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Tsuneyoshi N, Hosoya T, Takeno Y, Saitoh K, Murai H, Amimoto N, Tatsumi R, Watanabe S, Hasegawa Y, Kikkawa E, Goto K, Nishigaki F, Tamura K, Kimura H. Hypoimmunogenic human iPSCs expressing HLA-G, PD-L1, and PD-L2 evade innate and adaptive immunity. Stem Cell Res Ther 2024; 15:193. [PMID: 38956724 PMCID: PMC11218117 DOI: 10.1186/s13287-024-03810-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 06/23/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND The human induced pluripotent stem cells (hiPSCs) can generate all the cells composing the human body, theoretically. Therefore, hiPSCs are thought to be a candidate source of stem cells for regenerative medicine. The major challenge of allogeneic hiPSC-derived cell products is their immunogenicity. The hypoimmunogenic cell strategy is allogenic cell therapy without using immune suppressants. Advances in gene engineering technology now permit the generation of hypoimmunogenic cells to avoid allogeneic immune rejection. In this study, we generated a hypoimmunogenic hiPSC (HyPSC) clone that had diminished expression of human leukocyte antigen (HLA) class Ia and class II and expressed immune checkpoint molecules and a safety switch. METHODS First, we generated HLA class Ia and class II double knockout (HLA class Ia/II DKO) hiPSCs. Then, a HyPSC clone was generated by introducing exogenous β-2-microglobulin (B2M), HLA-G, PD-L1, and PD-L2 genes, and the Rapamycin-activated Caspase 9 (RapaCasp9)-based suicide gene as a safety switch into the HLA class Ia/II DKO hiPSCs. The characteristics and immunogenicity of the HyPSCs and their derivatives were analyzed. RESULTS We found that the expression of HLA-G on the cell surface can be enhanced by introducing the exogenous HLA-G gene along with B2M gene into HLA class Ia/II DKO hiPSCs. The HyPSCs retained a normal karyotype and had the characteristics of pluripotent stem cells. Moreover, the HyPSCs could differentiate into cells of all three germ layer lineages including CD45+ hematopoietic progenitor cells (HPCs), functional endothelial cells, and hepatocytes. The HyPSCs-derived HPCs exhibited the ability to evade innate and adaptive immunity. Further, we demonstrated that RapaCasp9 could be used as a safety switch in vitro and in vivo. CONCLUSION The HLA class Ia/II DKO hiPSCs armed with HLA-G, PD-L1, PD-L2, and RapaCasp9 molecules are a potential source of stem cells for allogeneic transplantation.
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Affiliation(s)
- Norihiro Tsuneyoshi
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Tomonori Hosoya
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Yuriko Takeno
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Kodai Saitoh
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Hidetaka Murai
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Naoki Amimoto
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Rie Tatsumi
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Sono Watanabe
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Yudai Hasegawa
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Eri Kikkawa
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Kumiko Goto
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Fusako Nishigaki
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan
| | - Kouichi Tamura
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan.
| | - Hironobu Kimura
- HEALIOS K.K. Kobe Research Institute, Kobe KIMEC Center Bldg. 3F, 1-5-2 Minatojima-Minamimachi, Chuo-Ku, Kobe, Hyogo, 650-0047, Japan.
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Menzies FM. Immunology of Pregnancy and Systemic Consequences. Curr Top Microbiol Immunol 2023; 441:253-280. [PMID: 37695432 DOI: 10.1007/978-3-031-35139-6_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Pregnancy is an immunological paradox, with renowned Nobel Prize winning transplantation biologist Sir Peter Brian Medawar being the first to introduce this concept back in 1953. This concept considers how the maternal immune system can tolerate the developing fetus, which is 50% antigenically foreign to the uterus. There have been significant advances in our understanding of the immune system in regulating fertility, pregnancy and in complications of these, and what was once considered a paradox can be seen as a highly evolved system. Indeed, the complexity of the maternal-fetal interface along with our ever-advancing knowledge of immune cells and mediators means that we have a better understanding of these interactions, with gaps still present. This chapter will summarise the key aspects of the role of the immune system at each stage of pregnancy and highlight the recent advances in our knowledge.
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Affiliation(s)
- Fiona M Menzies
- School of Health and Life Sciences, University of the West of Scotland, Lanarkshire, UK.
