sHLA-G Levels Research Articles

The synergy of morphokinetic parameters and sHLA-G in cleavage embryo enhancing implantation rates.

Objective: This study aimed to assess the relationship between implantation and soluble HLA-G (sHLA-G) expression in cleavage embryo culture medium (ECM) in conjunction with early developmental kinetics determined by time-lapse imaging (TLI). Methods: A retrospective, single-center study was conducted involving 238 embryos from 165 patients who underwent Frozen-thawed embryo transfer (FET) using autologous oocytes, with either single or double embryo transfer. TLI morphokinetic parameters (t2, t3, t4, t5, t6, t7, t8, cc2, s2, cc3, s3) of embryos were analyzed, and sHLA-G levels in D3 ECM were measured using an enzyme-linked immunosorbent assay (ELISA). A hierarchical classification model was developed to categorize embryos into five groups (A, B, C, D, E). The correlation between sHLA-G levels, TLI classification of embryos, and embryo implantation was investigated to establish a non-invasive method for evaluating implantation potential. Multivariate logistic regression analysis was performed to identify potential influencing factors, and receiver operating characteristic (ROC) curves were used to evaluate the predictive value for implantation. Results: Multivariate unconditional logistic regression analysis indicated that TLI parameters t5 and s3 and sHLA-G level in ECM were independent risk factors affecting embryo implantation. The implantation rate decreased from TLI classification A to E. The proposed classification model effectively assessed the implantation potential of embryos. The implantation rate was higher in the sHLA-G positive group compared to the sHLA-G negative group (p < 0.001). The expression of sHLA-G in D3 ECM, combined with the TLI classification model, accurately evaluated the implantation potential of embryos with an AUC of 0.876. Conclusion: The integration of cleavage kinetics and embryonic sHLA-G expression could reliably identify embryos with a high likelihood of successful implantation.

Immunomodulatory soluble HLA-G and HLA-E are associated with rapidly deteriorating CLAD and HCMV viremia after lung transplantation

Plasma-soluble (s)HLA-G and sHLA-E are immunoregulatory proteins that balance the activation of NKG2A+ immune cells. In lung-transplant recipients (LTRs), dysregulated NKG2A+ natural killer cell responses may result in high-level HCMV replication as well as chronic lung allograft dysfunction (CLAD), and especially the development of rapidly deteriorating CLAD is associated with high mortality. We thus analyzed the kinetics and function of sHLA-G and sHLA-E in follow-up samples of N=76 LTRs to evaluate whether these immunoregulatory proteins are associated with the risk for CLAD and high-level HCMV replication. Here, we demonstrate that rapidly deteriorating CLAD LTRs are hallmarked by continually low (<107 ng/mL) sHLA-G levels. In contrast, high sHLA-E levels were associated with the following development of high-level (>1000 copies/mL) HCMV episodes. Thus, sHLA-G and sHLA-E may serve as novel biomarkers for the development of rapidly deteriorating CLAD and high-level HCMV replication in LTRs.

How the Soluble Human Leukocyte Antigen-G levels in Amniotic Fluid and Maternal Serum Correlate with the Feto-Placental Growth in Uncomplicated Pregnancies.

