-G) is a non-classical MHC class I molecule with a strong immunosuppressive function, which plays a prominent role in immune tolerance. HLA-G triggers different reactions depending on the activation state of the immune cells and system. It also exerts a long-term immune tolerance mechanism by inducing regulatory cells. In this present review, we demonstrate the immunomodulatory properties of human leukocyte antigen-G and highlight the role of HLA-G as an immune regulator of GVHD. Furthermore, HLA-G could also serve as a good predictor of GVHD and represent a new therapeutic target for GVHD. [ABSTRACT FROM AUTHOR]

Background: The non-classical class I molecule human leukocyte antigen-G (HLA-G) has great potential to modulate the immune response. However, the mechanism underlying HLA-G induction remains unknown. Therefore, this study aimed to determine the factors that induce HLA-G expression on proximal tubular epithelial cells (pTECs) in renal transplanted allografts in vivo and in vitro. Methods: This study included 40 adult Japanese patients with renal allografts (35 and five patients with kidneys from living and deceased donors, respectively) who survived for at least 1 year. We evaluated HLA-G1/5 expression using an immunofluorescence method and investigated the induction of HLA-G expression in primary cultured human pTECs by cytokines and immunosuppressants. Results: The HLA-G expression was identified in the perinuclear region or on the basement membrane of pTECs of renal biopsy tissue in 12 (30%) of 40 patients at 2–4 weeks and at 1 year following transplantation. A reduction of 30% in the estimated glomerular filtration rate was lower in the HLA-G-positive group than that of the negative group (p = 0.016). Cox proportional hazard models also demonstrated that HLA-G1/5 expression on pTECs was an independent predictor of improved renal allograft function (hazard ratio, 0.189; 95% CI 0.041–0.850, p = 0.030). Interferon-beta was the most powerful inducer of HLA-G expression in vitro, whereas the immunosuppressants everolimus, tacrolimus, cyclosporin, and dexamethasone did not induce any expression. Conclusion: Unlike immunosuppressants, acquired HLA-G expression might confer long-term renal preservation effects in renal transplanted allografts. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen-G (HLA-G) has been widely acknowledged to play critical roles in fetal-maternal maintenance. However, the significance of using maternal serum sHLA-G to detect prenatal chromosomal abnormality has not been investigated. In China, prenatal screening using maternal α-fetoprotein (AFP), unconjugated estriol (uE3), and free β subunit human chorionic gonadotropin (β-hCG) in the second trimester has been widely applied. In this study, we evaluated the use of sHLA-G as a screening marker, compared with traditional second trimester prenatal screening. Serum samples from 1,019 singleton women in their second trimester were assessed. Among them, 139 infants were confirmed with trisomy 21 (T21) by karyotyping, 83 were confirmed with trisomy 18 (T18), and the remaining 797 infants had no abnormalities. The sHLA-G levels in maternal sera were significantly lower in pregnant women with T18 fetuses (median: 47.8 U/ml, range: 9.8–234.2 U/ml) and significantly higher in those with T21 fetuses (median: 125.7 U/ml, range: 28.7–831.7 U/ml), compared with the normal controls (median: 106.3 U/ml, range: 50.5–1136.4 U/ml) (p < 0.001). The risk values of the screening of T21 or T18 fetuses were assessed using mean and standard deviation log10 analyte multiples of median (MoM) which showed that the predictive values of sHLA-G were the same as free β-hCG, and superior to AFP and uE3 for T18 screening. Logistic regression analysis revealed that sHLA-G MoM was the highest risk factor associated with pregnant women carrying T18 fetuses [Exp(B): 171.26, 95% CI: 36.30–807.97, p < 0.001]. Receiver operating characteristic (ROC) analysis revealed that the area under ROC curve for sHLA-G MoM was 0.915 (95% CI, 0.871–0.959, p < 0.001), for AFP MoM was 0.796 (95% CI, 0.730–0.861, p < 0.001), for free β-hCG MoM was 0.881 (95% CI, 0.829–0.934, p < 0.001), and for uE3 MoM was 0.876 (95% CI, 0.828–0.923, p < 0.001) in the T18 group. sHLA-G MoM demonstrated the best sensitivity and negative predictive value. For the first time, our findings reveal that sHLA-G is a better second trimester screening marker for the detection of T18 fetuses and the combined application of sHLA-G with AFP, free β-hCG, and uE3 could improve clinical screening for T18 fetuses.

Human leukocyte antigen-G (HLA-G) has been widely acknowledged to play critical roles in fetal-maternal maintenance. However, the significance of using maternal serum sHLA-G to detect prenatal chromosomal abnormality has not been investigated. In China, prenatal screening using maternal α-fetoprotein (AFP), unconjugated estriol (uE3), and free β subunit human chorionic gonadotropin (β-hCG) in the second trimester has been widely applied. In this study, we evaluated the use of sHLA-G as a screening marker, compared with traditional second trimester prenatal screening. Serum samples from 1,019 singleton women in their second trimester were assessed. Among them, 139 infants were confirmed with trisomy 21 (T21) by karyotyping, 83 were confirmed with trisomy 18 (T18), and the remaining 797 infants had no abnormalities. The sHLA-G levels in maternal sera were significantly lower in pregnant women with T18 fetuses (median: 47.8 U/ml, range: 9.8–234.2 U/ml) and significantly higher in those with T21 fetuses (median: 125.7 U/ml, range: 28.7–831.7 U/ml), compared with the normal controls (median: 106.3 U/ml, range: 50.5–1136.4 U/ml) (p < 0.001). The risk values of the screening of T21 or T18 fetuses were assessed using mean and standard deviation log10 analyte multiples of median (MoM) which showed that the predictive values of sHLA-G were the same as free β-hCG, and superior to AFP and uE3 for T18 screening. Logistic regression analysis revealed that sHLA-G MoM was the highest risk factor associated with pregnant women carrying T18 fetuses [Exp(B): 171.26, 95% CI: 36.30–807.97, p < 0.001]. Receiver operating characteristic (ROC) analysis revealed that the area under ROC curve for sHLA-G MoM was 0.915 (95% CI, 0.871–0.959, p < 0.001), for AFP MoM was 0.796 (95% CI, 0.730–0.861, p < 0.001), for free β-hCG MoM was 0.881 (95% CI, 0.829–0.934, p < 0.001), and for uE3 MoM was 0.876 (95% CI, 0.828–0.923, p < 0.001) in the T18 group. sHLA-G MoM demonstrated the best sensitivity and negative predictive value. For the first time, our findings reveal that sHLA-G is a better second trimester screening marker for the detection of T18 fetuses and the combined application of sHLA-G with AFP, free β-hCG, and uE3 could improve clinical screening for T18 fetuses. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex class I (MHC I) molecule, and under physiological conditions, its expression is strictly restricted to the maternal–fetal interface and immune-privileged organs where HLA-G is expected to contribute to establishment and maintenance of immune tolerance. However, the expression of HLA-G has been found in various types of tumors, and the level of its expression frequently correlates with high-grade histology and poor prognosis, raising the possibility that it may play a negative role in tumor immunity. ILT2 and ILT4, present on a broad of immune cells, have been identified as the main receptors engaging HLA-G, and their interactions have been found to allow the conversion of effectors like NK cells and T cells to anergic or unresponsive state, activated DCs to tolerogenic state, and to drive the differentiation of T cells toward suppressive phenotype. Therefore, tumors can employ HLA-G to modulate the phenotype and function of immune cells, allowing them to escape immune attack. In this review, we discuss the mechanism underlying HLA-G expression and function, its role played in each step of the tumor-immunity cycle, as well as the potential to target it for therapeutic benefit.