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3
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Guettler J, Forstner D, Cvirn G, Maninger S, Brugger BA, Nonn O, Kupper N, Pritz E, Wernitznig S, Dohr G, Hutter H, Juch H, Isermann B, Kohli S, Gauster M. Maternal platelets pass interstices of trophoblast columns and are not activated by HLA-G in early human pregnancy. J Reprod Immunol 2021; 144:103280. [PMID: 33530024 DOI: 10.1016/j.jri.2021.103280] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/11/2020] [Accepted: 01/22/2021] [Indexed: 11/28/2022]
Abstract
In early human gestation, maternal arterial blood flow into the intervillous space of the developing placenta is obstructed by invaded trophoblasts, which form cellular plugs in uterine spiral arteries. These trophoblast plugs have recently been described to be loosely cohesive with clear capillary-sized channels into the intervillous space by 7 weeks of gestation. Here, we analysed localisation of maternal platelets at the maternal-foetal interface of human first trimester pregnancy, and tested the hypothesis whether HLA-G, which is primarily expressed by extravillous trophoblasts, affects aggregation and adhesion of isolated platelets. Immunohistochemistry of first trimester placental sections localised maternal platelets in vessel-like channels and adjacent intercellular gaps of extravillous trophoblasts in distal parts of columns. Furthermore, this localisation was confirmed by transmission electron microscopy. Neither co-incubation of HLA-G overexpressing JAR cells with isolated platelets, nor incubation with cell-derived soluble HLA-G or recombinant HLA-G affected platelet adhesion and aggregation. Our study suggests that maternal platelets flow through vessel-like channels of distal trophoblast columns and spread into adjacent lateral intercellular gaps, where platelet-derived factors could contribute to trophoblast differentiation into the invasive phenotype.
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Affiliation(s)
- Jacqueline Guettler
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Désirée Forstner
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Gerhard Cvirn
- Division of Physiological Chemistry, Otto Loewi Research Center, Medical University of Graz, Austria
| | - Sabine Maninger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Beatrice A Brugger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Olivia Nonn
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Nadja Kupper
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Elisabeth Pritz
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Stefan Wernitznig
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Gottfried Dohr
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Heinz Hutter
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Herbert Juch
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Berend Isermann
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Germany
| | - Shrey Kohli
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Germany
| | - Martin Gauster
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria.
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NKG2A/CD94 Is a New Immune Receptor for HLA-G and Distinguishes Amino Acid Differences in the HLA-G Heavy Chain. Int J Mol Sci 2020; 21:ijms21124362. [PMID: 32575403 PMCID: PMC7352787 DOI: 10.3390/ijms21124362] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/08/2020] [Accepted: 06/16/2020] [Indexed: 12/12/2022] Open
Abstract
Natural killer (NK) cell therapies are a tool to antagonize a dysfunctional immune system. NK cells recognize malignant cells, traffic to a tumor location, and infiltrate the solid tumor. The immune checkpoint molecule human leukocyte antigen (HLA)-G is upregulated on malignant cells but not on healthy surrounding cells, the requirement of understanding the basis of receptor mediated events at the HLA-G/NK cell interface becomes obvious. The NK cell receptors ILT2 and KIR2DL4 have been described to bind to HLA-G; however, their differential function and expression levels on NK cell subsets suggest the existence of an unreported receptor. Here, we performed a ligand-based receptor capture on living cells utilizing sHLA-G*01:01 molecules coupled to TriCEPS and bound to NK cells followed by mass spectrometric analyses. We could define NKG2A/CD94 as a cognate receptor of HLA-G. To verify the results, we used the reciprocal method by expressing recombinant soluble heterodimeric NKG2A/CD94 molecules and used them to target HLA-G*01:01 expressing cells. NKG2A/CD94 could be confirmed as an immune receptor of HLA-G*01:01. Despite HLA-G is marginal polymorphic, we could previously demonstrate that the most common allelic subtypes HLA-G*01:01/01:03 and 01:04 differ in peptide repertoire, their engagement to NK cells, their catalyzation of dNK cell proliferation and their impact on NK cell development. Continuing these studies with regard to NKG2A/CD94 engagement we engineered recombinant single antigen presenting K562 cells and targeted the surface expressed HLA-G*01:01, 01:03 or 01:04 molecules with NKG2A/CD94. Specificity and sensitivity of HLA-G*01:04/NKG2A/CD94 engagement could be significantly verified. The binding affinity decreases when using K562-G*01:03 or K562-G*01:01 cells as targets. These results demonstrate that the ligand-receptor assignment between HLA-G and NKG2A/CD94 is dependent of the amino acid composition in the HLA-G heavy chain. Understanding the biophysical basis of receptor-mediated events that lead to NK cell inhibition would help to remove non-tumor reactive cells and support personalized mild autologous NK cell therapies.
