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hla-g and single nucleotide polymorphism(SNP)associations with cancer in African populations:Implications in personal medicine

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genes & Diseases 2022年第5期9卷 1220-1233页

作者： Ismael Chatita Adolf Amany Almars Nazima Dharsee Teddy Mselle gokce Akan Irene Jeremiah Nguma Abdolrahman S.Nateri Fatmahan Atalar Mbeya College of Health and Allied Sciences University of Dar es SalaamMbeyaP.O Box 608Tanzania Cancer genetics&Stem Cell group BioDiscovery InstituteDivision of Cancer and Stem CellsSchool of MedicineUniversity of NottinghamNottinghamNG72UHUK Ocean Road Cancer Institute Department of OncologyDar es SalaamP.O Box 3592Tanzania Muhimbili University of Health and Allied Sciences MUHAS Genetic LaboratoryDepartment of BiochemistryDar es SalaamP.O Box 65001Tanzania Clinical Oncology Department Mbeya Zonal Referral Hospital(MZRH)Mbeya P.O Box 419Tanzania Child Health Institute Department of Rare DiseasesIstanbul UniversityIstanbul 34093Turkey

The immune system plays an important role in protecting the body against *** cancer immunoediting,the immune system can recognize and keep checking the tumor cells by down-expression of some self-molecules or by increasing expression of some novel ***,the microenvironment created in the course of cancer development hampers the immune ability to recognize and destroy the transforming *** Leukocyte Antigen g(hla-g)is emerging as immune checkpoint molecule produced more by cancer cells to weaken the immune response against ***-g is a non-classical hla class I molecule which is normally expressed in immune privileged tissues as a soluble or membrane-bound ***-g locus is highly polymorphic in the non-coding 3′untranslated region(UTR)and in the 5′upstream regulatory region(5′URR).hla-g expression is controlled by polymorphisms located in these regions,and several association studies between these polymorphic sites and disease predisposition,response to therapy,and/or hla-g protein expression have been *** polymorphisms are demonstrated to modulate its expression and this is increasingly finding more significance in cancer *** review focuses on the relevance of the hla-g gene and its polymorphisms in cancer *** highlight population genetics of hla-g as evidence to espouse the need and importance of exploring potential utility of hla-g in cancer diagnosis,prognosis and immunotherapy in the currently understudied African population.

关键词： African population Cancer hla-g Immune system checkpoints MHC Single nucleotide polymorphism

hla-g inhibits xenogenetic cytotoxicity mediated by human NK cells and T lymphocytes against PECs

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Chinese Science Bulletin 2003年第2期48卷 148-153页

作者： SHI Bin YIN Huijun HUANg Xiuying SUN Fangzhen Institute of genetics and Developmental Biology Chinese Academy of SciencesBeijing 100080China

In order to investigate whether the non-classi- cal hla-g classⅠmolecule protects the porcine endothelial cells (PECs) from the lysis mediated by human immune cells in pig to human discordant xenotransplantation, we have cloned hla-g cDNA from a human placenta by RT-PCR. Mammalian expression vector, pEFg-neo, was constructed by insertion of hla-g cDNA in pEF-neo. We obtained effi-ciently expressed PECs by stable transfection. Cytotoxicity assay showed that overexpression of hla-g on PECs was sufficient to inhibit human NK-92 cell lysis. The level of lysis was equal to or less than that of the lysis of human umbilical vein endothelial cells mediated by human NK-92 cells. It also indicated that hla-g inhibited the lysis of PECs mediated by xeno-antigen specific T lymphocytes. The reduction of lysis ranged between 59.1% and 88.9%. These findings sug-gest that the transgenic approach to overexpress hla-g is believed to be a new immunotherapy in overcoming the im-mune rejections in xenotransplantion, including delayed xenograft rejection and cell-mediated rejection.