Introduction: Trophoblast-derived angiogenic factors are considered to play an important role in the pathophysiology of various complications of pregnancy. Human Leukocyte Antigen-G (HLA-G) belongs to the non-classical human major histocompatibility complex (MHC-I) molecule and has membrane-bound and soluble forms. HLA-G is primarily expressed by extravillous cytotrophoblasts located in the placenta between the maternal and fetal compartments and plays a pivotal role in providing immune tolerance. The aim of this study was to establish a relationship between concentrations of soluble HLA-G (sHLA-G) in maternal serum and amniotic fluid at 16-22 weeks of gestation and the sonographic measurements of fetal and placental growth. Materials and methods: sHLA-G in serum and amniotic fluid, as well as fetal biometric data and placental volume and perfusion indices, were determined in 41 singleton pregnancies with no complications. The level of sHLA-G (U/mL) was tested with a sandwich enzyme-linked immunosorbent assay (ELISA) kit. Results: The sHLA-G levels were unchanged both in amniotic fluid and serum during mid-pregnancy. The sHLA-G level in serum correlated positively with amniotic sHLA-G level (β = 0.63, p < 0.01). Serum sHLA-G level was significantly correlated with abdominal measurements (β = 0.41, p < 0.05) and estimated fetal weight (β = 0.41, p < 0.05). Conversely, amniotic sHLA-G level and placental perfusion (VI: β = -0.34, p < 0.01 and VFI: β = -0.44, p < 0.01, respectively) were negatively correlated. A low amniotic sHLA-G level was significantly associated with nuchal translucency (r = -0.102, p < 0.05). Conclusions: sHLA-G assayed in amniotic fluid might be a potential indicator of placental function, whereas the sHLA-G level in serum can be a prognostic factor for feto-placental insufficiency.

Biomarker role of maternal soluble human leukocyte antigen G in pre-eclampsia: A meta-analysis.

Human leukocyte antigen-G (HLA-G) is a non-classical class I HLA molecule shown to regulate the immunomodulation of maternal immune cells to prevent fetal tissue destruction. Low levels of freely circulating maternal soluble HLA-G (sHLA-G) have been observed in pre-eclampsia, however, no pooled evidence exists. This meta-analysis aimed to generate pooled findings on the association of sHLA-G levels with pre-eclampsia and is the first study to perform a trimester-wise comparison of the levels of sHLA-G in preeclamptic cases and normal pregnant controls. The databases PubMed, Emba, Web of Science, and Google Scholar through May 31, 2023. Preeclamptic women were defined as cases and normal pregnancies as controls. Data on the level of sHLA-G in cases and controls was extracted and subjected to a meta-analysis using a random-effects model. The pooled effect was expressed in terms of standardized mean difference (SMD). Sensitivity analysis was performed to investigate the effect of the exclusion of each study on the pooled results. Publication bias was assessed statistically. Nine studies with altogether 567 PE cases and 1132 normal pregnancy controls were included in the meta-analysis. The first and third trimester levels of sHLA-G in PE cases were significantly lower than that of normal pregnant controls: (SMD: -0.84 [-1.29; -0.38]; p = .003; I2 = 54%) and (SMD: -0.39 [-0.71; -0.06]; p = .02; I2 = 79%) respectively. Sensitivity analysis revealed significant fluctuations in the pooled findings when few studies were excluded, raising questions on the consistency of results among studies. Although we found that first and third-trimester sHLA-G levels in pre-eclampsia are significantly lower, taking into consideration the inconsistent results from the sensitivity analysis, our findings advocate the demand for more studies with larger sample sizes to generate solid ground pooled evidence on the predictive role of sHLA-G in pre-eclampsia.

Modulation of sHLA-G, PD-1, and PD-L1 Expression in Cervical Lesions Following Imiquimod Treatment and Its Association with Treatment Success.

(1) Background: Cervical intraepithelial neoplasia (CIN) is a precancerous condition linked to human papillomavirus (HPV) infection, often necessitating surgical interventions carrying the risk of subsequent preterm births. This study explores the potential of imiquimod (IMQ), as a non-invasive alternative treatment. The focus is on understanding IMQ impact on immune checkpoint molecules, particularly PD-1, PD-L1, and sHLA-G, which play pivotal roles in shaping immune responses and cancer progression. (2) Methods: Forty-three patients diagnosed with a high-risk squamous intraepithelial lesion (HSIL, p16-positive) self-applied 5% IMQ encapsulated in sachets containing 250 g of cream into the vaginal cavity three times a week for 16 weeks. The impact of IMQ therapy on cervical lesion regression was assessed through immunohistochemistry (IHC), examining changes in sHLA-G, PD-L1, and PD-1 levels. The antiviral activity of IMQ was evaluated through HPV-E7 immunofluorescence. Ethical considerations were adhered to, and the research methods were based on a previously approved clinical trial (clinicaltrials.gov Identifier: NCT04859361). (3) Results: IMQ treatment demonstrated efficacy, leading to lesion regression. sHLA-G levels in CIN before starting IMQ application were associated with unsuccessful treatment (p = 0.0036). IMQ did not significantly alter the expression of PD-1. We observed a decrease in PD-L1 levels in those who were successfully treated (p = 0.0509) and a reduction in HPV burden. (4) Conclusions: IMQ exhibits promise as a non-invasive treatment for CIN, emphasising its potential to modulate the immune microenvironment. Baseline sHLA-G levels emerge as potential predictors of treatment response. Understanding the nuanced dynamics of immune checkpoints sheds light on IMQ mechanism of action. Further exploration is warranted to decipher the intricate mechanisms underlying IMQ treatment in the context of cervical lesions.