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Hirbod-Mobarakeh A, Shabani M, Keshavarz-Fathi M, Delavari F, Amirzargar AA, Nikbin B, Kutikhin A, Rezaei N. Immunogenetics of Cancer. CANCER IMMUNOLOGY 2020:417-478. [DOI: 10.1007/978-3-030-30845-2_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Buse E, Markert UR. The immunology of the macaque placenta: A detailed analysis and critical comparison with the human placenta. Crit Rev Clin Lab Sci 2019; 56:118-145. [PMID: 30632863 DOI: 10.1080/10408363.2018.1538200] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The cynomolgus monkey is increasingly considered in toxicological research as the most appropriate model for humans due to the species' close physiological contiguity, including reproductive physiology. Here, literature on the cynomolgus monkey placenta is reviewed in regards to its similarity to the human placenta and particularly for its immunological role, which is not entirely mirrored in humans. Pertinent original data are included in this article. The cynomolgus monkey placenta is evaluated based on three aspects: first, morphological development; second, the spatial and temporal appearance of maternal and fetal immune cells and certain immune cell products of the innate and adaptive immune systems; and third, the expression of relevant immune tolerance-related molecules including the homologs of anti-human leucocyte antigen, indoleamine 2,3-dioxygenase, FAS/FAS-L, annexin II, and progesterone. Parameters relevant to the immunological role of the placenta are evaluated from the immunologically immature stage of gestational day (GD) 50 until more mature stages close to birth. Selected comparisons are drawn with human and other laboratory animal placentas. In conclusion, the cynomolgus monkey placenta has a high degree of morphological and physiological similarity to the human placenta. However, there are differences in the topographical distribution of cell types and immune tolerance-related molecules. Three basic features are recognized: (1) the immunological capacity of the placenta changes throughout the lifetime of the organ; (2) these immunological changes include multiple parameters such as morphological adaptations, cell type involvement, and changes in immune-relevant molecule expression; and (3) the immune systems of two genetically disparate individuals (mother and child) are functionally intertwined at the maternal-fetal interface.
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Affiliation(s)
| | - Udo R Markert
- b Placenta Lab, Department of Obstetrics , University Hospital Jena , Jena , Germany
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7
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Abstract
In this chapter I describe Tumour Immune Escape mechanisms associated with MHC/HLA class I loss in human and experimental tumours. Different altered HLA class-I phenotypes can be observed that are produced by different molecular mechanisms. Experimental and histological evidences are summarized indicating that at the early stages of tumour development there is an enormous variety of tumour clones with different MHC class I expression patterns. This phase is followed by a strong T cell mediated immune-selection of MHC/HLA class-I negative tumour cells in the primary tumour lesion. This transition period results in a formation of a tumour composed only of HLA-class I negative cells. An updated description of this process observed in a large variety of human tumors is included. In the second section I focus on MHC/HLA class I alterations observed in mouse and human metastases, and describe the generation of different tumor cell clones with altered MHC class I phenotypes, which could be similar or different from the original tumor clone. The biological and immunological relevance of these observations is discussed. Finally, the interesting phenomenon of metastatic dormancy is analyzed in association with a particular MHC class I negative tumor phenotype.
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Affiliation(s)
- Federico Garrido
- Departamento de Analisis Clinicos e Inmunologia, Hospital Universitario Virgen de las Nieves, Facultad de Medicina, Universidad de Granada, Granada, Spain
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8
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Mociornita AG, Adamson MB, Tumiati LC, Ross HJ, Rao V, Delgado DH. Effects of everolimus and HLA-G on cellular proliferation and neutrophil adhesion in an in vitro model of cardiac allograft vasculopathy. Am J Transplant 2018; 18:3038-3044. [PMID: 29985558 DOI: 10.1111/ajt.15015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/03/2018] [Accepted: 07/04/2018] [Indexed: 01/25/2023]
Abstract
Human leukocyte antigen-G (HLA-G) expression is modulated by immunosuppressant use and is associated with lower incidence of graft rejection and cardiac allograft vasculopathy (CAV). We examined whether everolimus induces HLA-G expression and inhibits human coronary artery smooth muscle cell (HCASMC) proliferation, a critical event in CAV. Also, we examined whether TNFα-stimulated neutrophil adhesion is inhibited by HLA-G on human coronary artery endothelial cells (HCAECs). HLA-G expression in HCASMCs following everolimus treatment was determined by western-blot densitometric analysis. HCASMCs proliferation following incubation with recombinant HLA-G was determined by automated cell counter detecting 2-10 µm particles. Assessment of recombinant HLA-G on neutrophil adhesion to HCAECs in response to TNF-α induced-injury was determined by nonstatic adhesion assays. HLA-G expression was upregulated in HCASMCs following everolimus exposure (1000 ng/ml; P < .05). HLA-G (500, 1000 ng/ml; both P < .05) reduced HCASMC proliferation and inhibited TNFα-stimulated neutrophil adhesion to endothelial cells at all concentrations (0.1-1 ng/ml; all P < .001). Our study reveals novel regulation of HLA-G by everolimus, by demonstrating HLA-G upregulation and subsequent inhibition of HCASMC proliferation. HLA-G is a potent inhibitor of neutrophil adhesion to HCAECs. Findings support HLA-G's importance and potential use in heart transplantation for preventative therapy or as a marker to identify patients at high risk for developing CAV.
