Plasma Soluble Human Leukocyte antigen-G Research Articles

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.

Plasma soluble HLA-G levels in a cohort of heart failure patients exposed to chemicals

Heart failure (HF) is a syndrome caused by structural and/or functional cardiac abnormalities, resulting in a reduced cardiac output and/or elevated intracardiac pressures. Several studies reported a crucial role of immune activation and inflammation in the chronic heart failure (HF) pathogenesis, suggesting that pro-inflammatory and anti-inflammatory mediators could be predictive markers of the HF development and/or progression. Human Leukocyte Antigen-G (HLA-G), a tolerogenic and anti-inflammatory class I non-classical major histocompatibility complex molecule, was reported to be upregulated in patients diagnosed with HF, suggesting a tentative to regulate the inflammatory condition. We evaluated soluble (s)HLA-G plasmatic levels in patients with stable chronic heart failure at baseline visit and after 6 and 12 months. The 14 bp Insertion/Deletion polymorphisms of the HLA-G gene was also analyzed. We showed that in HF subjects, sHLA-G levels were higher in NYHA class II and III subjects (mild-severe symptoms) (6.11 ± 1.15 ng/ml; 8.25 ± 2.27 ng/ml, respectively) in comparison with NYHA class I subjects (no symptoms) (2.35 ± 0.43 ng/ml) (I vs II: p = 0.0156; I vs III: p = 0.0122). Moreover, the exposure to chemicals seems to affect sHLA-G levels, with higher sHLA-G levels in exposed patients (3.36 ± 5.12 ng/ml) in comparison with unexposed subjects (2.01 ± 2.84 ng/ml). The HLA-G 3′UTR 14 bp INS/DEL polymorphism correlated with sHLA-G, with the 14 bp INS/INS genotype associated with higher sHLA-G levels during the 12 months follow-up in unexposed subjects (p = 0.008). In conclusion, these results support a correlation between sHLA-G levels, genetics and HF disease in presence of work chemical exposition.

Evaluation of Plasma Soluble Human Leukocyte Antigen-G Level in Asthmatic Children Aged 2 to 14 Years Old in Ghaem Hospital

Introduction: To evaluate serum level of plasma soluble human leukocyte antigen-G (sHLA-G) in asthmatic children aged 2 to 14 years old. Materials and Methods: This prospective, cross-sectional study was conducted on 83 patients aged 2-14 years in Ghaem Hospital, Mashhad, Iran, during 2013-2015. The participants were divided into two groups of asthmatic patients (n=29) and healthy children (n=54). Blood samples were drawn from the case (on admission) and control groups. Results: In the control group, 33 cases were male (61.1%) and 21 (38.9%) were female. In the case group, 18 patients (62.1%) were male and 11 (37.9%) were female (P=0.65). Mean ages of the control and case groups were 4.75±3.57 and 4.93±2.38 years, respectively (P=0.17). Mean serum levels of sHLA-G in the control and case groups were 396.51±279 U/ml and 184.58±302.08 U/ml, respectively (P<0.001). Conclusion:Serum level of sHLA was significantly lower in the asthmatic children compared to healthy ones.

Assessment of Plasma Soluble Human Leukocyte Antigen-G as a Prognostic Marker in Post-Chemotherapy Breast Cancer Patients in Gaza Strip

Objectives: This study aims to investigate whether plasma soluble human leukocyte antigen-G (sHLA-G) can be used as a potential biomarker for the diagnosis and follow-up of breast cancer in post-chemotherapy patients in Gaza strip. Patients and methods: The study population was divided into two groups: 60 women with breast cancer and receiving chemotherapy (post- group) and 60 women with breast cancer who did not receive chemotherapy (pre- group). The control group consisted of 60 healthy women. Cancer antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA) levels were analyzed using the Axsym Immunoassay system. Results: Plasma sHLA-G levels were significantly higher in breast cancer patients compared to healthy controls (p<0.001). Area under receiver operating characteristic (ROC) curve of sHLA-G for discriminating patients with breast cancer (n=120) from the control group (n=60) was 0.919 (95% CI=0.882 - 0.956) and was smaller than those of CA15-3 (0.998, 95% CI=0.996-1.00) and CEA (0.985, 95% CI=0.973-0.997). The ROC curves of sHLA-G, CEA, and CA15-3 for differentiating the group of patient who did not receive chemotherapy yet (n=60) and the group of patient who received anti-cancer treatment (n=60) were 0.998, 0.781 and 0.698, respectively (p<0.001). Conclusion: Our study findings provide evidence in further support for the application of sHLA-G as a biomarker for diagnosis, prognosis, and follow-up of breast cancer therapy.