Predictive Capabilities of Human Leukocyte Antigen-G and Galectin-13 Levels in the Amniotic Fluid and Maternal Blood for the Pregnancy Outcome.

Background and Objectives: Increasing evidence points to the significant role of the angiogenic factor levels in screening for pregnancy outcome. To examine the potential relationship between concentrations of placental protein 13 (PP13) and soluble human leukocyte antigen-G (sHLA-G) in maternal serum and amniotic fluid at 16-23 weeks of gestation and the sonographic features of pregnancy as well as pregnancy outcome. Materials and Methods: PP13 and sHLA-G in serum and amniotic fluid, fetal biometrical data, and placental volume and perfusion indices were determined in 71 euploid, singleton pregnancies. Results: The serum sHLA-G level exhibits a negative correlation with the serum PP13 level (r = -0.186, p < 0.001) and a positive correlation with the sHLA-G level in amniotic fluid (r = 0.662, p < 0.001). A significant correlation was found between serum sHLA-G level and placental volume (r = 0.142, p < 0.05) and between amniotic sHLA-G level and placental perfusion (r = -0.450, p < 0.001). A low amniotic PP13 level significantly predicted the birth weight (r = -0.102, p < 0.05), the duration of pregnancy (r = -0.155, p < 0.05), and the fetal abdominal circumference (r = -0.098, p < 0.05). Conclusions: PP13 assayed in amniotic fluid might be a potential marker of fetal growth, and sHLA-G can be an adjunct modality reflecting placental sonographic parameters.

Предикторы рецидивов бронхиальной обструкции у детей раннего возраста

Aim. To provide overview information on predictors of relapses of bronchial obstruction in young children and the likelihood of them developing bronchial asthma in the future. Key points. Over the past few years, more than 280 papers have been published confirming the important role of HLA-G in the regulation of the human immune system, indicating HLA-G antigens as a prognostic factor in the development of various pathological conditions. HLA-G proteins have been shown to be involved in the immune regulation of the pathogenesis of autoimmune and allergic diseases, such as gastrointestinal, skin, neurological and rheumatological diseases, as well as in the pathology of pregnancy. Conclusion. The level of sHLA-G is particularly significant in the development of inflammatory processes in allergic diseases, in particular bronchial asthma, which opens up new opportunities for its use as an important marker of inflammation. In addition, sHLA-G, as an accessible diagnostic indicator, can be effectively introduced into the healthcare system, thereby aiding in the prediction of allergic diseases and monitoring maintenance therapy. Keywords: bronchial asthma, predictors, allergic diseases, HLA-G, children.

The correlation between soluble human leukocyte antigen (sHLA-G) levels and +3010 polymorphism.