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Affiliation(s)
| | - Mitchell B Adamson
- Division of Cardiology, University Health Network, Toronto, Ontario, Canada
| | - Laura C Tumiati
- Division of Cardiology, University Health Network, Toronto, Ontario, Canada
| | - Heather J Ross
- Division of Cardiology, University Health Network, Toronto, Ontario, Canada
| | - Vivek Rao
- Division of Cardiovascular Surgery, University Health Network, Toronto, Ontario, Canada
| | - Diego H Delgado
- Division of Cardiology, University Health Network, Toronto, Ontario, Canada
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Lazarte J, Adamson MB, Tumiati LC, Delgado DH. 10-Year Experience with HLA-G in Heart Transplantation. Hum Immunol 2018; 79:587-593. [PMID: 29859206 DOI: 10.1016/j.humimm.2018.05.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 05/19/2018] [Accepted: 05/21/2018] [Indexed: 11/19/2022]
Abstract
The Human Leukocyte Antigen-G (HLA-G) is a MHC-class Ib molecule with robust immunomodulatory properties; in transplant, it inhibits cytotoxic activity of immune cells and thus has a pivotal role in protecting the allograft from immune attack. The present review details a 10-year experience investigating the influence of HLA-G on heart transplantation, allograft rejection and cardiac allograft vasculopathy development. Exploration of HLA-G in transplantation began with the initial findings of its increased expression in allograft hearts. Since then, HLA-G has been recognized as an important factor in transplant immunology. We discuss inducers of HLA-G expression, and the importance of HLA-G as a potential biomarker in allograft rejection and heart failure. We also highlight the importance of polymorphisms and how they may influence both HLA-G expression and clinical outcomes. There remains much to be done in this field, however we hope that findings from our group and other groups will ignite interest and facilitate further expansion of HLA-G research in transplantation.
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Affiliation(s)
- Julieta Lazarte
- Departments of Medicine, Schulich School of Medicine, Western University, London, Ontario, Canada.
| | - Mitchell B Adamson
- Department of Medicine, Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Laura C Tumiati
- Department of Cardiovascular Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Diego H Delgado
- Department of Cardiology, Hear Failure and Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
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Hahn EC, Zambra FMB, Kamada AJ, Delongui F, Grion CMC, Reiche EMV, Chies JAB. Association of HLA-G 3'UTR polymorphisms and haplotypes with severe sepsis in a Brazilian population. Hum Immunol 2017; 78:718-723. [PMID: 28941746 DOI: 10.1016/j.humimm.2017.09.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 08/16/2017] [Accepted: 09/19/2017] [Indexed: 11/25/2022]
Abstract
BACKGROUND The human leukocyte antigen G (HLA-G) is a molecule involved in immune system modulation, acting in the maintenance of a state of immune tolerance. Some polymorphisms in the HLA-G gene 3' untranslated region (3'UTR) were associated to distinct levels of HLA-G expression and to sepsis development. In the present study, haplotypes and polymorphisms of the HLA-G 3'UTR were analyzed in Brazilian septic patients. METHODS The HLA-G 3'UTR was amplified by PCR, sequenced and eight polymorphisms were genotyped (the 14bp insertion/deletion, +3003T/C, +3010C/G, +3027A/C, +3035C/T, +3142G/C, +3187A/G and+3196C/G) in DNA samples from septic patients (with severe sepsis or septic shock) and controls. The haplotypes were inferred and association tests were performed through Chi square test and binary logistic regression. RESULTS The+3027AC genotype was associated asa risk factor to sepsis development (OR 3.17, PBonferroni 0.048). Further, the presence of the UTR-7 haplotype (OR 2.97, PBonferroni 0.018), and of 14bp-Ins_+3142G_+3187A haplotype (OR 2.39, PBonferroni 0.045) were associated with sepsis, conferring susceptibility. CONCLUSION Our data confirm an important role of HLA-G 3'UTR polymorphisms in the development of severe forms of sepsis (severe sepsis and septic shock). The genotyping of HLA-G genetic variants and haplotypes could be useful as a prediction tool of increased risk to severe sepsis.