Outcomes of Interferon/Ribavirin Therapy in Patients with HCV Defined by Expression of Plasma Soluble Human Leukocyte Antigen-G but Not IL-37

BackgroundChronic hepatitis C virus (HCV) infection leads to life-threatening complications worldwide. Immunomodulation signals the response to virus clearance. The immune-suppressive molecule human leukocyte antigen-G (HLA-G) has been shown to function in inhibiting both innate and adaptive immune responses. The objective of this study was to investigate the expression of HLA-G and IL-37 in sustained virological response (SVR) and non-SVR HCV-positive patients before and after complete treatment with a combination of pegylated interferon (IFN) and ribavirin (RBV).Material/MethodsOur study included 132 chronic hepatitis C patents who received combined therapy with IFN-α and RBV. Both SVR and non-SVR patients were included. The end-of-treatment response was defined as undetectable HCV RNA at week 48. Patients with end-of-treatment response were detected by HCV RNA at 24 weeks after therapy. The expression levels of HLA-G and IL-37 at the end and 24 weeks after treatment were detected by ELISA.ResultsPlasma HLA-G and IL-37 were significantly increased in HCV-infected patients compared with healthy individuals before treatment. Furthermore, HLA-G in SVR patients was noticeably decreased after treatment, while HLA-G in non-SVR patients had no changes after treatment. Additionally, both in SVR and non-SVR patients, the expression of IL-37 was remarkably reduced compared with baseline after treatment.ConclusionsThese findings suggest that elevation of HLA-G and IL-37 in HCV may play an important role in response to combined therapy with IFN-α and RBV. Monitoring the expression of HLA-G during therapy could contribute to adjusting the treatment program of HCV-infected patients.

Role of HLA-G as a Predictive Marker of Low Risk of Chronic Rejection in Lung Transplant Recipients: A Clinical Prospective Study

Human leukocyte antigen G (HLA-G) expression is thought to be associated with a tolerance state following solid organ transplantation. In a lung transplant (LTx) recipient cohort, we assessed (1) the role of HLA-G expression as a predictor of graft acceptance, and (2) the relationship between (i) graft and peripheral HLA-G expression, (ii) HLA-G expression and humoral immunity and (iii) HLA-G expression and lung microenvironment. We prospectively enrolled 63 LTx recipients (median follow-up 3.26 years [min: 0.44-max: 5.03]). At 3 and 12 months post-LTx, we analyzed graft HLA-G expression by immunohistochemistry, plasma soluble HLA-G (sHLA-G) level by enzyme-linked immunosorbent assay, bronchoalveolar lavage fluid (BALF) levels of cytokines involved in chronic lung allograft dysfunction (CLAD) and anti-HLA antibodies (Abs) in serum. In a time-dependent Cox model, lung HLA-G expression had a protective effect on CLAD occurrence (hazard ratio: 0.13 [0.03-0.58]; p = 0.008). The same results were found when computing 3-month and 1-year conditional freedom from CLAD (p = 0.03 and 0.04, respectively [log-rank test]). Presence of anti-HLA Abs was inversely associated with graft HLA-G expression (p = 0.02). Increased BALF level of transforming growth factor-β was associated with high plasma sHLA-G level (p = 0.02). In conclusion, early graft HLA-G expression in LTx recipients with a stable condition was associated with graft acceptance in the long term.

Elevation of human leukocyte antigen-G expression is associated with the severe encephalitis associated with neurogenic pulmonary edema caused by Enterovirus 71

Enterovirus 71 (EV71) infection can develop devastating clinical outcomes such as brain stem encephalitis (BE) and pulmonary edema (PE). Alteration of human leukocyte antigen-G (HLA-G) expression or cytokine production was considered playing important roles in virus-related pathogenesis. However, clinical relevance of HLA-G in EV71 infection remains unknown. In the current study, patients were stratified by disease severity as BE (n=107) and PE (n=18). HLA-G expression on peripheral blood monocytes from patients with BE (n=15), patients with PE (n=15) and control subjects (n=31) was analyzed with flow cytometry. Plasma soluble HLA-G (sHLA-G) (in 67 BE, 18 PE and 120 control subjects), IL-6 and IL-10 (in 50 patients with BE, 18 patients with PE and 45 control subjects) were determined with enzyme-linked immunosorbent assay. Data showed that the percentage of HLA-G-positive monocytes (mean 7.76 vs 3.68%, p<0.001), levels for sHLA-G (median 129.2 vs 70.6U/ml, p<0.001), IL-10 (median 160.5 vs 29.5pg/ml, p<0.001) and IL-6 (median 20.50 vs 5.21pg/ml, p=0.002) was significantly higher in patients with PE than in patients with BE. Taken together, our findings indicated that elevation of HLA-G expression on monocytes, plasma sHLA-G, IL-10 and IL-6 levels was associated with PE in patients infected with EV71.