Human Leukocyte Antigen-G (HLA-G), a polymorphic non-classical HLA (HLA-Ib) with immune-regulatory properties in cancers and infectious diseases, presents both membrane-bound and soluble (sHLA-G) isoforms. Polymorphism has implications in host responses to pathogen infections and in pathogenesis. Differential expression patterns of HLA-G/sHLA-G or its polymorphism seem to be related to different pathological conditions, potentially acting as a disease progression biomarker. Pathogen antigens might be involved in the regulation of both membrane-bound and sHLA-G levels and impact immune responses during co-infections. The upregulation of HLA-G in viral and bacterial infections induce tolerance to infection. Recently, sHLA-G was found useful to identify the prognosis of Coronavirus disease 2019 (COVID-19) among patients and it was observed that the high levels of sHLA-G are associated with worse prognosis. The use of pathogens, such as Plasmodium falciparum, as immune modulators for other infections could be extended for the modulation of membrane-bound HLA-G in COVID-19-infected tissues. Overall, such information might open new avenues concerning the effect of some pathogens such as parasites in decreasing the expression level of HLA-G to restrict pathogenesis in some infections or to influence the immune responses after vaccination among others.

Abstract Background Human leukocyte antigen (HLA)-G is an immune checkpoint molecule, which expression in cervical cancer cells enables them to escape immunosurveillance. To date, limited information has been published on the association of HLA-G genetic background in malignant cells with levels of HLA-G expression and the clinical outcome of patients. Methods We investigated the influence of the HLA-G 14 bp In/Del (rs66554220) and + 3142C/G (rs1063320) polymorphisms in 130 cases of HPV16 infection, 130 cases of HPV18 infection and 185 age-matched, unrelated, HPV-negative, and cytologically normal Chinese Han women. Case-matched cervical biopsy tissues were evaluated by immunohistochemistry. Results Our findings show that the frequency of alleles, 14 bp In (38.5% vs 29.2%, OR = 1.52, P

Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex class I (MHC I) molecule, and under physiological conditions, its expression is strictly restricted to the maternal–fetal interface and immune-privileged organs where HLA-G is expected to contribute to establishment and maintenance of immune tolerance. However, the expression of HLA-G has been found in various types of tumors, and the level of its expression frequently correlates with high-grade histology and poor prognosis, raising the possibility that it may play a negative role in tumor immunity. ILT2 and ILT4, present on a broad of immune cells, have been identified as the main receptors engaging HLA-G, and their interactions have been found to allow the conversion of effectors like NK cells and T cells to anergic or unresponsive state, activated DCs to tolerogenic state, and to drive the differentiation of T cells toward suppressive phenotype. Therefore, tumors can employ HLA-G to modulate the phenotype and function of immune cells, allowing them to escape immune attack. In this review, we discuss the mechanism underlying HLA-G expression and function, its role played in each step of the tumor-immunity cycle, as well as the potential to target it for therapeutic benefit. [ABSTRACT FROM AUTHOR]

Objective: To explore the correlation between the distribution of 14bp polymorphism in exon 8 of human leukocyte antigen-G (HLA-G) gene in Hainan Li nationality and susceptibility to severe preeclampsia. Methods: 100 cases of severe preeclampsia inpatients (experimental group) admitted to our hospital from June 2018 to September 2019 were selected. Among them, 50 were Li and 50 were Han, and 100 were admitted to our hospital during the same period Normal pregnant women were the control group, including 50 cases of Li nationality and 50 cases of Han nationality. Venous blood was collected to detect the 14bp polymorphism in HLA-G gene exon 8, and the correlation between the 14bp polymorphism in HLA-G gene exon 8 and susceptibility to severe preeclampsia was analyzed. Results: There was a statistically significant difference in the 14-bp genotyping and allele frequency in HLA-G exon 8 of the Li ethnic group in the control group and the experimental group (P <0.05). The SBP and DBP of the Li 14-14 / 14bp typing, + 14bp / -14bp typing, and allele -14bp typing were lower in the experimental group than in the Han group in the experimental group (P <0.05), and the SBP of + 14bp / -14bp typing DBP was higher than that of Han patients in the experimental group (P <0.05). Binary Logistic Regression Analysis + 14bp / -14bp was associated with the incidence of severe preeclampsia in Li women in Hainan region (P <0.05). The -14bp / -14bp classification was a protective factor for severe preeclampsia in Li women in Hainan region (P <0.05). Conclusion: The HLA-G gene exon 8 carrying a 14bp deletion polymorphism in the Hainan Li nationality is associated with preeclampsia susceptibility and progression. [ABSTRACT FROM AUTHOR]