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Affiliation(s)
- Eriza Cristina Hahn
- Department of Genetics, Universidade Federal do Rio Grande do Sul - UFRGS, Porto Alegre, RS, Brazil.
| | - Francis Maria Báo Zambra
- Department of Genetics, Universidade Federal do Rio Grande do Sul - UFRGS, Porto Alegre, RS, Brazil.
| | - Anselmo Jiro Kamada
- Department of Genetics, Universidade Federal de Pernambuco - UFPE, Recife, PE, Brazil.
| | - Francieli Delongui
- Department of Pathology, Clinical Analysis and Toxicology, Universidade Estadual de Londrina - UEL, PR, Brazil.
| | - Cíntia Magalhães Carvalho Grion
- Department of Clinical Medicine, Health Sciences Center, University Hospital, Universidade Estadual de Londrina - UEL, PR, Brazil.
| | - Edna Maria Vissoci Reiche
- Department of Pathology, Clinical Analysis and Toxicology, Universidade Estadual de Londrina - UEL, PR, Brazil.
| | - José Artur Bogo Chies
- Department of Genetics, Universidade Federal do Rio Grande do Sul - UFRGS, Porto Alegre, RS, Brazil.
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Alizadeh N, Mosaferi E, Farzadi L, Majidi J, Monfaredan A, Yousefi B, Baradaran B. Frequency of null allele of Human Leukocyte Antigen-G (HLA-G) locus in subjects to recurrent miscarriage. Int J Reprod Biomed 2016. [DOI: 10.29252/ijrm.14.7.4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
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Transcriptomics: A Step behind the Comprehension of the Polygenic Influence on Oxidative Stress, Immune Deregulation, and Mitochondrial Dysfunction in Chronic Kidney Disease. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9290857. [PMID: 27419142 PMCID: PMC4932167 DOI: 10.1155/2016/9290857] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/10/2016] [Indexed: 12/17/2022]
Abstract
Chronic kidney disease (CKD) is an increasing and global health problem with a great economic burden for healthcare system. Therefore to slow down the progression of this condition is a main objective in nephrology. It has been extensively reported that microinflammation, immune system deregulation, and oxidative stress contribute to CKD progression. Additionally, dialysis worsens this clinical condition because of the contact of blood with bioincompatible dialytic devices. Numerous studies have shown the close link between immune system impairment and CKD but most have been performed using classical biomolecular strategies. These methodologies are limited in their ability to discover new elements and enable measuring the simultaneous influence of multiple factors. The “omics” techniques could overcome these gaps. For example, transcriptomics has revealed that mitochondria and inflammasome have a role in pathogenesis of CKD and are pivotal elements in the cellular alterations leading to systemic complications. We believe that a larger employment of this technique, together with other “omics” methodologies, could help clinicians to obtain new pathogenetic insights, novel diagnostic biomarkers, and therapeutic targets. Finally, transcriptomics could allow clinicians to personalize therapeutic strategies according to individual genetic background (nutrigenomic and pharmacogenomic). In this review, we analyzed the available transcriptomic studies involving CKD patients.
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Hirbod-Mobarakeh A, Amirzargar AA, Nikbin B, Nicknam MH, Kutikhin A, Rezaei N. Immunogenetics of Cancer. CANCER IMMUNOLOGY 2015:295-341. [DOI: 10.1007/978-3-662-44006-3_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Morandi F, Pistoia V. Interactions between HLA-G and HLA-E in Physiological and Pathological Conditions. Front Immunol 2014; 5:394. [PMID: 25202308 PMCID: PMC4141331 DOI: 10.3389/fimmu.2014.00394] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 07/31/2014] [Indexed: 01/08/2023] Open
Abstract
HLA-G and HLA-E are immunoregulatory molecules that belong to HLA-Ib family. The role of these molecules in the control of the immune response has been extensively analyzed, both in physiological and pathological conditions. We have here summarized data present in the literature regarding the interaction of these molecules in different settings. These data suggested that HLA-G and -E co-operate in physiological conditions (i.e., establishment of an immune tolerance at maternal/fetal interface during pregnancy), whereas their role in the course of tumors or autoimmune/inflammatory diseases may be different or even opposite. Future studies aimed at investigating the interaction between HLA-G and HLA-E will help to clarify mechanism(s) underlying the regulation of immune effector cells in health and disease.
