HLA-G对人羊膜间充质细胞免疫调节功能的影响

人类白细胞抗原G(HLA-G)是一种非经典的HLA Ⅰ类抗原,具有抑制炎症反应,协助肿瘤细胞逃逸,促使移植物免疫耐受的作用.人羊膜间充质细胞(HAMC)表达和分泌HLA-G,它能参与HAMC的免疫调节功能,抑制NK、T、B细胞的功能,影响树突状细胞(DC)的活性,为阐述HAMC的免疫抑制机制提供了理论依据.本文主要综述HLA-G的基因及分子结构,HLA-G在HAMC免疫抑制功能中的可能机制及HLA-G与HAMC、NK、DC、T细胞和B细胞的关系.     

HLA-G与肾移植术后急性排斥反应和巨细胞病毒活动性感染的相关性研究

目的 探讨HLA-G的表达水平与肾移植术后急性排斥反应(AR)和巨细胞病毒(CMV)活动性感染的相关性.方法 根据术后是否发生AR或CMV活动性感染,将132例初次肾移植受者分为肾功能稳定组、AR组和CMV组.另选择41例健康供者作为对照组.采用流式细胞术、酶联免疫吸附试验、蛋白质印迹法以及实时定量聚合酶链法检测各组HLA-G及其mRNA的表达,并采用免疫组织化学法观察移植肾组织中HLA-G的表达.结果 肾移植前后各组膜结合型HLA-G1 (mHLA-G1)的表达均处于较低水平,仅术后CMV组mHLA-G1+的中性粒细胞出现显著升高(P＜0.05).术前可溶性HLA-G5(sHLA-G5)的表达水平肾功能稳定组显著高于对照组(P＜0.05);术后sHLA-G5的表达水平CMV组显著高于肾功能稳定组(P＜0.05),而肾功能稳定组均高于对照组和AR组(P＜0.05),AR组与对照组的差异无统计学意义(P＞0.05).术后CMV组sHLA-G5 mRNA的表达水平最高(P＜0.05),肾功能稳定组次之,对照组和AR组均较低.21例AR组移植肾组织活检样本中,17例HLA-G表达呈阴性,3例呈阳性,1例呈弱阳性;9例CMV组移植肾组织活检样本的HLA-G表达均为阳性.132例受者中,28例CMV感染者的AR发生率为7.1％(2/28),104例非CMV感染者的AR发生率为25.0％(26/104),二者间AR发生率的差异有统计学意义(P＜0.05).结论 sHLA-G5可作为预测AR和CMV感染的生物标志分子;CMV感染和AR与受者体内的免疫平衡状况相关.     

The HLA-G Genetic Contribution to Bipolar Disorder: A Trans-Ethnic Replication

Bipolar disorder (BD) is frequently associated with immune dysfunctions. Studying the genetic diversity of the immuno-modulatory human leukocyte antigen (HLA)-G locus in a French BD cohort, we previously reported an association between a functionally relevant 14 bp Ins/Del polymorphism and BD risk. The present study investigated the genetic and expression diversities of HLA-G in a geographically distinct South Indian population-group BD patients, as well as the influence of exposure to the neurotropic Toxoplasma gondii pathogen. Three functionally relevant HLA-G polymorphisms, i.e. HLA-G 14 bp Ins/Del (rs66554220), +3142G>C (rs1063320) and +3187A>G (rs9380142) were genotyped by polymerase chain reaction (PCR) and real-time PCR. Sub-samples of BD patients and healthy controls (HC) were investigated for plasma levels of soluble HLA-G (sHLA-G) isoforms, as well as circulating stigma of T. gondii infection.

Findings indicate: (i) the frequency of the HLA-G 14 bp Del/Del genotype was higher in BD cases, as compared to HC; (ii) the HLA-G + 3142 C allele and CC genotype were more prevalent in BD patients than in HC; (iii) sHLA-G levels were significantly higher in BD cases, especially in females and in the early onset sub-group; and (iv) the InsGA haplotype was more prevalent in HC.