The immunosuppressive non-classical human leukocyte antigen-G (HLA-G) promotes transplant tolerance as well as viral immune escape. HLA-G expression is associated with regulatory elements targeting certain single nucleotide polymorphisms (SNPs) in the HLA-G 3 ′ untranslated region (UTR). Thus, we evaluated the impact of HLA-G 3′UTR polymorphisms as surrogate markers for BK polyomavirus (BKPyV) replication or nephropathy (PyVAN) and acute cellular and antibody mediated rejection (ACR/AMR) in 251 living-donor kidney-transplant recipient pairs. After sequencing of the HLA-G 3 ′ UTR, fourteen SNPs between +2960 and +3227 and the 14 bp insertion/deletion polymorphism, which arrange as UTR haplotypes, were identified. The UTR-4 haplotype in donors and recipients was associated with occurrence of BKPyV/PyVAN compared to the other UTR haplotypes. While the UTR-4 recipient haplotype provided protection against AMR, the UTR-2 donor haplotype was deleteriously associated with ACR/AMR. Deduction of the UTR-2/4 haplotypes to specific SNPs revealed that the +3003C variant (unique for UTR-4) in donors as well as in recipients is responsible for BKPyV/PyVAN and also provides protection against AMR; whereas the +3196G variant (unique for UTR-2) promotes allograft rejection. Thus, HLA-G 3′UTR variants are promising genetic predisposition markers both in donors and recipients that may help to predict susceptibility to either viral infectious complication of BKPyV or allograft rejection. [ABSTRACT FROM AUTHOR]

Objective: This study evaluated human leucocyte antigen-G gene polymorphisms in patients with periodontitis and healthy controls.Material and methods: The insertion/deletion polymorphism of 14 bp and a single nucleotide polymorphism (SNP) C > G on the position +3142 of the 3' untranslated region of the gene were analyzed in chronic periodontitis (n = 62), aggressive periodontitis (n = 24) patients and healthy individuals (n = 47).Results: Considering the 14 bp insertion/deletion, a significant deviation from Hardy-Weinberg expectations in the chronic periodontitis group was observed, but not in the other groups. No significant deviations were observed in patients and control groups considering the +3142 C > G SNP. A significant increased frequency of homozygotes for the 14 bp deletion allele was observed in the chronic periodontitis group as compared to controls. This group also presented a higher frequency of the deletion allele, which was marginally not significant. Concerning this polymorphism, no significant differences were observed between the aggressive periodontitis and healthy control groups. In addition, no significant differences were seen amongst patients and controls when considering the +3142 C > G frequencies.Conclusion: No differences were found amongst patients and controls when considering the +3142 C > G SNP haplotypes frequencies, but a significant increased frequency of homozygotes for the 14 bp deletion allele was observed in chronic periodontitis patients compared to healthy controls, suggesting a susceptibility role of this polymorphism in the pathogenesis of this condition. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the relationship between hsa&#95;circ&#95;0051326 and HLA-G expression in the blood of patients with pre-eclampsia., Material and Methods: Real-time PCR (qRT-PCR) was used to detect the hsa&#95;circ&#95;0051326 expression level. Enzyme-linked immunosorbent assay (ELISA), qRT-PCR, and western blotting were used to detect HLA-G expression in blood in 50 patients with pre-eclampsia and 50 normal pregnant women., Results: HLA-G protein expression level was decreased significantly in the blood of patients with pre-eclampsia. hsa&#95;circ&#95;0051326 and HLA-G mRNA in blood were decreased significantly in the pre-eclampsia patients compared with normal pregnant women. There was a positive correlation between the expression of serum hsa&#95;circ&#95;0051326 with HLA-G mRNA., Conclusions: Serum hsa&#95;circ&#95;0051326 was a new diagnostic biomarker for pre-eclampsia with equivalent efficiency of HLA-G. Maternal serum hsa&#95;circ&#95;0051326 level may pre-diagnose potentially pre-eclampsia before delivery.

Oral squamous cell carcinoma (OSCC) is a common malignancy of the oral and maxillofacial regions. MicroRNAs (miRs) are a group of endogenous small noncoding RNAs that inhibit gene expression by binding to the mRNA of target genes, and serve important roles in numerous biological processes. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect gene and protein expression levels, respectively. Cell proliferation, migration and invasion were detected using MTT, wound healing and Matrigel assays, respectively. The association between miR-148a and human leukocyte antigen-G (HLA-G) was analyzed using Targetscan and Luciferase reporter assays. In the present study, miR-148a was revealed to be significantly downregulated in OSCC cells. To further investigate the functions of miR-148a in OSCC, the viability, migration, and invasive abilities of SCC-9 cells were investigated following transfection with miR-148a mimics or miR-148a inhibitor. It was revealed that transfection with miR-148a mimics significantly reduced the viability, migration and invasion of cells, whereas miR-148a inhibitor significantly enhanced these properties. In addition, HLA-G was identified as a direct target of miR-148a and demonstrated to be downregulated in OSCC cells. Furthermore, it was revealed that transfection with miR-148a mimics decreased the expression levels of HLA-G mRNA and protein in SCC-9 cells, whereas transfection with miR-148a inhibitor increased the expression of HLA-G mRNA and protein. The results indicated that there was an association between miR-148a and HLA-G expression, and suggested that miR-148a may be a potential target in the treatment of OSCC. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen-G (HLA-G) is highly expressed in numerous solid tumor cell types and has important roles in protecting tumor cells from host immune recognition and destruction. DNA methylation modification, which may regulate gene expression, is aberrant in numerous tumor cell types. However, whether the high expression of HLA-G in tumor cells is induced by aberrant DNA methylation has remained elusive. In the present study, HLA-G, DNA methyltransferase (DNMT) and ten-eleven translocation (TET) expression, as well as the DNA methylation level of HLA-G, were assessed in the HBL-100 breast cell line and the MCF-7 breast cancer cell line. The influence of TET on the expression and DNA methylation levels of HLA-G in MCF-7 was assessed through treatment with the TET inhibitor dimethyloxallyl glycine (DMOG). The results indicated that HLA-G expression was significantly greater in MCF-7 than that in HBL-100 cells; however, the DNA methylation level of HLA-G was lower in MCF-7 than that in HBL-100 cells. Furthermore, in MCF-7 cells, DNMT1 and DNMT3a were expressed at lower levels and TET2 was expressed at higher levels than in HBL-100 cells. Treatment with DMOG significantly decreased HLA-G expression, while increasing the DNA methylation level of HLA-G in MCF-7. In conclusion, the results indicated that overexpression of HLA-G in MCF-7 cells was induced by DNA methylation modification. The lower DNMT1 and DNMT3a and higher TET2 expression levels may be responsible for the abnormal DNA methylation of HLA-G in MCF-7. Treatment with TET inhibitor prevented aberrant HLA-G expression and DNA methylation in MCF-7. The present study may provide potential targets for novel anti-cancer drugs. [ABSTRACT FROM AUTHOR]