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Affiliation(s)
- Fabio Morandi
- Laboratory of Oncology, Istituto Giannina Gaslini , Genoa , Italy
| | - Vito Pistoia
- Laboratory of Oncology, Istituto Giannina Gaslini , Genoa , Italy
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Sadissou I, d'Almeida T, Cottrell G, Luty A, Krawice-Radanne I, Massougbodji A, Moreau P, Moutairou K, Garcia A, Favier B, Rouas-Freiss N, Courtin D. High plasma levels of HLA-G are associated with low birth weight and with an increased risk of malaria in infancy. Malar J 2014; 13:312. [PMID: 25115633 PMCID: PMC4248443 DOI: 10.1186/1475-2875-13-312] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 06/08/2014] [Indexed: 12/29/2022] Open
Abstract
Background The immunosuppressive properties of HLA-G protein can create a tolerogenic environment that may allow Plasmodium falciparum to avoid host immune responses. There are known associations between high levels of circulating soluble HLA-G (sHLA-G) and either parasite or viral infections and it has been suggested that the induction of sHLA-G expression could be a mechanism via which infectious agents subvert host immune defence. The study presented here is the first to investigate the possible association between sHLA-G and malaria or malaria related risk factors in Benin. Methods A parasitological and clinical follow-up of 165 mothers and their newborns from delivery through to one year of age was conducted in the Tori Bossito area of southern Benin. Plasma levels of sHLA-G were determined by ELISA in maternal peripheral and cord blood and again in infants' peripheral blood at 3, 6, 9 and 12 months of age. The associations between the levels of sHLA-G and malaria risk factors were investigated through multivariate mixed models. Results Strong correlations were observed between the maternal and cord plasma concentrations of sHLA-G. In multivariate analyses, high cord plasma levels of sHLA-G were independently associated with (i) low birth weight and (ii) an increased risk of P. falciparum infection in infancy. Conclusion These results show for the first time the possible involvement of sHLA-G in generating immune tolerance during pregnancy-associated malaria. Soluble HLA-G may represent a useful marker of susceptibility to malaria in infants and be associated with the higher susceptibility to infection observed for LBW children.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - David Courtin
- Centre d'Etude et de Recherche sur le Paludisme Associé à la Grossesse et à l'Enfance, Faculté des Sciences de la Santé, Université d'Abomey-Calavi, Cotonou, Bénin.
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Rebmann V, da Silva Nardi F, Wagner B, Horn PA. HLA-G as a tolerogenic molecule in transplantation and pregnancy. J Immunol Res 2014; 2014:297073. [PMID: 25143957 PMCID: PMC4131093 DOI: 10.1155/2014/297073] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 05/07/2014] [Accepted: 05/21/2014] [Indexed: 12/28/2022] Open
Abstract
HLA-G is a nonclassical HLA class I molecule. In allogeneic situations such as pregnancy or allograft transplantation, the expression of HLA-G has been related to a better acceptance of the fetus or the allograft. Thus, it seems that HLA-G is crucially involved in mechanisms shaping an allogeneic immune response into tolerance. In this contribution we focus on (i) how HLA-G is involved in transplantation and human reproduction, (ii) how HLA-G is regulated by genetic and microenvironmental factors, and (iii) how HLA-G can offer novel perspectives with respect to therapy.
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Affiliation(s)
- Vera Rebmann
- Institute for Transfusion Medicine, University Hospital Essen, Virchowstraße 179, 45147 Essen, Germany
| | - Fabiola da Silva Nardi
- Institute for Transfusion Medicine, University Hospital Essen, Virchowstraße 179, 45147 Essen, Germany
- CAPES Foundation, Ministry of Education of Brazil, 70.040-020 Brasília, DF, Brazil
| | - Bettina Wagner
- Institute for Transfusion Medicine, University Hospital Essen, Virchowstraße 179, 45147 Essen, Germany
| | - Peter A. Horn
- Institute for Transfusion Medicine, University Hospital Essen, Virchowstraße 179, 45147 Essen, Germany
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Abstract
Human leukocyte antigen-G (HLA-G) is a low polymorphic nonclassical HLA-I molecule restrictively expressed and with suppressive functions. HLA-G gene products are quite complex, with seven HLA-G isoforms, four membrane bound, and other three soluble isoforms that can suffer different posttranslational modifications or even complex formations. In addition, HLA-G has been described included in exosomes. In this review we will focus on HLA-G biochemistry with special emphasis to the mechanisms that regulate its expression and how the protein modifications affect the quantification in biological fluids.
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Bortolotti D, Gentili V, Rotola A, Cassai E, Rizzo R, Luca DD. Impact of HLA-G analysis in prevention, diagnosis and treatment of pathological conditions. World J Methodol 2014; 4:11-25. [PMID: 25237627 PMCID: PMC4145573 DOI: 10.5662/wjm.v4.i1.11] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 12/28/2013] [Accepted: 01/16/2014] [Indexed: 02/06/2023] Open
Abstract
Human leukocyte antigen-G (HLA-G) is a non-classical HLA class I molecule that differs from classical HLA class I molecules by low polymorphism and tissue distribution. HLA-G is a tolerogenic molecule with an immune-modulatory and anti-inflammatory function on both innate and adaptative immunity. This peculiar characteristic of HLA-G has led to investigations of its role in pathological conditions in order to define possible uses in diagnosis, prevention and treatment. In recent years, HLA-G has been shown to have an important implication in different inflammatory and autoimmune diseases, pregnancy complications, tumor development and aggressiveness, and susceptibility to viral infections. In fact, HLA-G molecules have been reported to alternate at both genetic and protein level in different disease situations, supporting its crucial role in pathological conditions. Specific pathologies show altered levels of soluble (s)HLA-G and different HLA-G gene polymorphisms seem to correlate with disease. This review aims to update scientific knowledge on the contribution of HLA-G in managing pathological conditions.
