12例肾移植术后重症肺部感染患者可溶性HLA-G的表达分析

目的探讨肾移植术后重症肺部感染患者HLA-G的表达及临床意义。方法回顾性分析了12例肾移植术后因急性排斥反应血肌酐未降至正常患者,肺部感染后因病情需要停用免疫抑制剂后HLA-G的表达情况及血肌酐的变化。结果12例患者因肾移植术后1次或多次急性排斥,移植肾功能未完全恢复,于术后1～3月出现肺部感染,给予抗炎等治疗,因病情需要停用免疫抑制剂,1周以后患者血肌酐反而逐步下降至正常,且移植肾功能恢复良好。结论肺部感染后HLA-G的上调表达有利于移植肾功能的恢复。     

HLA-G 14 bp insertion/deletion polymorphism and its association with sHLA-G levels in Behçet’s disease Tunisian patients

The purpose of this study was to investigate the HLA-G 3’UTR 14 bp polymorphism and sHLA-G levels in Tunisian patients with BD. The study included 119 patients with BD and 170 healthy blood donors (HD). HLA-G 14 bp polymorphism was genotyped by polymerase chain reaction. Serum levels of soluble HLA-G (sHLA-G) were measured using a commercial ELISA kit. A significant increased frequency of the −14 bp HLA-G allele was detected in patients with BD compared to HD (0.58 vs 0.49, p = 0.023), and a significant increased frequency of HLA-G −14/−14 bp was observed in patients with BD compared to HD [0.37 vs 0.22, p = 0.007, OR 2.04 (95% CI 1.21–3.42)]. The mean plasmatic concentration of sHLA-G levels were significantly increased in patients with active disease [231.63 ± 286.4 U/mL] compared to those with inactive disease (103.14 ± 77.8 U/mL, p = 0.03) and HD (121.41 ± 24.1 U/mL, p = 0.04). Furthermore, our results showed that there is no association between HLA-G 14 bp polymorphism and sHLA-G plasma levels.     

A comparative study on regulation of HLA-G expression in bad obstetric history and in head and neck squamous cell carcinoma from Northeast India

The expression of immunomodulatory molecule HLA-G is tissue restricted with abundant expression in placenta, mediating immune tolerance to fetus. Tumors hijack HLA-G to establish nutrient supply and evade host immune response. 14 base pair Insertion/Deletion polymorphism (rs371194629) and + 3142 G/C SNP (rs1063320) of 3′UTR of HLA-G were investigated in conjunction with miR-148A, miR-152 and HLA-G expression in SAB (Spontaneous abortion) history placenta and HNSCC tumor in a hospital-based case control study. Higher frequency of G allele of rs1063320 was seen in study participants as reported in other global populations. Both miR-148A and miR-152 were downregulated in tumor tissue. Predominance of 14 base pair “IN” allele of rs371194629 was noted in SAB placental tissue (p =<0.0001) with lower expression of HLA-G levels. In conclusion, 14 base pair Insertion/Deletion in linkage with + 3142 G/C SNP was related to lower HLA-G protein expression in SAB tissue, contradictorily HLA-G protein level was manipulated by tumors by suppressing microRNAs.     

A pilot study on Hla-G locus control region haplotypes and cervical intraepithelial neoplasias

Human papillomavirus (HPV) can induce cervical intraepithelial neoplasias (CIN) grades 1, 2 and 3. Untreated, these lesions may progress to cervical cancer (CC) which is the third most common cancer in women worldwide. HLA-G plays an immunotolerant role in the immune response. The aim of this study was to characterize the configuration of SNPs located at the distal promoter of HLA-G in patients with CIN2 and CIN3 and control women. The study sample was composed of 207 women as follows: 73 diagnosed with CIN2 lesions, 56 with CIN3 and 78 healthy control women. Genotyping was performed by sequence base typing. Eleven haplotype configurations subdivided in two main haplogroups (H1dist and H2dist), were characterized and compared between patients and controls. The haplotypes H1.1Dist (GAGAACGC) and H2.1Dist (AGGTACAC) were more frequent in Euro-Descendants as well as in Brazilian Mixed. Nevertheless, the haplotype H2.1Dist standed out as a susceptibility haplotype in Brazilian Mixed patients while the H1.1Dist presented a protector effect in this same ethnic group. Whether such LCR haplotype configurations can impact on HLA-G gene expression levels in women who developed cervical intraepithelial neoplasia is still unknown and it is of utmost importance that more investigation on this field be pursued.     

