NKG2A、NKG2C受体及其配体HLA-E在子痫前期患者蜕膜中的表达

目的 研究杀伤细胞C型凝集素样受体-1（KLC1或NKG2A）和受体-2（KLC2或NKG2C）及其配体人类白细胞抗原（HLA）-E在子痫前期患者蜕膜中的表达水平,探讨其与子痫前期发病的关系。方法 收集46例正常足月妊娠孕妇、30例轻度子痫前期和42例重度子痫前期患者的蜕膜标本,采用逆转录-聚合酶链反应法（RT-PCR）和免疫组化法检测蜕膜中NKG2A、NKG2C mRNA和受体蛋白的表达,以及HLA-E mRNA的表达。结果HLA-E mRNA的表达水平在子痫前期患者,特别是重度子痫前期患者蜕膜中降低（P<0.05）。重度子痫前期患者NKG2A、NKG2C mRNA和受体蛋白表达水平较正常足月妊娠孕妇增加（P<0.05）,重度子痫前期患者NKG2A和NKG2C表达水平之比较正常足月妊娠孕妇低（P<0.05）,且重度子痫前期组中NKG2C mRNA和受体蛋白表达水平较NKG2A高（P<0.05）。HLA-E和NKG2A、NKG2C mRNA表达水平均与孕晚期血压、24 h尿蛋白等临床及实验室指标相关。结论 HLA-E表达降低和NKG2A、NKG2C不均衡地表达增加可能参与了子痫前期发病机制。     

The ILT2(LIR1) and CD94/NKG2A NK cell receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells

Previous studies on NK recognition of HLA-G1 employed as targets 721.221 transfectants (.221-G1) that unknowingly co-expressed the HLA-E molecule, subsequently found to be a major ligand for the CD94/NKG2 receptors. In the present study we re-evaluated the relative role played by CD94/NKG2 and ILT2(LIR1) molecules in recognition of HLA-G1 by NK clones. We employed as targets .221-G1 cells and a surface HLA-E-negative transfectant, .221-G1(E_neg), generated by site-directed mutagenesis of the HLA-G1 leader sequence. The antagonistic effects of receptor- (i.e. CD94/NKG2A, ILT2) and ligand-specific mAb (i.e. HLA-G, HLA-E) were assessed. In addition, binding of an ILT2-Ig fusion protein to the .221-AEH, expressing only HLA-E, and the .221-G1(E_neg) transfectants was analyzed. Our data demonstrate that NK recognition of cells expressing HLA-G1 involves at least two non-overlapping receptor-ligand systems: the CD94/NKG2 interaction with HLA-E, and the engagement of the ILT2(LIR1) receptor by HLA-G1 molecules.     

Donor Unrestricted T Cells: Linking innate and adaptive immunity

Donor Unrestricted T Cells (DURTs) are characterized by their use of antigen presentation molecules that are often invariant. As these cells recognize diverse mycobacterial antigens, often found in BCG, these cells have the potential to either serve as targets for vaccination, or as a means to enable the induction of traditional T and B cell immunity. Here, we will review specific DURT family members, and their relationship to BCG.     

Immune-refractory cancers and their little helpers—An extended role for immunetolerogenic MHC molecules HLA-G and HLA-E?

There is strong evidence to support a role for non-classical MHC class I (class Ib) molecules, most notably HLA-E and HLA-G in tumour immune escape. In this article, we summarize the current knowledge on their expression, regulation and functional relevance in various malignancies, particularly brain tumours. Special emphasis is devoted to the phenomenon that these tolerogenic molecules are expressed by non-transformed cells that are found in close neighborhood to tumour cells representing either parenchymal cells or immune cells attracted to the tumour microenvironment. Here they may act as “natural” or “inducible” suppressors of anti-tumoural immune responses. We thus speculate about the role of HLA-G expressing T cells, a novel population of natural regulatory cells that was identified recently. It is suggested that various cell types within a tumour cooperate in order to inhibit anti-tumour immunity—and that immunetolerogenic HLA-G may play a major role in this context.     