关键词： hla-g xenotrasplantation immune rejection gene overexpression cytotoxicity

Residues Met76 and gln79 in hla-g α1 domain involved in KIR2DL4 recognition

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Cell Research 2005年第3期15卷 176-182页

作者： Wei Hua YAN1,2,*,Li An FAN1,2,** 1Laboratory of Immunogenetics,Shanghai Second Medical University,280 South Chongqing Road,Shanghai 200025,China 2Laboratory of Immunogenetics,Shanghai Institute of Immunology,280 South Chongqing Road,Shanghai 200025,China Laboratory of Immunogenetics Shanghai Second Medical University Shanghai China Laboratory of Immunogenetics Shanghai Institute of Immunology Shanghai China Laboratory Center Wenzhou Medical College Affiliated Taizhou Hospital LinHai China

Human leukocyte antigen-g (hla-g) has long been speculated as a beneficial factor for a successful pregnancy for its restricted expression on fetal-maternal extravillous cytotrophoblasts and its capability of modulating uterine natural killer cell (uNK) function such as cytotoxicity and cytokine production through NK cell receptors. hla class I α1 domain is an important killer cell Ig-like receptor (KIR) recognition site and the Met76 and gln79 are unique to hla-g in this region. NK cell receptor KIR2DL4 is a specific receptor for hla-g, yet the recognition site on hla-g remains unknown. In this study, retroviral transduction was applied to express the wild type hla-g (hla-wtg), mutant hla-g (hla-mg) on the chronic myelogenous leukemia cell line K562 cells and KIR2DL4 molecule on NK-92 cells, respectively. KIR2DL4-Igg Fc fusion protein was generated to determine the binding specificity between KIR2DL4 and hla-g. Our results showed that residue Met76, gln79 mutated to Ala76,79 in the α1 domain of hla-g protein could affect the binding affinity between KIR2DL4 and hla-g, meanwhile, the KIR2DL4 transfected NK-92 cells (NK-92- 2DL4) showed a considerably different cytolysis ability against the hla-wtg and hla-mg transfected K562 targets. Taken together, our data indicated that residue Met76 and gln79 in hla-g α1 domain plays a critical role in the recogni- tion of KIR2DL4, which could be an explanation for the isoforms of hla-g, all containing the α1 domain, with the potential to regulate NK functions.

关键词： NK cell KIR2DL4 hla-g receptor.

Induction of hla-g expression in a melanoma cell line OCM-1A following the treatment with 5-aza-2'-deoxycytidine

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Cell Research 2005年第7期15卷 523-531页

作者： Chien Chung CHANg,Soldano FERRONE Department of Immunology Roswell Park Cancer Institute Buffalo.NY 14263 USA Department of Immunology Roswell Park Cancer Institute Buffalo.NY 14263 USA

The non-classical hla class I antigen hla-g is an immune modulator which inhibits the functions of T cells, NK cells, and the Dendritic cells (DC). As a result, hla-g expression in malignant cells may provide them with a mechanism to escape the immune surveillance. In melanoma, hla-g antigen expression has been found in 30% of surgically removed lesions but in less than 1% of established cell lines. One possible mechanism underlying the differential hla-g expression in vivo and in vitro is that the hla-g gene is epigenetically repressed in melanoma cells in vitro. To test this hypothesis, we treated the hla-g negative melanoma cell line OCM-1A with the DNA methyltransferase inhibitor 5-aza-2'-deoXycytidine (5-AC) and analyzed whether hla-g expression can be restored. Our data strongly suggest that hla-g is silenced as a result of Cpg hypermethylation within a 5' regulatory region encompassing 220 bp upstream of the start codon. After treatment, hla-g mRNA expression was dramatically increased. Western blot and flow cytometry showed that hla-g protein was induced. Interestingly, hla-g cell surface expression on the 5-AC treated OCM-1 A cells is much less than that on the hla-g positive JEg-3 cells while a similar amount of total hla-g was observed. Possible mechanisms for the difference were analyzed in the study such as cell cold-treatment, peptide loading and antigen processing machinery components (APM) as well as β2 microglobulin (β2-m) expression. Data revealed that the APM component calreticulin might be involved in the lower hla-g surface expression on OCM-1 A cells. Taken together, our results indicated that DNA methylation is an important epigenetic mechanism by which hla-g antigen expression is modulated in melanoma cells in vitro. Furthermore, to the first time, we hypothesized that the deficiency of calreticulin might be involved in the low hla-g surface expression on the 5-AC treated OCM-1 A cells.

关键词： hla-g methylation 5-aza-2’-deoxycytidine APM.