Introduction: Circulating soluble programmed death 1 (PD-1), neuropilin 1 (NRP-1) and human leukocyte antigen-G (HLA-G) take part in modulating immune tolerance causing disturbances in the molecular mechanisms responsible for maintenance of balance between effector and regulatory components of the immune system. Since their cell-surface expression levels were found to be changed in lesional and/or non-lesional skin of psoriatic patients, analysis of soluble PD-1, NRP-1 and HLA-G concentrations sheds more light on their role in detecting unbalanced immune tolerance in psoriasis. Aim: To assess soluble PD-1, NRP-1 and HLA-G concentrations in psoriasis. Material and methods: The study included 57 psoriatic patients and 29 controls. Duration of psoriasis was in the range 1 to 55 years; the median was 19 years. The plasma concentrations of soluble HLA-G (sHLA-G), soluble NRP-1 (sNRP-1) and soluble PD-1 (sPD-1) were examined using the ELISA method. Severity of the skin lesions was assessed by means of Psoriasis Area Severity Index (PASI), body surface area (BSA) and Physician Global Assessment (PGA). Results: Psoriasis Area Severity Index in the studied group was in the range 3 to 43; the median was 12. Body surface area was in the range 2-75%; the median was 15%. The median value of PGA was 3. Soluble NRP concentration was significantly higher in the psoriatic patients (median: 1.59 pg/ml; range: 0.67-2.62 pg/ml) than in the control group (median: 1.35 pg/ml; range: 0.05-2.61 pg/ml) (p = 0.010). Soluble PD-1 and sHLA-G concentrations were not significantly different between the studied and control groups (p = 0.094 and p = 0.482, respectively). Conclusions: Increased concentrations of sNRP-1 and unchanged values of sHLA-G and sPD-1 concentrations may be indicative of impaired immune tolerance mechanisms in psoriasis. [ABSTRACT FROM AUTHOR]

Women with scleroderma (SSc) maintain significantly higher quantities of persisting fetal microchimerism (FMc) from complete or incomplete pregnancies in their peripheral blood compared to healthy women. The non-classical class-I human leukocyte antigen (HLA) molecule HLA-G plays a pivotal role for the implantation and maintenance of pregnancy and has often been investigated in offspring from women with pregnancy complications. However data show that maternal HLA-G polymorphisms as well as maternal soluble HLA-G (sHLA-G) expression could influence pregnancy outcome. Here, we aimed to investigate the underlying role of maternal sHLA-G expression and HLA-G polymorphisms on the persistence of FMc. We measured sHLA-G levels by enzyme linked immunosorbent assay in plasma samples from 88 healthy women and 74 women with SSc. Male Mc was quantified by DYS14 real-time PCR in blood samples from 58 women who had previously given birth to at least one male child. Furthermore, eight HLA-G 5′URR/3′UTR polymorphisms, previously described as influencing HLA-G expression, were performed on DNA samples from 96 healthy women and 106 women with SSc. Peripheral sHLA-G was at lower concentration in plasma from SSc (76.2 ± 48.3 IU/mL) compared to healthy women (117.5 ± 60.1 IU/mL, p

Human leukocyte antigen (HLA)-G, a HLA class Ib molecule, interacts with receptors on lymphocytes such as T cells, B cells, and natural killer cells to influence immune responses. Unlike classical HLA molecules, HLA-G expression is not found on all somatic cells, but restricted to tissue sites, including human bronchial epithelium cells (HBEC). Individual variation in HLA-G expression is linked to its genetic polymorphism and has been associated with many pathological situations such as asthma, which is characterized by epithelium abnormalities and inflammatory cell activation. Studies reported both higher and equivalent soluble HLA-G (sHLA-G) expression in different cohorts of asthmatic patients. In particular, we recently described impaired local expression of HLA-G and abnormal profiles for alternatively spliced isoforms in HBEC from asthmatic patients. sHLA-G dosage is challenging because of its many levels of polymorphism (dimerization, association with β2-microglobulin, and alternative splicing), thus many clinical studies focused on HLA-G single-nucleotide polymorphisms as predictive biomarkers, but few analyzed HLA-G haplotypes. Here, we aimed to characterize HLA-G haplotypes and describe their association with asthmatic clinical features and sHLA-G peripheral expression and to describe variations in transcription factor (TF) binding sites and alternative splicing sites. HLA-G haplotypes were differentially distributed in 330 healthy and 580 asthmatic individuals. Furthermore, HLA-G haplotypes were associated with asthmatic clinical features showed. However, we did not confirm an association between sHLA-G and genetic, biological, or clinical parameters. HLA-G haplotypes were phylogenetically split into distinct groups, with each group displaying particular variations in TF binding or RNA splicing sites that could reflect differential HLA-G qualitative or quantitative expression, with tissue-dependent specificities. Our results, based on a multicenter cohort, thus support the pertinence of HLA-G haplotypes as predictive genetic markers for asthma.