Soluble Human Leukocyte Antigen-G and Its Insertion/Deletion Polymorphism in Papillary Thyroid Carcinoma: Novel Potential Biomarkers of Disease?

Human leukocyte antigen-G (HLA-G), a nonclassical major histocompatibility complex class I antigen, plays a pivotal role in immune tolerance and a paradoxical role in cancers. Our aims were to evaluate plasma soluble HLA-G (sHLA-G) concentrations and the 14-bp insertion/deletion polymorphism of the HLA-G gene in patients with papillary thyroid carcinoma (PTC) or Hashimoto's thyroiditis (HT) and to assess the possible association of these parameters with PTC aggressiveness. Samples for the analysis of sHLA-G and +14/-14-bp HLA-G polymorphism were obtained from 121 patients with HT and 183 with PTC; 245 gender- and age-matched healthy subjects served as controls. PTC histopathological aggressiveness was defined according to the last American Thyroid Association guidelines. Positive serum antithyroid antibody titers were observed in 22% of PTC patients and lymphocyte infiltration of thyroid parenchyma at histological examination in 21%, whereas both circulating and histological autoimmunity was detectable in 12% of PTC patients. No differences in the +14/-14-bp polymorphism frequencies were observed between the study groups. The prevalence of detectable sHLA-G was lower in healthy controls (52%) as compared with both HT (57%) and PTC (62%) patients. By stratifying the study groups according to sHLA-G level of positive subjects, significantly higher plasma sHLA-G values in PTC (42.9 ± 3.3 ng/ml; P = 0.002) and HT patients (49.1 ± 2.6 ng/ml; P < 0.002) as compared with healthy controls (8.5 ± 1.8 ng/ml) were obtained. Moreover, PTC patients with detectable plasma sHLA-G levels showed a higher aggressive behavior (P < 0.04) than those without. Although confirming the frequent association between PTC and chronic autoimmune thyroiditis, these data suggest that elevated circulating sHLA-G levels, besides an important signal of alterations of immune homeostasis, may be considered a potential, novel marker of PTC histopathological aggressiveness at diagnosis. Additional studies are needed to confirm the actual role and clinical relevance of the HLA-G complex in PTC development and progression.

Plasma soluble human leukocyte antigen-G expression is a potential clinical biomarker in patients with hepatitis B virus infection

The significance of upregulated soluble human leukocyte antigen-G (sHLA-G) expression under various pathologic conditions has been discussed. In this study, we evaluated the potential significance of plasma sHLA-G expression in patients with hepatitis B virus (HBV) infection. The study included 90 acute hepatitis B patients (AHB), 131 chronic hepatitis B patients (CHB), 152 resolved hepatitis B individuals (RHB), and 129 normal controls. sHLA-G were determined using enzyme-linked immunosorbent assay. A receiver operating characteristic (ROC) curve was used to evaluate the feasibility of plasma sHLA-G as a biomarker for distinguishing patients with HBV infection. sHLA-G levels in AHB (median, 193.1 U/mL; p < 0.001), CHB (median, 324.6 U/mL; p < 0.001), and RHB (median, 14.8 U/mL; p = 0.006) patients was much higher than that in normal controls (median, 9.0 U/mL). A significant difference for sHLA-G levels was also observed between patients with HBV infection (AHB vs CHB, AHB vs RHB, and CHB vs RHB; all p < 0.001). The area under the ROC curve for sHLA-G levels was 1.000 (p < 0.001) for AHB, 0.993 (p < 0.001) for CHB, and 0.604 (p = 0.003) for RHB patients versus normal controls, respectively. Data also indicated that the percentage of CD4(+)CD25(+)FoxP3(+) T regulatory cells and HLA-G(+)CD14(+) monocytes was significantly increased in AHB and CHB patients compared with normal controls (all p < 0.001). Our findings indicated that induction of HLA-G expression may play a role in HBV immune evasion and sHLA-G levels could be a useful biomarker in HBV infection.