Human leukocyte antigen-G (HLA-G) is classified as non-classical HLA, located in the short arm of chromosome 6 and composed of seven introns and eight exons. The HLA-G gene has a lower frequency polymorphism in the coding area and higher variability at the regulatory 5'- and 3'-untranslated regions linked to HLA-G microRNA regulation. HLA-G molecule is known to have an immunomodulatory and tolerogenic features role. In 199 Saudi individuals, we examined the association between plasma soluble HLA-G (sHLA-G) levels and eight polymorphic different sites, including 14bp ins/del/+3003T-C/+3010C-G/+3027C-A/+3035C-T/+3142C-G/+3187A-G/+3196C-G single nucleotide polymorphisms (SNPs) in exon 8 in the HLA-G gene. Our results revealed higher frequency for rs17179101C (97%), rs1707T (92%) and rs9380142A (73%) alleles. Greater frequencies for the tested genotypes were observed in 3027C/C (rs17179101) (93%), 14bp (rs1704) ins/del (92%), +3003T/T (rs1707) (85%) and +3035C/T (rs17179108) (79%) SNP genotypes. Moreover, we observed a significant association of sHLA-G with +3010G/C (rs1710) SNP. In conclusion, we showed a significant association between 3010G/C (rs1710) SNP and the sHLA-G level among our sample for Saudi populations. Our findings demonstrated that specific SNP within the HLA-G gene is linked to sHLA-G molecule secretion, suggesting sHLA-G levels may be regulated genetically.

Investigation the role of Human Leukocyte Antigen-G in Iraqi patients with papillary thyroid carcinoma

Human leukocyte antigen G (HLA-G) is a non-classical major histocompatibility complex (MHC) protein with well-known immunomodulatory characteristics. It is also believed to be an important sign of immune tolerance in cancer cells. Immune Escape. HLA-G is also associated with disease development and prognosis in cancer patients. The goal of this study was to compare soluble HLA-G (sHLA-G) levels before and after radioactive iodine therapy (RAI) by enzyme immunoassay (ELISA). Immunohistochemistry was used to examine HLA-G protein expression in thyroid tissues from patients with papillary thyroid cancer (PTC) to investigate the relationship between HLA-G expression and patients' clinical variables. Prospective research included 138 blood samples from patients and controls, as well as 25 thyroid paraffin-embedded tissues from individuals suffering from papillary thyroid cancer (PTC) and controls. Our findings demonstrated a significant difference in the means of people who had radioactive iodine therapy against those who did not (Mean SE = 4.19 0.31, 2.216 0.08, respectively). HLA-G staining, on the other hand, was identified in tumor cells in papillary thyroid cancer, all sections were positive, strongly stained and completely membranous, indicating the presence of HLA-G protein in the tested material. These findings suggest that HLA-G may be involved in the pathogenesis of papillary thyroid cancer.

Expression and clinical implications of HLA-G and PD-L1 following kidney transplantation: A cohort study.

Kidney transplantation (KT) is the preferred treatment for end-stage renal diseases. Human leukocyte antigen G (HLA-G) and programmed death-ligand 1 (PD-L1) have notable clinical and therapeutic significance in transplantation because of their roles in promoting tolerance. This study aimed to assess HLA-G and PD-L1 levels at various stages following KT. A cohort of 12 patients was monitored from the pretransplant phase to 12 months post-surgery. Blood samples were taken at specific intervals: before kidney transplantation (T0), and then on the 7th (T7), 30th (T30), 90th (T90), 180th (T180), and 365th days post transplantation. Renal biopsies were performed in patients with graft dysfunction. Plasma levels of soluble HLA-G (sHLA-G) and PD-L1 were quantified using enzyme-linked immunosorbent assays. Additionally, immunohistochemistry was used to detect the presence of both molecules in biopsy samples. Multivariate analysis indicated that episodes of rejection were correlated with decreased expression of sHLA-G (P < .001) and PD-L1 (P < .001). Over the course of the study, the sHLA-G levels also declined (P < .001). Patients who had been transfused had lower PD-L1 levels (P = .03). Furthermore, kidney recipients from related live donors had increased HLA-G expression (P < .001). Our findings suggest that diminished HLA-G and PD-L1 levels correlate with an increased risk of graft rejection. Notably, HLA-G expression significantly decrease after the third-month posttransplantation.