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Bortolotti D, Gentili V, Rotola A, Di Luca D, Rizzo R. Implication of HLA-G 3′ untranslated region polymorphisms in human papillomavirus infection. ACTA ACUST UNITED AC 2014; 83:113-8. [DOI: 10.1111/tan.12281] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2013] [Revised: 11/29/2013] [Accepted: 12/02/2013] [Indexed: 11/30/2022]
Affiliation(s)
- D. Bortolotti
- Department of Medical Sciences, Section of Microbiology and Medical Genetics; University of Ferrara; Ferrara Italy
| | - V. Gentili
- Department of Medical Sciences, Section of Microbiology and Medical Genetics; University of Ferrara; Ferrara Italy
| | - A. Rotola
- Department of Medical Sciences, Section of Microbiology and Medical Genetics; University of Ferrara; Ferrara Italy
| | - D. Di Luca
- Department of Medical Sciences, Section of Microbiology and Medical Genetics; University of Ferrara; Ferrara Italy
| | - R. Rizzo
- Department of Medical Sciences, Section of Microbiology and Medical Genetics; University of Ferrara; Ferrara Italy
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21
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Tureck LV, Santos LC, Wowk PF, Mattar SB, Silva JS, Magalhães JCM, Roxo VMMS, Bicalho MG. HLA-G 5' URR SNPs and 3' UTR 14-bp insertion/deletion polymorphism in an Afro-Brazilian population from Paraná State. Int J Immunogenet 2013; 41:29-33. [PMID: 23829564 DOI: 10.1111/iji.12068] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Revised: 04/04/2013] [Accepted: 05/15/2013] [Indexed: 11/28/2022]
Abstract
The present study investigated 23 SNPs in the 5'URR promoter region and the 14 bp ins/del polymorphism at the 3'UTR region of the HLA-G gene in 150 individuals with Afro-Brazilian ancestry. Three haplotypes were found to be the most frequent. Comparing these polymorphisms in other samples, our data suggest that Afro-Brazilians are more similar to the Euro-Brazilians than to Hutterite population.
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Affiliation(s)
- L V Tureck
- Department of Genetics, Laboratory of Immunogenetics and Histocompatibility, Universidade Federal do Paraná, Curitiba, Brazil
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22
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Zaza G, Granata S, Rascio F, Pontrelli P, Dell'Oglio MP, Cox SN, Pertosa G, Grandaliano G, Lupo A. A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients. BMC Med Genomics 2013; 6:17. [PMID: 23663527 PMCID: PMC3655909 DOI: 10.1186/1755-8794-6-17] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Accepted: 05/07/2013] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) patients present a complex interaction between the innate and adaptive immune systems, in which immune activation (hypercytokinemia and acute-phase response) and immune suppression (impairment of response to infections and poor development of adaptive immunity) coexist. In this setting, circulating uremic toxins and microinflammation play a critical role. This condition, already present in the last stages of renal damage, seems to be enhanced by the contact of blood with bioincompatible extracorporeal hemodialysis (HD) devices. However, although largely described, the cellular machinery associated to the CKD- and HD-related immune-dysfunction is still poorly defined. Understanding the mechanisms behind this important complication may generate a perspective for improving patients outcome. METHODS To better recognize the biological bases of the CKD-related immune dysfunction and to identify differences between CKD patients in conservative (CKD) from those in HD treatment, we used an high-throughput strategy (microarray) combined with classical bio-molecular approaches. RESULTS Immune transcriptomic screening of peripheral blood mononuclear cells (1030 gene probe sets selected by Gene-Ontology) showed that 275 gene probe sets (corresponding to 213 genes) discriminated 9 CKD patients stage III-IV (mean±SD of eGFR: 32.27+/-14.7 ml/min) from 17 HD patients (p<0.0001, FDR=5%). Seventy-one genes were up- and 142 down-regulated in HD patients. Functional analysis revealed, then, close biological links among the selected genes with a pivotal role of PTX3, IL-15 (up-regulated in HD) and HLA-G (down-regulated in HD). ELISA, performed on an independent testing-group [11 CKD stage III-IV (mean±SD of eGFR: 30.26±14.89 ml/min) and 13 HD] confirmed that HLA-G, a protein with inhibition effects on several immunological cell lines including natural killers (NK), was down-expressed in HD (p=0.04). Additionally, in the testing-group, protein levels of CX3CR1, an highly selective chemokine receptor and surface marker for cytotoxic effector lymphocytes, resulted higher expressed in HD compared to CKD (p<0.01). CONCLUSION Taken together our results show, for the first time, that HD patients present a different immune-pattern compared to the un-dialyzed CKD patients. Among the selected genes, some of them encode for important biological elements involved in proliferation/activation of cytotoxic effector lymphocytes and in the immune-inflammatory cellular machinery. Additionally, this study reveals new potential diagnostic bio-markers and therapeutic targets.