Human leukocyte antigen‐G is closely associated with tumor immune escape in gastric cancer by increasing local regulatory T cells

Human leukocyte antigen-G (HLA-G) plays an important role in tumor cell escape. We investigated HLA-G expression and regulatory T cells (Tregs) infiltrates in patients with gastric cancer (GC), analyzed their relationship with clinicopathologic features, and characterized their role in tumor immune escape. We also investigated the plasma soluble HLA-G level and its potential in the diagnosis of GC. Effect of HLA-G on Tregs was further assessed by coculture experiments in vitro. Most interestingly, HLA-G positive expression was detected in GC tissues and it was significantly correlated with the presence of tumor-infiltrating Tregs. Patients with HLA-G positive expression or high Tregs had significantly poorer survival at 5 years after operation. Multivariate analysis indicated that HLA-G positive expression was an independent prognostic factor of GC. The coculture experiment showed overexpression of HLA-G in GC cell lines significantly enhanced the frequency of Tregs when GC cells were directly cocultured with human peripheral blood mononuclear cell. However, this effect disappeared when the indirect coculture system was applied. Some cytokines such as interleukin-6, interleukin-10, and tumor necrosis factor-α significantly changed in the coculture system. Moreover, plasma soluble HLA-G level in GC patients was higher than that in normal controls. Taken together, our results indicated that HLA-G expression was closely associated with tumor progression and involved in tumor evasion by increasing the frequency of infiltrating Tregs locally. Thus, HLA-G might be a promising predictor for disease prognosis and a possible novel target for immunotherapy in GC patients.

Induction of cell surface human leukocyte antigen–G expression in pandemic H1N1 2009 and seasonal H1N1 influenza virus–infected patients

A novel H1N1 virus of swine origin (H1N1v) recently caused a pandemic; however, knowledge of immunologic aspects of the virus infection are limited. Human leukocyte antigen–G (HLA-G) was speculated to play critical roles in viral infection, although its clinical relevance in H1N1 infection remains unknown. In this study, HLA-G expression in peripheral T lymphocytes, monocytes, and CD4 + CD25 + FoxP3+ regulatory T (Treg) cells (in 50 H1N1v-infected and 41 seasonal H1N1–infected patients and 27 control subjects) were analyzed by flow cytometry. Plasma-soluble HLA-G (sHLA-G, in 28 H1N1v–infected, 29 seasonal H1N1–infected patients and 85 control subjects) were determined with enzyme-linked immunosorbent assay. The percentage of HLA-G–positive T lymphocytes and monocytes among patients with H1N1v and seasonal H1N1 infections was dramatically increased compared with controls (all p < 0.001). Treg was markedly increased among H1N1v- infected patients compared with normal controls ( p = 0.041), but not for the seasonal H1N1–infected patients. Meanwhile, no significant difference was observed for sHLA-G levels between the groups. Together, cell surface HLA-G expression was markedly induced in H1N1v–infected and seasonal H1N1–infected patients, and increased Treg was observed only in H1N1v-infected patients. Given its immune-suppressive property, elevated cell surface HLA-G expression may help to explain the virus escaping from host immune responses.

Increased soluble human leukocyte antigen–G levels in peripheral blood from climbers on Mount Everest

Soluble human leukocyte antigen–G (HLA-G) is involved in maternal–fetal tolerance, transplant acceptance, and tumor escape from immunosurveillance, operating by inhibiting activity of T, antigen presenting cells (APC), and natural killer (NK) cells. HLA-G gene expression is modulated in vitro after hypoxic conditions, a situation evidenced during pregnancy and tumor progression. In extreme altitude, mountaineers are in hypoxic conditions that generate physiologic adaptative responses, some of them giving rise to pathologic signs. We performed measurements of plasma soluble HLA-G in six climbers before departure of the expedition and during their ascent to and descent from summit of Mount Everest, and in 3 Sherpas at 5300–6400 m. We found that HLA-G levels are upregulated during the ascent with a unique pattern in comparison with angiogenic/lymphangiogenic factors. Our data suggest that HLA-G has to be taken into account in the mechanisms participating in adaptation to high altitudes and reinforce hypoxia as an important factor in the regulation of HLA-G expression.