Evaluation of HLA-G 14 base-pair Insertion/ Deletion Polymorphism and Soluble HLA-G Level in Patients with Rheumatoid Arthritis in Mosul City: A Case-Control Study

Background: HLA-G antigens are unconventional “class Ib” entities that are found on human leukocytes; they are essential in immunomodulation and regulation of inflammatory processes. Studies on the effects of the gene variations of HLA-G on rheumatoid arthritis have inconsistent results. Objective: To estimate the potential relationship between soluble HLA-G and the rs66554220 14 base-pair insertion/deletion polymorphism of HLA-G with disease activity parameters of rheumatoid patients in Iraqi patients. Methods: Using a DNA extraction kit, the genomic DNA was retrieved from 190 rheumatoid cases and 190 control individuals. Using primers for the HLA-G gene, the polymerase chain reaction was utilized for the genotyping of HLA-G 14ֺ base-pair insertion/deletion variants. The levels of soluble HLA-G were assessed by means of an ELISA test. Results: The results did not show a link between polymorphic HLA-G 14 base-pair insertion/deletion alleles and the possibility of getting rheumatoid disease. Serum levels of soluble HLA-G were substantially lower than those of controls (median=1.548 vs. median=7.391 U/mL), respectively. sHLA-G has a statistically substantial adverse link with ESR (r= -0.245, p&lt;0.05). Furthermore, there are statistically substantial differences between the DAS-28 activity score and the sHLA-G level. Conclusion: There is no link between the risk of developing RA and polymorphic HLA-G 14 base-pair insertion or deletion in Iraqi patients. However, sHLA-G might serve as a diagnostic predictor of disease activity.

HLA-G Gene Variability Is Associated with Papillary Thyroid Carcinoma Morbidity and the HLA-G Protein Profile.

Human leukocyte antigen (HLA)-G is an immune checkpoint molecule that is highly expressed in papillary thyroid carcinoma (PTC). The HLA-G gene presents several functional polymorphisms distributed across the coding and regulatory regions (5'URR: 5' upstream regulatory region and 3'UTR: 3' untranslated region) and some of them may impact HLA-G expression and human malignancy. To understand the contribution of the HLA-G genetic background in PTC, we studied the HLA-G gene variability in PTC patients in association with tumor morbidity, HLA-G tissue expression, and plasma soluble (sHLA-G) levels. We evaluated 185 PTC patients and 154 healthy controls. Polymorphic sites defining coding, regulatory and extended haplotypes were characterized by sequencing analyses. HLA-G tissue expression and plasma soluble HLA-G levels were evaluated by immunohistochemistry and ELISA, respectively. Compared to the controls, the G0104a(5'URR)G*01:04:04(coding)UTR-03(3'UTR) extended haplotype was underrepresented in the PTC patients, while G0104a(5'URR)G*01:04:01(coding)UTR-03(3'UTR) was less frequent in patients with metastatic and multifocal tumors. Decreased HLA-G tissue expression and undetectable plasma sHLA-G were associated with the G010102a(5'URR)G*01:01:02:01(coding)UTR-02(3'UTR) extended haplotype. We concluded that the HLA-G variability was associated with PTC development and morbidity, as well as the magnitude of the encoded protein expression at local and systemic levels.

Soluble HLA-G (sHLA-G) measurement might be useful as an early diagnostic biomarker and screening test for gastric cancer