Regulatory role of tryptophan degradation pathway in HLA-G expression by human monocyte-derived dendritic cells

Dendritic cells (DC) are strong inducers of immunity but they can also be tolerogenic. During monocyte differentiation to DC the immunosuppressive indoleamine-2,3-dioxygenase (IDO) is induced. IDO degrades Trp to kynurenine, which is further metabolized to 3-hydroxyanthranilic acid. DC can also express mRNA and protein of the tolerogenic molecule HLA-G, but there is no surface expression. We studied the effect of the Trp degrading pathway on HLA-G expression by DC. When monocytes were differentiated to immature DC in presence of either Trp or its metabolites kynurenine or 3-hydroxyanthranilic acid they expressed cell surface HLA-G, and Trp also increased shedding of HLA-G1. Trp induced HLA-G cell surface expression when present during maturation with IFN-γ + LPS, but not with TNF-. Kynurenine increased HLA-G expression in both TNF- and IFN-γ + LPS matured DC, and 3-hydroxyanthranilic acid had a very weak effect on HLA-G cell surface expression when present during maturation. Shedding of HLA-G1 was more pronounced in IFN-γ + LPS-matured DC than in immatured DC. Maturation with IFN-γ + LPS in presence of kynurenine also increased HLA-G5 secretion. The mechanism involved seems to be post-translational as mRNA and cellular HLA-G protein content was not increased with Trp, kynurenine or 3-hydroxyanthranilic acid treatments. Finally, immature DC preincubated with Trp, kynurenine and 3-hydroxyanthranilic acid have after a decreased capacity to stimulate T cells in mixed lymphocyte reaction. In IFN-γ + LPS-matured DC this decreased capacity was obtained with kynurenine and 3-hydroxyanthranilic acid. These results suggest that IDO can induce HLA-G cell surface expression in DC, and that these two molecules can cooperate in the immune suppression.     

HLA—G蛋白在肿瘤组织及患者血清中的表达及其在肿瘤免疫逃逸中的作用

随着对人类白细胞抗原G（HLA—G）蛋白作用机制的深入了解,越来越多的研究发现HLA—G与肿瘤的免疫逃逸密切相关。大量研究显示在肿瘤患者的血浆、肿瘤组织中均可检测到HLA—G蛋白、mRNA的表达。     

Clinical and biological significance of HLA-G expression in ovarian cancer

Ovarian cancer is the most lethal gynecologic neoplastic disease in which the molecular etiology remains largely unclear. Like other cancer types, evolution of ovarian tumor cell species is accompanied by acquisition of novel gene products and these new tumor-associated antigens elicit a host immune response that creates selection pressure upon the emerging tumor clones. One of the mechanisms that ovarian cancer cells evade immune surveillance is by upregulating human leukocyte antigen-G (HLA-G) expression. HLA-G is a non-classical MHC class I molecule and accumulated evidence has suggested its biological role in inactivating immune response. It has been well known that HLA-G expression is frequently detected in the most aggressive type of ovarian cancer, i.e., high-grade serous carcinoma, and measurement of HLA-G protein levels has shown promise for detection and prognosis prediction in ovarian cancer. This review summarizes those recent studies on HLA-G expression in ovarian cancer with special focus on its clinical and biological significance which is fundamental to elucidate the molecular mechanisms in ovarian cancer development and paves the foundation for future HLA-G-based diagnostics and therapeutics.     

