可溶性MICA 在胆管癌患者外周血中表达及其临床意义

目的:探讨可溶性MICA(sMICA)在胆管癌患者外周血中的表达及其临床意义.方法:应用酶联免疫吸附试验法(ELISA)检测42例胆管癌患者的外周血sMICA的表达水平,分析其与临床病理特征的关系.结果:胆管癌患者血清sMICA水平显著高于正常对照组(P＜0.01);胆管癌患者血清中sMICA的表达水平与血清中CA19-9水平、肿瘤浸润及淋巴结转移等临床病理特征密切相关(P＜0.05);手术后胆管癌患者血清中sMICA水平明显下降.结论:胆管癌患者血清中sMICA水平明显增高,血清sMICA可作为胆管癌诊断的一种重要的指标.     

Down-regulation of the NKG2D ligand MICA by the human cytomegalovirus glycoprotein UL142

Human cytomegalovirus (HCMV) employs a variety of strategies to modify or evade the host immune response, and natural killer (NK) cells play a crucial role in controlling cytomegalovirus infections in mice and humans. Activation of NK cells through the receptor NKG2D/DAP10 leads to killing of NKG2D ligand-expressing cells. We have previously shown that HCMV is able to down-regulate the surface expression of some NKG2D ligands, ULBP1, ULBP2, and MICB via the viral glycoprotein UL16. Here, we show that the viral gene product UL142 is able to down-regulate another NKG2D ligand, MICA, leading to protection from NK cytotoxicity. UL142 is not able to affect surface expression of all MICA alleles, however, which may reflect selective pressure on the host to thwart viral immune evasion, further supporting an important role for the MICA-NKG2D interaction in immune surveillance.     

Soluble MICB in malignant diseases: analysis of diagnostic significance and correlation with soluble MICA

Expression of ligands of the immunoreceptor NKG2D such as MICA and MICB has been proposed to play an important role in the immunosurveillance of tumors. Proteolytic shedding of NKG2D ligands from cancer cells therefore constitutes an immune escape mechanism impairing anti-tumor reactivity by NKG2D-bearing cytotoxic lymphocytes. Serum levels of sMICA have been shown to be of diagnostic significance in malignant diseases of various origins. Here, we investigated the potential of soluble MICB, the sister molecule of MICA, as a marker in cancer and its correlation with soluble MICA. Analysis of MICB in sera of 512 individuals revealed slightly higher MICB levels in patients with various malignancies (N = 296; 95th percentile 216 pg/ml; P = 0.069) than in healthy individuals (N = 62; 95th percentile 51 pg/ml). Patients with benign diseases (N = 154; 95th percentile 198 pg/ml) exhibited intermediate MICB levels. In cancer patients, elevated MICB levels correlated significantly with cancer stage and metastasis (P = 0.007 and 0.007, respectively). Between MICB and MICA levels, only a weak correlation was found (r = 0.24). Combination of both markers resulted only in a slightly higher diagnostic power in the high specificity range. The reduction of MICA and MICB surface expression on cells by shedding and the effects of sMICA and sMICB in serum on host lymphocyte NKG2D expression might play a role in late stages of tumor progression by overcoming the confining effect of NK cells and CD8 T cells. While MICB levels are not suited for the diagnosis of cancer in early stages, they may provide additional information for the staging of cancer disease.Alexander Steinle and Helmut R. Salih contributed equally to this work.     

MICA 基因与肿瘤免疫关系的研究进展

MICA是主要组织相容性复合体I类分子链相关基因(MHC class I chain-related Gene,MIC)家族的功能性基因之一,具有较高的多态性。MICA蛋白在多数正常组织中并不表达,只在正常的胃肠道上皮和大多数上皮性肿瘤细胞表达。MICA可与C型凝集素样活化性受体NKG2D结合,从而影响多种免疫效应细胞的功能,在肿瘤免疫中发挥着重要作用。本文就MICA基因与肿瘤免疫关系的研究进展进行综述。     

MICA/B基因多态性与血吸虫病相关性研究

本研究采用PCR-SSP与PCR-SBT方法对正常健康对照组与血吸虫病感染组、血吸虫病性重度肝纤维化病人组和轻度肝纤维化病人组中MICA/B基因进行分型,并比较各组基因的多态性。结果在血吸虫感染组与健康对照组中共发现13种MICA等位基因和5种MICA-STR基因型,MICA*012:01(11.58%vs 5.83%)、MI-CA*017(2.11%vs 0.00%)及MICA*027(3.16%vs 0.97%)在对照人群组较血吸虫病人组中分布频率较高,但Pc值显示没有统计学意义(Pc>0.05)。MICA-STR型别分析显示,MICA-STR与血吸虫病易感没有相关性,但MICA*A5基因型的分布频率在重度肝纤维化组显著高于轻度肝纤维化组(45.10%vs 26.92%,Pc<0.05)。在血吸虫病人组中一共检出10种MICB等位基因。在本研究人群中未发现与日本血吸虫感染显著相关的MICB等位基因。同时MICB等位基因多态性在重度纤维化组、轻度纤维化组、以及正常对照组相互之间均无显著的相关性。研究显示在血吸虫病人组中,MICA和MICB具有连锁不平衡,其中单倍型MICB*008-MICA*002:01和MICB*014-MICA*045在血吸虫病人组中显示具有显著的连锁不平衡。     