Gastric cancer (GC) is the fifth most frequent malignancy worldwide and has a high mortality rate related to late diagnosis. Although the gold standard for the GC diagnosis is endoscopy with biopsy, nonetheless, it is not cost-effective and is invasive for the patient. The Human leukocyte antigen G (HLA-G) molecule is a checkpoint of the immune response. Its overexpression in cancer is associated with immune evasion, metastasis, poor prognosis, and lower overall survival. We evaluate the plasma levels of soluble HLA-G, (sHLA-G) in patients with GC and benign gastric pathologies using an ELISA test. A higher concentration of sHLA-G in patients with GC than in those with benign pathologies, higher levels of plasma sHLA-G in women with GC compared with men and significant differences in the sHLA-G levels between the benign gastric pathologies evaluated, was our main findings. As no significant differences were found between the GC assessed stages in our study population, we suggest that sHLA-G is not an adequate marker for staging GC, but it does have diagnostic potential. In addition to providing information on the potential of sHLA-G as a diagnostic marker for GC, our study demonstrate that HLA-G molecules can be found in the membrane of exosomes, which highlights the need to perform studies with a larger number of samples to explore the functional implications of HLA-G positive exosomes in the context of gastric cancer, and to determine the clinical significance and possible applications of these findings in the development of non-invasive diagnostic methods.

Association between Serum HLA-G Levels in The First Trimester of Pregnancy and The Onset of Preeclampsia: A Systematic Review and Meta-analysis Study.

Human leukocyte antigen G (HLA-G) levels are among the biomarkers suggested for pre-eclampsia (PE). This study is aimed at determining the possible relationship between low soluble HLA-G (sHLA-G) levels in maternal blood at the beginning of pregnancy and subsequent PE. We searched the international scientific databases of Web of Science, Embase, PubMed, Cochrane, and Scopus. We extracted the studies investigating the relationship between the serum levels of HLA-G in the first trimester of pregnancy and the onset of PE using the appropriate keywords. The collected data were analyzed using the random-effects meta-analysis model and STATA (version 14). A total of 5 studies met the eligibility criteria, and the total sample size was 668 subjects. The mean and SD age of case subjects was 31.41 ± 4.16 years, while it was 30.56 ± 3.5 for control subjects. According to the findings, there was an inverse relationship between HLA-G serum level in the first trimester of pregnancy and the subsequent onset of PE, standard mean difference (SMD)=-1.51 [95% confidence interval (CI): -2.26, -0.75, I2=90.8%, P=0.000]. Based on these results, low sHLA-G level in early pregnancy has a positive correlation with subsequent PE, and the significant role of sHLA-G in the early stages of placentation can be proven.

Dynamics of Soluble Forms of the Immune Checkpoint Components PD-1/PD-L1/B7-H3, CD314/ULBP1, and HLA-G in Peripheral Blood of Melanoma Patients Receiving Blockers of Programmed Cell Death Protein PD-1.

The content of the soluble forms of immune checkpoint components sPD-1, sPD-L1 in blood serum, and sB7-H3, sCD314, sULBP1, sHLA-G in blood plasma of 30 melanoma patients receiving immunotherapy with anti-PD-1 antibodies (nivolumab, pembrolisumab) was measured before and in 4 and 8 weeks after the start of immunotherapy. The control group comprised 70 practically healthy donors. Standard immunoassay kits were used. In melanoma patients, the levels of sPD-L1 and sB7-H3 were significantly higher than in the control group (p<0001), sPD-1 level did not differ from the control, while sCD314 and sHLA-G levels were insignificantly decreased. During therapy, opposite changes in the levels of markers in individual patients were observed, and frequently after the initial increase (or decrease) after the first 4 weeks normalization did occur in the further 4 weeks. No statistically significant associations between the initial levels of markers and direction of their changes during treatment were found, but some trends indicating to the potential benefits from assessment of soluble forms of immune checkpoint proteins for evaluation and monitoring of the efficiency of the therapy with immune checkpoint blockers were revealed: significant decrease of sB7-H3 and sPD-1 levels in the course of treatment, higher initial sPD-1 level in patients with future progression than in those with stabilization or partial effect, and lower progression frequency in patients with increasing sPD-1 and sPD-L1 levels than in those with decreasing markers levels.

Therapeutic Effects of HLA-G5 Overexpressing hAMSCs on aGVHD After Allo-HSCT: Involving in the Gut Microbiota at the Intestinal Barrier.