Background. Immunosuppression at the feto-maternal interface is crucial for a successful pregnancy outcome. Human leukocyte antigen-G (HLA-G) seems to be a major contributor to fetal tolerance. The HLA-G expression is seen in cytotrophoblasts and in maternal blood. Fetal HLA-G acts on decidual antigen-presenting cells (APCs), natural killers (NKs) and T cells. Recent findings revealed that defects in placentation and their consequences are associated with maternal HLA-G variants and their expression levels. Objectives. The objective of this article is to investigate the relationship between fetal HLA-G alleles and miscarriage, which has not been investigated to date. Material and methods. The present study includes 204 recurrent miscarriage (RM) cases who were admitted to our clinic between 2012 and 2016. Twenty-eight miscarriage products without maternal cell contamination and any known pathology were analyzed by HLA-G typing. In addition, 3' untranslated region (UTR) 14-base pair (bp) insertion/deletion polymorphism was also investigated by Sanger sequencing. Results. For our population, the most frequent HLA-G type was G*01:01, both in the study group (30.3%) and in the control group (47%). The study revealed that the G*01:04 allele was significantly associated with miscarriage (p = 0.007). The 3' UTR 14bp deletion was more frequent in the miscarriage group, but there was no significant correlation. Conclusions. HLA-G alleles seem to be related with miscarriage and should be considered in RM cases. [ABSTRACT FROM AUTHOR]

Women with scleroderma (SSc) maintain significantly higher quantities of persisting fetal microchimerism (FMc) from complete or incomplete pregnancies in their peripheral blood compared to healthy women. The non-classical class-I human leukocyte antigen (HLA) molecule HLA-G plays a pivotal role for the implantation and maintenance of pregnancy and has often been investigated in offspring from women with pregnancy complications. However data show that maternal HLA-G polymorphisms as well as maternal soluble HLA-G (sHLA-G) expression could influence pregnancy outcome. Here, we aimed to investigate the underlying role of maternal sHLA-G expression and HLA-G polymorphisms on the persistence of FMc. We measured sHLA-G levels by enzyme linked immunosorbent assay in plasma samples from 88 healthy women and 74 women with SSc. Male Mc was quantified by DYS14 real-time PCR in blood samples from 58 women who had previously given birth to at least one male child. Furthermore, eight HLA-G 5'URR/3'UTR polymorphisms, previously described as influencing HLA-G expression, were performed on DNA samples from 96 healthy women and 106 women with SSc. Peripheral sHLA-G was at lower concentration in plasma from SSc (76.2 ± 48.3 IU/mL) compared to healthy women (117.5 ± 60.1 IU/mL, p < 0.0001), independently of clinical subtypes, autoantibody profiles, disease duration, or treatments. Moreover, sHLA-G levels were inversely correlated to FMc quantities (Spearman correlation, p < 0.01). Finally, women with SSc had lower sHLA-G independently of the eight HLA-G 5'URR/3'UTR polymorphisms, although they were statistically more often homozygous than heterozygous for HLA-G polymorphism genotypes -716 (G/T), -201 (G/A), 14 bp (ins/del), and +3,142 (G/A) than healthy women. In conclusion, women with SSc display less sHLA-G expression independently of the eight HLA-G polymorphisms tested. This decreased production correlates with higher quantities of persisting FMc commonly observed in blood from SSc women. These results shed some lights on the contribution of the maternal HLA-G protein to long-term persistent fetal Mc and initiate new perspectives in this field. [ABSTRACT FROM AUTHOR]

The Human Leukocyte Antigen-G (HLA-G) is a MHC-class Ib molecule with robust immunomodulatory properties; in transplant, it inhibits cytotoxic activity of immune cells and thus has a pivotal role in protecting the allograft from immune attack. The present review details a 10-year experience investigating the influence of HLA-G on heart transplantation, allograft rejection and cardiac allograft vasculopathy development. Exploration of HLA-G in transplantation began with the initial findings of its increased expression in allograft hearts. Since then, HLA-G has been recognized as an important factor in transplant immunology. We discuss inducers of HLA-G expression, and the importance of HLA-G as a potential biomarker in allograft rejection and heart failure. We also highlight the importance of polymorphisms and how they may influence both HLA-G expression and clinical outcomes. There remains much to be done in this field, however we hope that findings from our group and other groups will ignite interest and facilitate further expansion of HLA-G research in transplantation. [ABSTRACT FROM AUTHOR]

The focus of the current study was a G protein-coupled estrogen receptor (GPER)/microRNA (miR)-148a/human leukocyte antigen-G (HLA-G) signaling pathway in ovarian endometriosis. Reverse transcription-quantitative polymerase chain reaction was performed to analyze the changes in miR-148a expression. A MTT assay, flow cytometry and caspase-3/9 activity assays were performed to analyze cell proliferation, apoptosis and caspase-3/9 activity levels, respectively. Protein expression was measured using western blot analysis. In tissue samples from healthy controls, and patients with endometriosis and endometriosis-associated ovarian cancer, the expression of miR-148a was lower in in endometriosis and EAOC samples compared with healthy controls. Overexpression of miR-148a using miR mimics significantly decreased proliferation, promoted apoptosis, increased the Bcl-2 associated X apoptosis regulator (Bax)/Bcl-2 apoptosis regulator (Bcl-2) ratio and caspase3/9 activity, and suppressed HLA-G protein expression in Hs 832(C).T cells. miR-148a downregulation using miR inhibitor significantly increased cell viability, inhibited apoptosis, and reduced the Bax/Bcl-2 ratio and caspase3/9 activity, and induced HLA-G protein expression in Hs 832(C).T cells. The GPER inhibitor, G15, suppressed GPER protein expression, upregulated miR-148a expression, decreased cell proliferation, promoted apoptosis, increased the Bax/Bcl-2 ratio and caspase3 activity, and suppressed HLA-G protein expression in Hs 832(C).T cells. The findings indicate that GPER/miR-148a/HLA-G signaling pathway may mediates the development of ovarian endometriosis and may become a potential therapeutic target for the treatment of endometriosis. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA)-G, a HLA class Ib molecule, interacts with receptors on lymphocytes such as T cells, B cells, and natural killer cells to influence immune responses. Unlike classical HLA molecules, HLA-G expression is not found on all somatic cells, but restricted to tissue sites, including human bronchial epithelium cells (HBEC). Individual variation in HLA-G expression is linked to its genetic polymorphism and has been associated with many pathological situations such as asthma, which is characterized by epithelium abnormalities and inflammatory cell activation. Studies reported both higher and equivalent soluble HLA-G (sHLA-G) expression in different cohorts of asthmatic patients. In particular, we recently described impaired local expression of HLA-G and abnormal profiles for alternatively spliced isoforms in HBEC from asthmatic patients. sHLA-G dosage is challenging because of its many levels of polymorphism (dimerization, association with β2-microglobulin, and alternative splicing), thus many clinical studies focused on HLA-G single-nucleotide polymorphisms as predictive biomarkers, but few analyzed HLA-G haplotypes. Here, we aimed to characterize HLA-G haplotypes and describe their association with asthmatic clinical features and sHLA-G peripheral expression and to describe variations in transcription factor (TF) binding sites and alternative splicing sites. HLA-G haplotypes were differentially distributed in 330 healthy and 580 asthmatic individuals. Furthermore, HLA-G haplotypes were associated with asthmatic clinical features showed. However, we did not confirm an association between sHLA-G and genetic, biological, or clinical parameters. HLA-G haplotypes were phylogenetically split into distinct groups, with each group displaying particular variations in TF binding or RNA splicing sites that could reflect differential HLA-G qualitative or quantitative expression, with tissue-dependent specificities. Our results, based on a multicenter cohort, thus support the pertinence of HLA-G haplotypes as predictive genetic markers for asthma. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen-G (HLA-G) is a non-classical HLA molecule, predominantly expressed in cytotrophoblast cells to protect the fetus during pregnancy. Notably, a high frequency of HLA-G expression has been observed in a wide variety of cancer types in previous studies. Furthermore, HLA-G expression in cancer has been considered to be detrimental, since it can protect cancer cells from natural killer cell cytotoxic T lymphocyte-mediated destruction, promote tumor spreading and shorten the survival time of patients by facilitating tumor immune evasion. In addition, HLA-G polymorphisms have been investigated in numerous types of cancer and are considered as risk factors and predictive markers of cancer. This review focuses on HLA-G expression and its polymorphisms in cancer, analyzing the mechanisms of HLA-G in promoting cancer development, and evaluating the potential and value of its clinical application as a diagnostic and prognostic biomarker, or even as a prospective therapeutic target in certain types of tumors. [ABSTRACT FROM AUTHOR]