Possible Polyphyletic Origin of Major Histocompatibility Complex Class I Chain-Related Gene A (MICA) Alleles

Phylogenetic relationships among 23 nonhuman primate (NHP) major histocompatibility complex class I chain-related gene (MIC) sequences, 54 confirmed human MICA alleles, and 16 human MICE alleles were constructed with methods of sequence analysis. Topology of the phylogenetic tree showed separation between NHP MICs and human MICs. For human MICs, the topology indicated monophyly for the MICB alleles, while MICA alleles were separated into two lineages, LI and LII. Of these, LI MICA alleles shared a common ancestry with gorilla (Ggo) MIC. One conservative amino acid difference and two nonconservative amino acid differences in the 3 domain were found between the MICA lineages. The nonconservative amino acid differences might imply structural and functional differences. Transmembrane (TM) trinucleotide-repeat variants were found to be specific to the MICA lineages such as A4, A9, and A10 to LI and A5 to LII. Variants such as A5.1 and A6 were commonly found in both MICA lineages. Based on these analyses, we postulate a polyphyletic origin for MICA alleles and their division into two lineages, LI and LII. As such, there would be 30 alleles in LI and 24 alleles in LII, thereby reducing the current level of polymorphism that exists, based on a presumed monophyletic origin. The lower degree of polymorphism in MICA would then be in line with the rest of the human major histocompatibility complex nonclassical class I genes.     

A hypoxia-induced decrease of either MICA/B or Hsp70 on the membrane of tumor cells mediates immune escape from NK cells

Recent findings suggest that hypoxia of the tumor microenvironment contributes to immune escape from natural killer (NK) cell-mediated cytotoxicity. Heat shock protein 70 (Hsp70) and the stress-regulated major histocompatibility class I chain-related protein A and B (MICA/B) both serve as ligands for activated NK cells when expressed on the cell surface of tumor cells. Herein, we studied the effects of hypoxia and hypoxia-inducible factor-1α (HIF-1α) on the membrane expression of these NK cell ligands in H1339 with high and MDA-MB-231 tumor cells with low basal HIF-1α levels and its consequences on NK cell-mediated cytotoxicity. We could show that a hypoxia-induced decrease in the membrane expression of MICA/B and Hsp70 on H1339 and MDA-MB-231 cells, respectively, is associated with a reduced sensitivity to NK cell-mediated lysis. A knockdown of HIF-1α revealed that the decreased surface expression of MICA/B under hypoxia is dependent on HIF-1α in H1339 cells with high basal HIF-1α levels. Hypoxia and HIF-1α did not affect the MICA/B expression in MDA-MB-231 cells but reduced the Hsp70 membrane expression which in turn also impaired NK cell recognition. Furthermore, we could show that the hypoxia-induced decrease in membrane Hsp70 is independent of HIF-1α in MDA-MB-231. Our data indicate that hypoxia-induced downregulation of both NK cell ligands MICA/B and Hsp70 impairs NK cell-mediated cytotoxicity, whereby only MICA/B appears to be regulated by HIF-1α.     

Histone deacetylase inhibitors suppress natural killer cell cytolytic activity

Treatment of transformed cells from leukemia or solid tumors with histone deacetylase inhibitors (HDACi) was shown to increase their sensitivity to NK cell lysis. In this study, treatment of IL-2-activated NK cells with HDACi including suberoylanilide hydroxamic acid and valproic acid was studied. Both drugs at therapeutic concentrations inhibited NK cell cytotoxicity on human leukemic cells. This inhibition was associated with decreased expression and function of NK cell activating receptors NKp46 and NKp30 as well as impaired granule exocytosis. NFkappaB activation in IL-2-activated NK cells was inhibited by both HDACi. Pharmacologic inhibition of NFkappaB activity resulted in similar effects on NK cell activity like those observed for HDACi. These results demonstrate for the first time that HDACi prevent NK cytotoxicity by downregulation of NK cell activating receptors probably through the inhibition of NFkappaB activation.     

可溶性MICA在胆管癌患者外周血中表达及其临床意义

目的：探讨可溶性MICA（sMICA）在胆管癌患者外周血中的表达及其临床意义。方法：应用酶联免疫吸附试验法（ELISA）检测42例胆管癌患者的外周血sMICA的表达水平,分析其与临床病理特征的关系。结果：胆管癌患者血清sMICA水平显著高于正常对照组（P〈0.01）;胆管癌患者血清中sMICA的表达水平与血清中CA19-9水平、肿瘤浸润及淋巴结转移等临床病理特征密切相关（P〈0.05）;手术后胆管癌患者血清中sMICA水平明显下降。结论：胆管癌患者血清中sMICA水平明显增高,血清sMICA可作为胆管癌诊断的一种重要的指标。