NK细胞治疗多发性骨髓瘤的研究进展

多发性骨髓瘤（multiple myeloma,MM）是一种表达高水平HLA-E分子的血液系统常见的恶性肿瘤,其发病率占血液系统恶性疾病的第二位,至今仍无法治愈。HLA-E主要与自然杀伤细胞(natural killer cells,NK cells)表面的抑制性受体NKG2A相结合,起到抑制NK细胞杀伤功能的作用。从而使MM细胞逃逸NK细胞的免疫杀伤。而NK细胞具有强大的抗肿瘤作用以及良好的安全性,阻止HLA-E与NKG2A相互作用,恢复NK细胞的功能,可能对MM的治疗提供重大的帮助。本文将重点探讨NK细胞在治疗MM中的作用,包括恢复NK细胞自身功能以及过继性输注NK细胞的疗效。     

The Impact of HLA-G 3′UTR Polymorphisms in Breast Cancer in a Tunisian Population

Human leukocyte antigens G and E (HLA-G and HLA-E) are nonclassical major histocompatibility complex (MHC) class I molecules. These molecules play an important role in immune surveillance by inhibiting natural killer and cytotoxic T cells responsible for immune escape. The expression of HLA-G and HLA-E has been associated with several diseases including tumor. The main objective of the study is to evaluate the impact of three HLA-G 3?UTR potential polymorphisms: +3187 A > G (rs9380142), +3142 G > C (rs1063320), +2960 14-base pair (bp) Insertion/Deletion (Ins/Del) (rs66554220), and the HLA-E*01:01/01:03 A > G (rs1264457) polymorphism in Tunisian breast cancer population. A total of 355 patients and 381 controls were genotyping for HLA-G and HLA-E polymorphisms using a Taq Man assay. +3142 C allele and +3142 C/C genotype were significantly associated with increased risk of breast cancer (p = 0.00002; OR = 1.58; 95% CI = 27–1.97) (49% versus 35%; p = 0.0001; OR = 1.79; 95% CI = 1.32–2.44). In addition, Del allele and the homozygous state for Del/Del genotype confer a risk for breast cancer (52% versus 45%, p = 0.006; OR = 1.33, 95% CI = 1.08–1.64) (28% versus 22%, p = 0.039; OR = 1.43, 95% CI = 0.90–2.25). However, no statistical significant differences were reported for HLA-G + 3187 A > G and HLA-E variations and breast cancer in a Tunisian population.

The found results indicate that HLA-G may play an important role in the breast cancer.     

HLA-E*0101 and HLA-G*010101 reduce the risk of Behcet's disease

The nonclassical human leukocyte antigen (HLA)-E and -G molecules have previously been shown to inhibit natural killer- and cytotoxic T-lymphocyte-mediated cell lysis and have also been shown to prevent the proliferation of CD4 T cells and secrete cytokines that appear to be important in the modulation of the Behcet's disease (BD) immune systems. Polymorphisms in the HLA-E and HLA-G genes have been associated with differential expression and function. Thus, we conducted an analysis of the HLA-E and HLA-G alleles using Amplification Refractory Mutation System-polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism techniques in a study comprising 312 patients with BD and 486 controls. The HLA-E*0101 and HLA-G*010101 alleles were associated with a reduced risk of BD (P = 0.0002, odds ratio (OR) = 0.7 and P = 0.002, OR = 0.7, respectively). By way of contrast, the variants HLA-E*010302, HLA-G*010102, G*0105N alleles and 3741_3754ins14bp were all associated with an increased risk of BD (P < 0.0001, OR = 1.6; P = 0.002, OR = 1.8; P = 0.024, OR = 2.0 and P = 0.003, OR = 1.4, respectively). Individuals carrying both the HLA-E*0101 and the HLA-G*010101 alleles evidenced significantly lower frequency in the patients than in the controls (35.6% vs 49.6%; P < 0.0001, OR = 0.6). These results indicate that variant HLA-E and HLA-G molecules appear to function independently and synergistically, increasing the risk of BD, and may result in an imbalance of lymphocytic functions, which may culminate in the development of BD.     

007 妊娠免疫耐受与器官移植

正常妊娠显示母体对同种异体胎儿的免疫耐受.最近研究表明母胎耐受与非经典HLA-Ⅰ类分子HLA-G及HLA-E表达和TNF相关的凋亡诱导配体(TNF-related apoptosis-inducing ligand,TRAIL))及其受体TRAILR相互作用以及和Fas配体(FasL)表达有关.本文就这些分子在母胎耐受中的作用机制及在移植免疫中的应用前景作一综述.