Preeclampsia remains enigmatic and responsible for vast maternal and fetal morbidity and mortality worldwide. Our objective was to assess the strength of the effect of the 14 bp deletion/insertion polymorphism in exon 8 of the 3′UTR region of the human leukocyte antigen-G (HLA-G) gene on preeclampsia risk across different populations. A systematic review by a meta-analysis was performed to summarize the scattered epidemiologic evidence, which remains inconclusive and controversial. A systematic literature search according to the PRISMA guidelines was conducted to screen relevant publications. Odds ratio and corresponding 95% confidence interval were estimated to measure the magnitude of the association between this polymorphism and preeclampsia onset. Thirty studies comprising 9402 subjects were eligible. Pooled estimates suggested that both fetal and paternal insertion variants were significantly associated with increased odds of this disease. Nevertheless, the presence of the 14 bp insertion sequence in mothers does not seem to increase the risk of preeclampsia. Moreover, the results of subgroup analysis suggested that the fetal, maternal, and paternal polymorphism has a significant deleterious impact on the preeclampsia risk in the Asian population. In addition, the significant association between the paternal polymorphism and preeclampsia in primigravida was observed in the pooled estimation with a small sample size. By summarizing the amount of significant evidence, our study nominated this polymorphism as a potential biomarker for early risk stratification for Asians. Further large-scale validation is needed to establish fully solid and conclusive evidence for the impact of the insertion polymorphism on preeclampsia risk. • Maternal insertion is not significantly associated with preeclampsia risk. • Both fetal and paternal insertions significantly associate with the disease risk. • This polymorphism shows a significant deleterious impact on Asians. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA)-G plays a crucial role in conferring fetal–maternal tolerance and ensuring a successful pregnancy. CD56bright natural killer (NK) cells accumulate at the maternal decidua in large numbers during pregnancy and are found in direct contact with fetal trophoblasts. There are increasing evidences that decidual NK (dNK) cells are crucial for pregnancy. However, the regulation of dNK cells is mostly unknown. Here, we provide evidences that the secretion function of dNK cells in recurrent spontaneous abortion was impaired, which led to the impairment of the proinvasion and proangiogenesis functions of dNK cells. Decreased HLA-G expression induced by the transfection of miR-133a mimics in HTR-8/SVneo affected the secretory functions of dNK cells. Thus, our data revealed that the functions of dNK cells could be suppressed by the decreased expression of HLA-G and suggest a possible mechanism of recurrent miscarriage.

The expression modulation of the immunosuppressive non-classical Human leukocyte antigen-G (HLA-G) molecule and its soluble isoforms is an immune evasion strategy being deployed by cytomegalovirus (CMV). The +3142 C>G single nucleotide polymorphism (SNP) located within the 3' untranslated region (3'UTR) is of crucial importance for the regulation of HLA-G expression. Therefore, we analyzed the influence of the +3142 C>G HLA-G SNP on the occurrence of CMV infection in a cohort of 178 living-donor kidney recipients and their 178 corresponding donors. In addition, soluble HLA-G (sHLA-G) levels were quantified before and after transplantation. The presence of the HLA-G +3142 CC genotype in recipients, but not donors of our cohort as along with elevated sHLA-G levels (≥6.1 ng/mL) were associated with higher susceptibility to CMV infection after transplantation. Our results provided evidence that (i) HLA-G is implicated in the establishment of CMV after living-donor kidney transplantation and (ii) recipient HLA-G +3142 CC genotype and sHLA-G concentration levels could represent important predictive risk markers for CMV infection. [ABSTRACT FROM AUTHOR]