Expression of hla-g in Hemangioma and Its Clinical Significance

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2012年第5期32卷 713-718页

作者：陕光唐甜张端莲 Department of Urology Renmin Hospital of Wuhan University Department of Oncology Renmin Hospital of Wuhan University Department of Anthropotomy and Histology and Embryology School of MedicineWuhan University

This study examined the roles of hla-g in the pathogenesis,development and immune tolerance of *** 2000 to 2007,52 paraffin-embedded specimens (26 from males and 26 from females) of skin capillary hemangioma and 7 samples of adjacent normal skin tissues were *** fresh specimens of hemangioma were also *** samples were HE-stained and proliferative cell nuclear antigen (PCNA) was immunohistochemically detected by using SP *** samples were classified into proliferative group and degenerative group according to the Mulliken criteria and the expression pattern of *** method and quantum dots double staining were applied to detect the expression of hla-g and PCNA in hemangioma and normal tissue *** expression of hla-g was detected by *** results showed that among the 52 samples of hemangioma,29 were of proliferative type and 23 degenerative type,and of the four fresh samples of hemangioma,2 were of proliferative type and 2 degenerative *** method results showed that hla-g was expressed in both proliferative and degenerative hemangioma,but not in normal *** quantum dots double staining exhibited that hla-g expression was significantly higher in proliferative group than in degenerative (Pgroups (Pgnificant difference between the latter two groups (P>0.05).RT-PCR revealed that hla-g was transcribed in both the proliferative and degenerative hemangioma tissues,but not in normal *** are led to conclude that the elevated expression of hla-g in proliferative hemangioma cells may lead to immune tolerance,which allows cells to escape immune surveillance and *** the other hand,the lower expres-sion of hla-g in degenerative hemangioma may result in immune cells-induced degeneration of hemangioma.

关键词： hemangioma hla-g immunohistochemistry quantum dots

黑色素瘤细胞OCM-1A中DNA甲基化对hla-g分子表达的影响

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中华微生物学和免疫学杂志 2006年第5期26卷 472-475页

作者：林爱芬颜卫华浙江省台州医院临海317000

目的探讨黑色素瘤细胞OCM-1A中表观遗传因素DNA甲基化对hla-g分子表达的影响。方法利用DNA甲基化抑制剂5-aza-2′-deoxycytidine(ADC)处理hla-g阴性黑色素瘤细胞OCM-1A,检测经不同浓度、不同时间的ADC处理后hla-g基因及蛋白表达的变化... 详细信息

目的探讨黑色素瘤细胞OCM-1A中表观遗传因素DNA甲基化对hla-g分子表达的影响。方法利用DNA甲基化抑制剂5-aza-2′-deoxycytidine(ADC)处理hla-g阴性黑色素瘤细胞OCM-1A,检测经不同浓度、不同时间的ADC处理后hla-g基因及蛋白表达的变化。序列测定分析ADC处理前后hla-g基因启动子区220bp片段的甲基化水平,RT-PCR检测hla-gmRNA水平的变化,Westernblot检测细胞hla-g分子合成总量以及FACS检测细胞表面hla-g分子的表达水平。结果hla-g阴性黑色素瘤细胞OCM-1A经ADC处理后,hla-g基因启动子区的Cpg甲基化程度明显降低,诱导hla-g基因转录,hla-g分子获得表达。hla-g基因及蛋白的表达水平与处理时间相关,随着处理时间的延长,hla-g表达量上升。结论OCM-1A细胞中,hla-g基因的表达调控受DNA甲基化影响,ADC对hla-g的表达调控具有时相性。

关键词： 5-aza-2'-deoxycytidine DNA甲基化黑色素瘤 hla-g

hla-g expression in the peripheral blood of live kidney transplant recipients

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Chinese Medical Journal 2013年第14期126卷 2652-2655页

作者： XIAO Li ZHOU Wen-qiang SHI Bing-yi FENg Kai HE Xiu-yun WEI Yu-xiang gAO Yu MENg Xiao-yun XIAO Wei Beijing Key Laboratory of Immunology Regulatory and Organ Transplantation Basic Research Lab of Organ Transplant Institue 309th Hospital of the People's Liberation Army Beijing 100091 China