Our findings further support the genetic contribution of HLA-G to BD risk, as well as indicate relevant expression profiles. Such data may also indicate a potential developmental role in BD etiology, given that HLA-G is an important immune regulator from the intrauterine period and across development.     

细胞膜表达的HLA-G诱导免疫耐受性树突状细胞的产生

为了探讨体外诱导免疫耐受性树突状细胞（dendritic cell,DC）产生的方法及其机制,利用人HLA-G1真核表达载体转染K562细胞并与DC共培养后,用流式细胞术检测DC表面CD80、CD86、ILT3和ILT4分子表达情况,同时采用氚胸腺嘧啶核苷（3H-TdR）掺入法检测DC对T细胞功能的影响。结果表明,膜表达的HLA-G1分子与树突状细胞作用后,DC表面免疫共刺激分子CD80、CD86表达下调,而抑制性分子ILT3、ILT4表达上调。HLA-G1作用后DC异基因抗原诱导淋巴细胞增殖的活性明显下降。结论：HLA-G1分子可以在体外条件下,下调DC表面免疫共刺激分子水平,促进ILT3、ILT4表达,诱导免疫耐受性树突状细胞产生。     

HLA-G蛋白在垂体瘤中的表达及意义

目的：探讨垂体瘤中HLA-G基因编码产物的表达情况及临床病理意义。方法：应用免疫组织化学技术检测64例非侵袭性垂体瘤、8例侵袭性垂体瘤、13例复发垂体瘤、8例正常脑组织中HLA-G蛋白的表达情况。结果：8例正常脑组织HLA-G蛋白无阳性表达,64例非侵袭垂体瘤中HLA-G蛋白表达无强阳性表达,阳性表达率为25.0%,阳性信号存在于胞质中,与正常对照组比较阳性率差异有统计学意义（P〈0.05）;而8例侵袭性垂体瘤中HLA-G蛋白表达全部为阳性,强阳性率为83.3%（7/8）;13例复发垂体瘤中HLA-G蛋白表达全部为阳性,强阳性率为72.4%（9/13）。侵袭性垂体瘤及复发垂体瘤中HLA-G蛋白表达与正常对照组及非侵袭性垂体瘤比较皆有显著性差异（P〈0.01）。结论：垂体瘤的发生发展中存在HLA-G基因的过量表达现象,其阳性表达与垂体瘤的侵袭性和预后相关。     

HLA-G Expression in Tumor Tissues and Soluble HLA-G Plasma Levels in Patients with Gastrointestinal Cancer

Background: Overexpression of human leukocyte antigen G (HLA-G) and increased plasma levels of solubleHLA-G (sHLA-G) have been reported in different human malignancies, and are believed to be involved in tumor immuneevasion. Objectives: This study was designed to evaluate the expression of HLA-G in tumor tissues and the plasmalevels of sHLA-G in patients with gastrointestinal cancer, and to determine their associations with clinicopathologicalfactors. The link between Helicobacter pylori infection and increased HLA-G expression or sHLA-G levels was alsoinvestigated in patients with gastric cancer. Methods: HLA-G expression was investigated in tumor tissues from 100patients with gastric and colorectal adenocarcinoma using immunohistochemistry test, and plasma levels of sHLA-Gwere measured in 82 patients with ELISA method. The presence of H. pylori genome was investigated in tumortissues from 25 patients with gastric cancer by PCR method. Results: HLA-G expression was observed in 43% ofcolorectal cancers and 34.6% of gastric cancers, and was not related with any of the clinicopathological factors. Therewas a significant correlation between increased sHLA-G level and stage I tumors. Eight of 25 (32%) gastric cancerspecimens were positive for H. pylori, of which 3 samples were positive for HLA-G. Soluble HLA-G levels were abovethe cut-off value in all H. pylori-positive patients. Conclusion: Plasma levels of sHLA-G were significantly increasedin our patients with a sensitivity of 89% and a specificity of 62%. Soluble HLA-G level can be considered a usefulindicator for the early diagnosis of gastric and colorectal adenocarcinoma.     