Esophageal cancer (EC) is a common malignant tumor type, and esophageal squamous cell carcinoma (ESCC) accounts for the majority of EC cases. Previous studies have reported that microRNA (miR)-148a is downregulated in patients with recurrent EC. The human leukocyte antigen-G (HLA-G) is expressed to a high level in primary ESCC tissues and is associated with prognosis. A previous luciferase assay indicated that HLA-G is a target of miR-148a regulation. The aim of the current study was to investigate the expression level of miR-148a in primary ESCC. The regulatory role of miR-148a in HLA-G expression and cell proliferation in ESCC cells was also investigated. The relative expression level of miR-148a was compared between ESCC tumor tissues and adjacent normal tissues. The human ESCC cell line EC9706 was transfected with miR-148a mimic, non-homologous RNA duplex (negative control; NC) or empty vector (blank control; BC). Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to assess the level of HLA-G expression. The cells were stained with Annexin V-fluorescein isothiocyanate/propidium iodide and cell apoptosis was evaluated by flow cytometry. The level of miR-148a expression was significantly lower in primary ESCC tissues compared with adjacent normal tissues (P<0.01). In EC9706 cells transfected with miR-148a mimic, the rate of apoptosis was increased ~13-fold when compared with BC cells (P<0.01). Furthermore, the mRNA level of HLA-G was significantly reduced in cells transfected with miR-148a mimic (P<0.01). The protein levels of HLA-G were also notably decreased. Transfection with non-homologous RNA duplex did not influence the rate of cell apoptosis or expression of HLA-G when compared with the BC group. In conclusion, miR-148a was indicated to be involved in carcinogenesis in primary ESCC through the regulation of HLA-G expression. The current results suggest that miR-148a is a potential biomarker of ESCC. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen-G (HLA-G) presents inhibitory functions in immune cells and is located in a chromosomal region associated with systemic lupus erythematosus (SLE) susceptibility. Polymorphisms in 3′ untranslated region (3′UTR) of HLA-G gene may influence protein expression. To date, no study analyzing HLA-G polymorphism and expression in childhood-onset systemic lupus erythematosus (cSLE) has been conducted. Therefore, we investigated the influence of HLA-G 3′UTR polymorphisms in 50 cSLE patients and 144 healthy controls. For the expression analysis, the control group included 26 healthy individuals. No significant difference in allele, genotype, and haplotype frequencies was observed between patients and control group. However, both the 14 bp deletion allele (odds ratio [OR] = 2.76, 95% confidence interval [CI] = 1.17-6.52, P = .028) and the 14 bp deletion-deletion genotype (OR = 8.00, 95% CI = 1.57-40.65, P = .006) showed an association with lupus nephritis. After Bonferroni correction, none P-value remained statistically significant. Regarding HLA-G expression, no significant difference was observed between plasma levels of cSLE patients (56.02 U/mL, interquartile range [IQR] = 37.54-75.41) and control group (49.2 U/mL, IQR = 27.84-154.4, P = .952). However, when the patients were stratified according to clinical manifestations, patients with hematological manifestations showed a lower plasma concentration of soluble HLA-G (sHLA-G) (47.08 U/mL, IQR = 34.15-61.56) than patients with no hematological manifestations (65.26 U/mL, IQR = 47.69-102.60, P = .013). These results suggest that HLA-G polymorphism has small effect on cSLE susceptibility and that sHLA-G may be involved in the pathogenesis of the disease. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to unravel the link between human leukocyte antigen-G untranslated region (HLA-G 3-UTR) single-nucleotide polymorphism (SNP) and preeclampsia by examining polymorphisms in HLA-G 3-UTR in preeclampsia patients and their newborns, as well as those of women with normal pregnancy and their newborns. Methods: Single pregnant mothers and their newborns at the Third Affiliated Hospital of Zhengzhou University, China, were divided into preeclampsia group (144 cases), and normal pregnancy group (122 cases). Blood samples from the two groups were collected for DNA extraction, and the DNA samples were analyzed for HLA-G 3'-UTR SNP by polymerase chain reaction (RT-PCR) and direct sequencing method. Results: The frequency of CG genotype in HLA-G 3-UTR 3127 gene in the preeclampsia group was significantly lower, while the frequency of AA genotype in HLA-G 3-UTR 3172 gene in the preeclampsia group was significantly higher (p < 0.05) when compared with the normal pregnancy group. Furthermore, frequencies of the compatible genotype AA/AA (mothers/newborns) in HLA-G 3-UTR 3172 gene in the preeclampsia group were significantly higher relative to the normal pregnancy group (p< 0.05). Conclusion: These results suggest that when CC/GG is the compatible genotype in HLA-G 3-UTR 3127 gene of mothers/newborns, preeclampsia risk may decrease, but it may increase if the compatible genotype is AA/AA. Thus, SNP in HLA-G 3-UTR 3127 gene may be a protective factor against preeclampsia in Chinese Han pregnant women, while SNP in 3172 gene may be associated with susceptibility to preeclampsia. [ABSTRACT FROM AUTHOR]

Background. Major barriers in using classical FOXP3+ regulatory T cells (Tregs) in clinical practice are their low numbers in the circulation, the lack of specific cell surface markers for efficient purification and the loss of expression of Treg signature molecules and suppressive function after in vitro expansion or in a pro-inflammatory microenviroment. A surface molecule with potent immunosuppressive function is the human leukocyte antigen-G (HLA-G), which is normally expressed in placenta protecting the “semi-allogeneic” fetus from maternal immune attack. Because HLA-G expression is strongly regulated by methylation, we asked whether hypomethylating agents (HA) may be used in vitro to induce HLA-G expression on conventional T cells and convert them to Tregs. Methods. Human peripheral blood T cells were exposed to azacytidine/decitabine and analyzed for HLA-G expression and their in vitro suppressor properties. Results. HA treatment induces de novo expression of HLA-G on T cells through hypomethylation of the HLA-G proximal promoter. The HA-induced CD4+HLA-Gpos T cells are FOXP3 negative and have potent in vitro suppression function, which is dependent to a large extent, but not exclusively, on the HLA-G molecule. Converted HLA-Gpos suppressors retain their suppressor function in the presence of tumor necrosis factor (TNF) and preserve hypomethylated the HLA-G promoter for at least 2 days after azacytidine exposure. Decitabine-treated T cells suppressed ex vivo the proliferation of T cells isolated from patients suffering from graft-versus-host disease (GVHD). Discussion. We propose, in vitro generation of HLA-G–expressing T cells through pharmacological hypomethylation as a simple, Good Manufacturing Practice (GMP)-compatible and efficient strategy to produce a stable Treg subset of a defined phenotype that can be easily purified for adoptive immunotherapy. [ABSTRACT FROM AUTHOR]