Acute graft-versus-host disease (aGVHD) initiated by intestinal barrier dysfunction and gut microbiota dysbiosis, remains one of the main obstacles for patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) to achieve good prognosis. Studies have suggested that mesenchymal stem cells (MSCs) can suppress immune responses and reduce inflammation, and human leukocyte antigen-G5 (HLA-G5) plays an important role in the immunomodulatory effects of MSCs, but very little is known about the potential mechanisms in aGVHD. Thus, we explored the effect of HLA-G5 on the immunosuppressive properties of human amnion MSCs (hAMSCs) and demonstrated its mechanism related to the gut microbiota at the intestinal barrier in aGVHD. Patients undergoing allo-HSCT were enrolled to detect the levels of plasma-soluble HLA-G (sHLA-G) and regulatory T cells (Tregs). Humanized aGVHD mouse models were established and treated with hAMSCs or HLA-G5 overexpressing hAMSCs (ov-HLA-G5-hAMSCs) to explore the mechanism of HLA-G5 mediated immunosuppressive properties of hAMSCs and the effect of ov-HLA-G5-hAMSCs on the gut microbiota at the intestinal barrier in aGVHD. The plasma levels of sHLA-G on day +30 after allo-HSCT in aGVHD patients were lower than those in patients without aGVHD, and the sHLA-G levels were positively correlated with Tregs percentages. ov-HLA-G5-hAMSCs had the potential to inhibit the expansion of CD3+CD4+ T and CD3+CD8+ T cells and promote Tregs differentiation, suppress proinflammatory cytokine secretion but promote anti-inflammatory cytokines release. Besides, ov-HLA-G5-hAMSCs also could reverse the intestinal barrier dysfunction and gut microbiota dysbiosis in aGVHD. We demonstrated that HLA-G might work with Tregs to create a regulatory network together to reduce the occurrence of aGVHD. HLA-G5 mediated hAMSCs to exert higher immunosuppressive properties in vivo and reverse the immune imbalance caused by T lymphocytes and cytokines. Furthermore, HLA-G5 overexpressing hAMSCs could restore gut microbiota and intestinal barriers, thereby ameliorating aGVHD.

Elevated sHLA-G plasma levels post chemotherapy combined with ILT-2 rs10416697C allele status of the sHLA-G-related receptor predict poorest disease outcome in early triple-negative breast cancer patients.

Triple negative breast cancer (TNBC) shows an aggressive growing and spreading behavior and has limited treatment options, often leading to inferior disease outcome. Therefore, surrogate markers are urgently needed to identify patients at high risk of recurrence and more importantly, to identify additional therapeutic targets enabling further treatment options. Based on the key role of the non-classical human leukocyte antigen G (HLA-G) and its related receptor immunoglobulin-like transcript receptor-2 (ILT-2) in immune evasion mechanisms of tumors, members of this ligand-receptor axis appear to be promising tool for both, defining risk groups and potential therapeutic targets. To follow this, sHLA-G levels before and after chemotherapy (CT), HLA-G 3' UTR haplotypes, and allele variations rs10416697 at the distal gene promoter region of ILT-2 were defined in healthy female controls and early TNBC patients. The results obtained were associated with clinical status, presence of circulating tumor cell (CTC) subtypes, and disease outcome of patients in terms of progression-free or overall survival. sHLA-G plasma levels were increased in TNBC patients post-CT compared to levels of patients pre-CT or controls. High post-CT sHLA-G levels were associated with the development of distant metastases, the presence of ERCC1 or PIK3CA-CTC subtypes post-CT, and poorer disease outcome in uni- or multivariate analysis. HLA-G 3' UTR genotypes did not influence disease outcome but ILT-2 rs10416697C allele was associated with AURKA-positive CTC and with adverse disease outcome by uni- and multivariate analysis. The prognostic value of the combined risk factors (high sHLA-G levels post-CT and ILT-2 rs10416697C allele carrier status) was an even better independent indicator for disease outcome in TNBC than the lymph nodal status pre-CT. This combination allowed the identification of patients with high risk of early progression/death with positive nodal status pre-CT or with non-pathological complete therapy response. The results of this study highlight for the first time that the combination of high levels of sHLA-G post-CT with ILT-2 rs10416697C allele receptor status is a promising tool for the risk assessment of TNBC patients and support the concept to use HLA-G/ILT-2 ligand-receptor axis as therapeutic targets.