HLA-G profile of infertile couples who underwent assisted reproduction treatment

HLA-G codes for a non-classical class I (Ib) protein which is mainly expressed in trophoblast cells. Many pieces of evidence pointed out its essential role conferring immunological tolerance to the fetus. Some HLA-G alleles have been linked to enhanced or reduced HLA-G protein levels expression, which have been associated with reproductive failure. In this study 33 couples undergoing ART (assisted reproduction treatment; n = 66) and 120 couples who conceived naturally (controls; n = 240) were enrolled in the study. Genotyping was performed by SBT and tagged an 1837 bp at 5′URR as well as exons 2, 3 and 4 of HLA-G. Alleles, genotypes and haplotypes were compared between infertile and control groups using Fisher Exact Test. The haplotype HLA-G¹010101b/HLA-G¹01:01:01 showed statistically significant higher frequency in control groups. The immunogenetics of infertility is complex and might be dependent on different genes involved in the establishment of a successful pregnancy. A better understanding of HLA-G alleles and haplotypes structure and how the genetic diversity at their regulatory sites could impact on their level of expression and build up the susceptibility or protection conditions may shed light on the comprehension of immunogenetics mechanisms acting at the fetus-maternal interface.     

Pemetrexed combined with dual immune checkpoint blockade enhances cytotoxic T lymphocytes against lung cancer

Chemotherapy, in combination with immune checkpoint blockade (ICB) targeting to programmed death-1 (PD-1) or its ligand PD-L1, is one of the first-line treatments for patients with advanced non–small-cell lung cancer (NSCLC). However, a large proportion of patients, especially those with PD-L1 negative tumors, do not benefit from this treatment. This may be due to the existence of multiple immunosuppressive mechanisms other than the PD-1/PD-L1 axis. Human leukocyte antigen-G (HLA-G) has been identified as an immune checkpoint protein (ICP) and a neoexpressed tumor-associated antigen (TAA) in a large proportion of solid tumors. In this study, we evaluated the induction of HLA-G as well as PD-L1 using sublethal doses of chemotherapeutics including pemetrexed in different NSCLC cell lines. Except for gefitinib, most of the chemotherapeutic agents enhanced HLA-G and PD-L1 expression in a dose-dependent manner, whereas pemetrexed and carboplatin treatments showed the most consistent upregulation of PD-L1 and HLA-G in each cell line. In addition to protein levels, a novel finding of this study is that pemetrexed enhanced the glycosylation of HLA-G and PD-L1. Pemetrexed potentiated the cytotoxicity of cytotoxic T lymphocytes (CTLs) to treat NSCLC. Both in vitro and in vivo experiments revealed that CTL-mediated cytotoxicity was most pronounced when both anti-PD-L1 and anti-HLA-G ICBs were combined with pemetrexed treatment. In conclusion, anti-HLA-G could be an intervention strategy in addition to the anti-PD-1/PD-L1 pathway for NSCLC. Moreover, dual targeting of PD-L1 and HLA-G combined with pemetrexed might have a better extent of CTL-based immunotherapy.     

HLA—G基因14bp插入／缺失多态性与我国汉族类风湿关节炎相关性研究HLA—G基因14bp插入／缺失多态性与我国汉族类风湿关节炎相关性研究

目的探讨HLA—G基因14bp插入／缺失多态性与类风湿关节炎（RA）易感性的相关性,并分析其不同基因型间RA患者临床特点的差异。方法多聚酶链式反应（PCR）检测154例RA患者及367名健康体检者的HLA—G基因14bp插入／缺失多态性,比较不同基因型RA患者间关节肿胀数、关节压痛数、关节晨僵时间、病情活动指数DAS28积分及实验室指标如C反应蛋白（CRP）、血沉（ESR）、类风湿因子（RF）、抗CCP抗体滴度的差异。结果HLA-G 14bp插入／缺失多态性基因型频率分布在正常人和RA患者均显示Hardy-Weinberg平衡（正常人组：χ^2=0．095,P=0．953;RA组：χ^2=0．533,P=0．766）;HLA—G1 4bp插入／缺失多态性基因和基因型频率与RA易感性均元显著性的相关性联系;与＋14bp／＋14bp和＋14bp／-14bp基因型RA患者比较,-14bp／-14bp纯合子基因型RA患者的压痛关节数（P=0．049）、肿胀关节数（P=0．004）明显增多,病情活动指数DAS28明显更重（P=0．028）,RF滴度更高（P=0．001）。结论HLA-G基因14bp插入／缺失多态性与RA疾病易感性无关,但可影响RA患者的临床表现,HLA-G—14／-14bp纯合子型可能作为预后不良因素参与到RA疾病机制之中。