Background Soluble human leukocyte antigen-G (sHLA-G) is a non-classical HLA class I molecule, exhibiting strong immunosuppressive properties by inducing the differentiation of T regulatory cells (Treg). Mesenchymal stem cells (MSCs) transplantation alleviates disease progression in systemic lupus erythematosus (SLE) patients. However, the underlying mechanisms are largely unknown. Objectives To explore whether sHLA-G is involved in upregulating effects of MSCs on Treg, which contributes to therapeutic effects of MSCs transplantation in SLE. Methods The serum sHLA-G levels of SLE patients and healthy controls were detected by ELISA. The percentages of peripheral blood CD4 + ILT2 +, CD8 + ILT2 +, CD19 + ILT2 + cells and Treg cells were examined by flow cytometry. Ten patients with active SLE, refractory to conventional therapies, were infused with umbilical cord derived MSCs (UC-MSCs) and serum sHLA-G was measured 24 h and 1 month after infusion. The mice were divided into three groups: C57BL/6 mice, B6.MRL- Fas lpr mice infused with phosphate buffer saline (PBS), and B6.MRL- Fas lpr mice infused with bone marrow MSCs (BM-MSCs). Then, the concentrations of serum Qa-2 were detected. Peripheral blood mononuclear cells (PBMCs) were isolated from SLE patients and co-cultured with UC-MSCs for 3 days at different ratios (50:1, 10:1, and 2:1) with or without HLA-G antibody, and the frequencies of CD4 + CD25 + Foxp3 + T cells were then determined by flow cytometry. Results The concentrations of serum sHLA-G were comparable between SLE patients and healthy controls. However, there was a negative correlation between sHLA-G levels and SLE disease activity index (SLEDAI) scores in active SLE patients (SLEDAI > 4). We found that serum sHLA-G levels were negatively correlated with blood urea nitrogen, serum creatinine and 24-hour urine protein in SLE patients. The sHLA-G levels were significantly lower in SLE patients with renal involvement than those without renal involvement. The expression of ILT2 on CD4 + T cells from SLE patients decreased significantly compared to that of healthy controls. A positive correlation between the frequencies of Treg and CD4 + ILT2 + T cells was found in SLE patients. The levels of sHLA-G increased 24 h post UC-MSCs transplantation. The concentrations of Qa-2 in BM-MSCs transplanted mice were significantly higher than those of control group. In vitro studies showed that MSCs increased the frequency of Treg cells in SLE patients in a dose-dependent manner, which was partly abrogated by the anti-HLA-G antibody. Conclusions Our results suggested that MSCs may alleviate SLE through upregulating Treg cells, which was partly dependent on sHLA-G. [ABSTRACT FROM AUTHOR]

A growing body of evidence indicates a possible involvement of HLA (human leukocyte antigen)-G antigens in rheumatoid arthritis (RA), mainly in the HLA-G dimeric isoform, the most active HLA-G form with the strongest immunosuppression, that showed an excellent anti-inflammatory effect in collagen-induced arthritis model mice. However, the relevance of HLA-G dimers in RA response to methotrexate (MTX) treatment is still unknown. We analyzed the HLA-G dimers' amount in plasma samples from early rheumatoid arthritis (ERA) patients before MTX therapy and evaluated the role of these molecules as biomarker of the different response to the treatment. Plasma sHLA-G levels were detected by ELISA, and HLA-G dimeric and monomeric forms were revealed by Western blot in 12 MTX responder (reaching DAS28 remission <2.6) and 8 MTX non-responder (DAS28 ≥5.1) patients before the therapy. The response to MTX was evaluated after 6 months of treatment. All ERA patients reaching remission showed higher plasma sHLA-G levels and the 78 kDa HLA-G dimeric form. Unresponsive ERA patients were characterized by lower plasma sHLA-G levels, and only one patient presented the 78 kDa HLA-G dimeric form (DAS28 5.1). Our preliminary results support the hypothesis that in ERA patients, sHLA-G and, in particular, the presence of the dimeric form in plasma samples before MTX therapy could be an a priori biomarker for the response to MTX treatment. [ABSTRACT FROM AUTHOR]

Background Hepatitis C virus ( HCV) is able to bypass the immune system modulating innate and adaptive immune response and blocking T helper 1 (Th1) cell production. Because the human leukocyte antigen ( HLA)-G molecule has immunomodulatory properties inhibiting the function and production of natural killer and cytotoxic lymphocyte T cells, as well as promoting shift from Th1 toward Th2 response, we hypothesized its involvement in susceptibility to HCV infection. Materials and Methods Considering that HLA-G mRNA expression has been reported to be under genetic control, an association study was conducted analyzing 800 base pairs upstream the ATG at the 5′upstream regulator region ( URR) and 850 base pairs from ATG to exon 3 and the 3′untranslated region ( UTR) of HLA-G gene in Italian HCV-positive patients and uninfected controls. Results Four 5′ URR polymorphisms (− 725C>G>T, − 509C>G, − 400G>A and − 398G>A), 7 polymorphisms at coding region (+ 15G>A, + 36G>A, + 243G>A, insC506, 531G>C, delA615 and 685G>A), the + 644G>T polymorphism, and 1 haplotype ( TTGTTCCIGAC) showed different frequency distributions between HCV patients and uninfected controls. Conclusion The results from our study suggest a possible involvement of HLA-G in the risk modulation toward HCV infection. [ABSTRACT FROM AUTHOR]

Human Leukocyte Antigen-G (HLA-G) is a non-classical class 1b protein, whose gene is located on chromosome 6 (6p21.31). HLA-G inhibits the immune cells’ cytotoxic activity by interacting with specific receptors on their membranes. Since it is a naturally occurring immune modulator, HLA-G has been investigated in transplantation. Indeed, a number of investigations reveal that HLA-G expression is influenced by genetic polymorphisms and in turn, those polymorphisms are associated with detrimental or beneficial outcomes in various pathological situations. The present review introduces the HLA-G molecule, the gene and its polymorphisms. It focuses on the expression of HLA-G and the role of polymorphisms primarily in heart transplant outcomes, secondarily in other transplant organs, as well as the role of the allograft and effect of medical therapy. We discuss the limitations in HLA-G transplant investigations and future directions. The immune inhibiting activity of HLA-G has a great deal of potential for its utilization in enhancing diagnostic, preventive and therapeutic strategies against rejection in the setting of transplantation. [ABSTRACT FROM AUTHOR]