Determination of soluble HLA-G serum levels in patients with adenomyosis and uterine fibroids before and after surgery

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 byELISAassay. 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.

Serum Level of Soluble Human Leukocyte Antigen G in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis.

This study aimed to evaluate the serum level of human leukocyte antigen G [HLA-G] in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) compared to healthy controls; moreover, it attempted to assess its relationship with SLE and RA disease activity indices. This descriptive study was conducted on 31 SLE patients (17 cases with a recent diagnosis and 14 cases with a previous diagnosis), 21 RA patients (7 cases with a recent diagnosis and 14 cases with a previous diagnosis), and 18 healthy controls who visited Ghaem Hospital affiliated to Mashhad University of Medical Sciences, Mahhad, Iran. SLE and RA activity indices were measured and recorded. Furthemore, soluble isoforms, including shed HLA-G1 and HLA-G5, were measured in serum samples via the ELISA method. A comparison of the five groups showed no significant differences in the serum level of sHLA-G. However, sHLA-G serum level was significantly higher in SLE and RA patients compared to healthy controls (P<0.05). sHLA-G level showed no correlation with disease duration and activity in SLE and RA patients (P>0.05). However, a strong positive correlation was observed between the serum level of sHLA-G and 24-h urine protein in the previously diagnosed SLE group (r=0.83, P=0.01). It seems that the serum level of sHLA-G is higher in RA and SLE patients compared to healthy controls. Furthermore, a strong correlation was found between sHLA-G serum levels and 24-h urine protein in cases with a previous diagnosis of SLE.

HLA-G 3'UTR polymorphism diplotypes and soluble HLA-G plasma levels impact cervical cancer susceptibility and prognosis.

Human leukocyte antigen G (HLA-G) is an immune checkpoint molecule with relevance in several cancers. The aim of this study was to evaluate the potential role of soluble HLA-G (sHLA-G), its genetic polymorphisms and its haplotype structure in the susceptibility and prognosis of primary cervical cancer in a Chinese Han population. We investigated sHLA-G plasma levels and 3' untranslated region (3'UTR) polymorphisms through ELISA and direct DNA sequencing, respectively, in cervical cancer patients (120 cases) and healthy control women (96 cases). The data were analyzed for associations using PowerMarker, Haploview, and GraphPad Prism. In this study, 8 polymorphic sites, 16 haplotypes and 23 diplotypes in the HLA-G 3'UTR were identified in our study population. We observed that each pair of 8 polymorphic sites exhibited linkage disequilibrium. The heterozygote CT genotype at position +3422 (rs17875408) was more common in cervical cancer patients than in healthy women (OR=5.285, P<0.05). Haplotypes UTR-1, UTR-3, and UTR-7 accounted for more than 85% of both groups, but no significant difference was found. The frequency of the UTR-1/UTR-3 diplotype in patients was significantly higher than that in controls (P<0.05). In addition, we further observed that HLA-G 3'UTR polymorphisms may influence the sHLA-G plasma level in patients' peripheral blood, especially 14 bp Ins/Del (rs371194629) and +3142 C/G (rs1063320). A receiver operating characteristic (ROC) curve analysis showed that the sHLA-G level had good diagnostic performance in differentiating patients with cervical cancer from healthy women (AUC>0.7). Among patients, mean sHLA-G levels increased with increasing FIGO stages but were not related to the overall survival time. The results of the present study enhance our understanding of how HLA-G 3'UTR polymorphisms can influence the peripheral sHLA-G plasma level and play a key role in cervical carcinogenesis. This study further confirmed that sHLA-G may represent a novel plasma biomarker for the prognosis and potential therapeutic target of cervical cancer.