14-bp ins/del polymorphism and +3142C>G SNP of the HLA-G gene have a significant impact on acute rejection after liver transplantation

Expression of human leukocyte antigen G (HLA-G) has been associated with increased graft survival and decreased rejection episodes. It has been described that the HLA-G 14-base pair (bp) insertion/deletion (ins/del) (rs66554220) and +3142C>G (rs1063320) gene polymorphisms modify the expression level of HLA-G. The aim of the study was to investigate whether these HLA-G polymorphisms have an impact on acute rejection after liver transplantation. In total, 146 liver transplant recipients (57 with acute rejection and 89 without acute rejection) and 99 corresponding liver donors were genotyped for both polymorphisms. In liver transplantation the 14-bp ins/ins and the +3142GG genotypes are more frequent in recipients without rejection compared to recipients with rejection (3.5% vs. 31.5%, p = <0.001; 12.3% vs. 41.6%, p = <0.001) demonstrating an association with protection from acute rejection. In contrast, in liver donors we could not reveal an association. We conclude that 14-bp ins/ins and +3142GG genotypes of HLA-G in liver transplant recipients are of importance for prediction of acute rejection after liver transplantation. Thus genotyping of liver recipients for both polymorphisms might be useful to stratify liver transplant recipients according to the risk of acute liver transplant rejection.     

Behavior of non-classical soluble HLA class G antigens in human immunodeficiency virus 1-infected patients before and after HAART: Comparison with classical soluble HLA-A, -B, -C antigens and potential role in immune-reconstitution

We have reported that serum level of soluble HLA-A, -B, -C (sHLA-A,-B,-C) antigens is elevated in HIV-infected subjects and decreases after antiretroviral therapy (HAART). In this study, we measured the levels of soluble HLA-G (sHLA-G) antigens in a cohort of HIV-infected patients before and during HAART. sHLA-G and sHLA-A, -B, -C levels were significantly elevated in HIV-infected subjects as compared with controls before antiretroviral treatment and significantly decreased after 36 months of HAART. sHLA-G levels were correlated with sHLA-A, -B, -C levels, the decrease of plasma HIV-RNA level, the increase of CD4+ T-lymphocyte number and the decrease of CD8+ T-lymphocyte number. These results suggest that the measurement of sHLA-G and sHLA-A, -B, -C antigen serum levels might represent a useful surrogate marker to monitor virological response and immune reconstitution in HIV-positive subjects undergoing HAART treatment.     

HLA-G expression in human ovarian carcinoma counteracts NK cell function.

BACKGROUND: Human leukocyte antigen-G (HLA-G) is an important immunotolerant which could be a part of the strategies applied by malignant cells applied to avoid host immunosurveillance. Aberrant expression of HLA-G has been found in ovarian carcinoma. The aim of this study was to evaluate the HLA-G expression in ovarian cancer tissues and to explore its function in vitro. MATERIALS AND METHODS: HLA-G expression in 33 primary ovarian carcinoma tissues was analyzed using immunohistochemistry with the anti-HLA-G monoclonal antibody (mAb) 4H84. Furthermore, the function of HLA-G in NK cell cytotoxicity was determined in vitro by cloning and expression of HLA-G on the ovarian carcinoma cell OVCAR-3. RESULTS: HLA-G expression was detected in 22/33 (66.7%) primary tumor tissues, but was absent in normal ovarian tissues (P<0.01). Cytotoxicity studies showed that HLA-G expression dramatically inhibits cell lyses by NK-92 cells (P<0.01), which could be restored by the anti-HLA-G conformational mAb 87G (P<0.01). CONCLUSION: HLA-G was expressed in a significant number of primary ovarian carcinoma tissues, and HLA-G expression in OVCAR-3 could directly inhibit NK-92 cell lysis. Taken together, our results indicated that expression of HLA-G plays an important role in evasion of ovarian cancer cells from host immunosurveillance.     

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.