Analysis of the plasma soluble human leukocyte antigen–G and interleukin-10 levels in childhood atopic asthma

Human leukocyte antigen–G (HLA-G) has been hypothesized to be associated with the pathogenesis of asthma; however, results remain controversial. Furthermore, HLA-G expression could be modulated by the HLA-G 14-bp insertion (+)/deletion (−) polymorphism and by interleukin-10. In this study, the 14-bp polymorphism in exon 8 of the HLA-G gene, plasma soluble HLA-G, and interleukin-10 (IL-10) levels in untreated atopic asthmatic children, and in a group of age-, gender-, and ethnicity-matched normal controls were analyzed. Data showed that HLA-G 14-bp +/− polymorphism was not significant difference between the asthmatic patients and normal controls. Plasma soluble human leukocyte antigen (sHLA)–G in atopic asthma patients ( n = 72; median, 179.28 U/ml) was dramatically higher compared with that of the normal controls ( n = 76; median, 35.23 U/ml; p < 0.001). Receiver operating characteristic (ROC) curve analysis showed that the area under ROC curve for sHLA-G was 0.986 ( p < 0.001) in atopic asthma patients versus normal controls. IL-10 levels in the asthmatic children ( n = 50; median, 5.02 pg/ml) was significantly lower than that of the normal controls ( n = 48; median, 12.82 pg/ml; p < 0.001). Both HLA-G 14-bp polymorphism and IL-10 levels were unrelated to plasma sHLA-G concentration in both groups. Our findings indicated that the HLA-G 14-bp polymorphism was not a risk factor, but that sHLA-G might be considered as a biomarker for the atopic asthmatic patients. Dramatically increased sHLA-G with decreased IL-10 levels may have implications in the pathogenesis of atopic asthma.

Tumor-specific upregulation of human leukocyte antigen–G expression in bladder transitional cell carcinoma

Human leukocyte antigen–G (HLA-G) is a potent immunosuppressive molecule that induces functional silencing of both innate and adaptive immune responses. The relevance of the aberrant HLA-G expression in malignant contexts has been intensively investigated. However, its expression status and clinical significance in bladder cancer remain to be elucidated. In the current study, HLA-G expression in 75 primary bladder transitional cell carcinoma (TCC) lesions was analyzed with immunohistochemistry, and relationship between HLA-G expression and clinical parameters, including disease stage was evaluated. Plasma soluble HLA-G levels were analyzed in 15 TCC patients and 109 normal controls. Data revealed that HLA-G was expressed in 68.0% (51/75) primary TCC lesions, whereas it was undetectable in adjacent normal bladder tissues. The proportion of HLA-G expression in TCC samples varied from negative to 100%, and no significant association was observed for the HLA-G expression status with the patient age, gender, and disease stage. Furthermore, no significance for sHLA-G levels was observed between the TCC patients and normal controls (median 10.75 vs 8.69 U/ml, p = 0.578). Given its immunotolerant properties, our finding suggested that lesion HLA-G expression upregulated in bladder TCC lesions might be an additional mechanism for tumor cells evading from host immunosurveillance; however, its clinical relevance needs further investigation.

HLA-G Expression in Human Breast Cancer: Implications for Diagnosis and Prognosis, and Effect on Allocytotoxic Lymphocyte Response After Hormone Treatment In Vitro

The aim of this study is to investigate clinical implications of human leukocyte antigen-G (HLA-G) expression in breast cancer. HLA-G expression in 235 primary breast cancer tissues was investigated using immunohistochemistry, and plasma soluble HLA-G (sHLA-G) was measured in 44 breast cancer patients using a specific HLA-G enzyme-linked immunosorbent assay (ELISA). Effects of estradiol/progesterone and their antagonists tamoxifen/RU486 on HLA-G expression in cultured breast cancer MCF-7 cells were determined by real-time polymerase chain reaction (PCR) and the ELISA. Alterations of HLA-G expression by the hormone treatments on subsequent allocytotoxic lymphocyte (allo-CTL) response were also examined. In the study, approximately 66% of neoplasm lesions were identified to have positive HLA-G expression. This expression was significantly correlated with tumor size, nodal status, and clinical disease stage (P = 0.0001, 0.012, and 0.0001, respectively). Patients with positive HLA-G expression had a lower survival rate than those with negative expression (P < 0.028). Plasma sHLA-G levels were significantly higher in breast cancer patients than in healthy controls (P < 0.001), with the area under the receiver-operating characteristic (ROC) curve being 0.95. HLA-G expression in breast cancer MCF-7 cells was enhanced by estradiol/progesterone but reduced by their antagonists. Cytotoxicity studies showed that allo-CTL response in MCF-7 cells was inhibited by prior treatment with estradiol/progesterone, but was amplified by their antagonists. The effects could be restored or further strengthened by the addition of anti-HLA-G antibodies. Our findings suggest that HLA-G may have potential clinical implications in diagnosis, prognosis, and immunotherapy of patients with breast cancer.