Background The human leukocyte antigen-g （hla-g） has been considered to be an important tolerogeneic molecule playing an essential role in maternal-fetal tolerance, upregulated in the context of transplantation, malignancy, and inflammation, and has been correlated with various clinical outcomes. The aim of this study was to investigate the clinical relevance of the expression of membrane hla-g （mhla-g）, intracellular hla-g （ihla-g）, and soluble hla-g （shla-g） in the peripheral blood of live kidney transplant recipients. Methods We compared the expression of the three hla-g isoforms in three groups, healthy donors （n=20）, recipients with acute rejection （n=19）, and functioning transplants （n=30）. Flow cytometry was used to detect the expression of mhla-g and ihla-g in the T lymphocytes of peripheral blood from subjects in the three groups. Enzyme-linked immunosorbent assays were used to detect shla-g in the plasma from the three groups. Results There were no significant differences in mhla-g and intracellular hla-g among the three groups, but the shla-g plasma level was higher in the functioning group than in the acute rejection or healthy group. We found a subset of CD4＊hla-g~ and CD8~hla-g＋T lymphocytes with low rates of mhla-g expression in the peripheral blood of kidney transplantation recipients. Intracellular expression of hla-g was detected in T lymphocytes. However, there was no correlation between acute rejection and the mhla-g or intracellular hla-g expression. Conclusion shla-g was the major isoform in the peripheral blood of live kidney transplant recipients and high shla-g levels were associated with allograft acceptance.

关键词： hla-g kidney transplantation

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hla-g的遗传、功能及临床意义

中华医学遗传学杂志 2002年第4期19卷 350-353页

作者：孟海英侯一平四川大学华西基础医学和法医学院成都610041

HL A- g属非经典的 HL A 类分子 ,与经典的 HL A 类分子相比它有 3个特点 :(1)多态性水平低 ;(2 )体内分布局限于特定组织 ;(3)由于内含子和外显子间的剪接位点改变可形成 4种膜结合型和两种可溶型 HL A- g异构体。过去几年大量研究结... 详细信息

HL A- g属非经典的 HL A 类分子 ,与经典的 HL A 类分子相比它有 3个特点 :(1)多态性水平低 ;(2 )体内分布局限于特定组织 ;(3)由于内含子和外显子间的剪接位点改变可形成 4种膜结合型和两种可溶型 HL A- g异构体。过去几年大量研究结果表明 ,HL A- g是一种免疫耐受分子。在此将系统地介绍 HL A- g的遗传多态性、表达、功能、对免疫相关疾病的影响、演变及 HL A-

关键词： hla-g 人类白细胞抗原-g 遗传多态性滋养层免疫耐受

hla-g α1结构域Met^(76)和gln^(79)在KIR2DL4特异性识别中的作用研究

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中华微生物学和免疫学杂志 2006年第10期26卷 875-878页

作者：颜卫华林爱芬范丽安温州医学院附属浙江省台州医院临海317000

目的探讨hla-gα1结构域中特异的Met^(76)和gln^(79)两个位点在hla-g特异性受体KIR2DL4识别中的作用。方法采用真核表达载体CD51neg1,克隆表达KIR2DL4胞外区与Igg Fc段的可溶性融合蛋白；利用“桥式”PCR和“点突变”方法,将位于hla-g... 详细信息

目的探讨hla-gα1结构域中特异的Met^(76)和gln^(79)两个位点在hla-g特异性受体KIR2DL4识别中的作用。方法采用真核表达载体CD51neg1,克隆表达KIR2DL4胞外区与Igg Fc段的可溶性融合蛋白；利用“桥式”PCR和“点突变”方法,将位于hla-g目的基因α1结构域中编码Met^(76)和gln^(79)的密码子突变为Ala^(76,79)(hla-mg),通过逆转录病毒表达载体分别使野生型hla-g及其突变体在hlaI分子阴性的K562细胞上表达。流式细胞术分别测定KIR2DL4-Igg Fc融合蛋白与野生型hla-g及Met^(76)、gln^(79)→Ala^(76,79)hla-g突变体结合的荧光强度,通过比较两者的平均荧光强度分析hla-g分子Mel^(76)、gln^(79)残基在hla-g与其受体KIR2DL4识别过程中的作用。结果Western blot结果显示,本实验成功表达KIR2DL4-Igg Fc融合蛋白。FACS结果表明,野生型hla-g及Met^(76)、gln^(79)→Ala^(76,79)hla-g突变体在K562细胞上高表达。Met^(76)、gln^(79)突变为Ala^(76,79)后能显著影响KIR2DL4对hla-g分子的识别。结论hla-gα1结构域中Met^(76)和gln^(79)可能是其特异性受体KIR2DL4识别的关键位点。

关键词： KIR2DL4 hla-g 受体识别