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Affiliation(s)
- Gianluigi Zaza
- Renal Unit, Department of Medicine, University-Hospital of Verona, Piazzale A, Stefani 1, Verona 37126, Italy.
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23
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Alkhouly N, Shehata I, Ahmed MB, Shehata H, Hassan S, Ibrahim T. HLA-G expression in acute lymphoblastic leukemia: a significant prognostic tumor biomarker. Med Oncol 2013; 30:460. [PMID: 23335072 DOI: 10.1007/s12032-013-0460-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2012] [Accepted: 01/07/2013] [Indexed: 10/27/2022]
Abstract
Human leukocyte antigen G (HLA-G) is a non-classical major histocompatibility class Ib antigen with multiple immune regulatory functions including the induction of immune tolerance in malignancies. The goal of our study was to investigate the expression of membrane form of HLA-G in acute lymphoblastic leukemia (ALL) before and after therapy in a trial to evaluate its role as a tumor escape mechanism and prognosis. So we measured its expression by reverse transcription (RT)-PCR in peripheral blood mononuclear cells of 25 (ALL) patients and 15 healthy controls and correlated our findings with a variety of clinical and laboratory variables and two important cytokines, IL-10 and INF-γ, and with natural killer (NK) cells. Serum levels of IL-10 and INF-γ were measured by ELISA. NK cells were quantitated by flow cytometry. The best cutoff values for the investigated markers were determined by ROC curve. The current study showed that membrane-bound HLA-G expression levels and positivity rates above the cutoff value 0.37 were significantly higher in ALL patients at diagnosis compared to after therapy and both showed significant higher levels than in normal control group (P < 0.01). Moreover, IL-10 and INF-γ serum levels were significantly elevated in ALL patients at time of diagnosis compared to healthy controls with a significant reduction in their levels in ALL patients after receiving chemotherapy. Membrane HLA-G expression showed a significant positive correlation with lactate dehydrogenase, peripheral and bone marrow blast cells and with IL-10 and INF-γ. The positive correlation of membrane HLA-G expression with both IL-10 and INF-γ serum levels supports the speculation that both cytokines may be involved in the control of HLA-G expression. HLA-G showed a negative correlation with NK cells confirming its importance in tumor escape through down-regulation of NK cells. In conclusion, HLA-G expression could be used as a prognostic tumor marker to monitor disease state and improvement in ALL.
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Affiliation(s)
- Noura Alkhouly
- Medical Biochemistry, Faculty of Medicine, Ain Shams University, Abbasia, Cairo, Egypt
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24
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Martinez-Laso J, Herraiz MA, Peñaloza J, Barbolla ML, Jurado ML, Macedo J, Vidart J, Cervera I. Promoter sequences confirm the three different evolutionary lineages described for HLA-G. Hum Immunol 2012; 74:383-8. [PMID: 23220497 DOI: 10.1016/j.humimm.2012.11.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 11/16/2012] [Accepted: 11/27/2012] [Indexed: 01/03/2023]
Abstract
HLA-G alleles follow a different pattern of polymorphism generation that those of the HLA classical I alleles. However, this polymorphism maintenance could have an evolutionary specific pathways based on non coding regions as introns, 14 bp deletion/insertion (exon 8) or promoter regions. For this reason, a systematic sequencing study of HLA-G promoter region was done in 36 individuals with a total of 15 different alleles. From the 12 sequences obtained, 7 were new sequences and not previously described. Results show that the sequences have three different patterns of evolution confirming the results obtained in the rest of the sequence regions (exons, introns and 3'UTR) where three different lineages were established. Only one of these lineages includes the non-human primate promoter sequences suggesting the possibility of this lineage could come directly from non-human primates while the other two could be generated after the speciation. More non-human primates MHC-G promoter sequences must be obtained to confirm this hypothesis. Expression and functional assays could be done considering the differences obtained in the promoter regions involving the HLA-G function (mRNA expression, isoforms).
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Affiliation(s)
- J Martinez-Laso
- Unidad de Inmunoterapia Celular, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra. Majadahonda-Pozuelo, Km 2.2, 28220 Majadahonda, Madrid, Spain.
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25
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Shan G, Tang T, Zhang D. Expression of HLA-G in hemangioma and its clinical significance. ACTA ACUST UNITED AC 2012; 32:713-718. [DOI: 10.1007/s11596-012-1023-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Indexed: 11/30/2022]
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26
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Bortolotti D, Gentili V, Melchiorri L, Rotola A, Rizzo R. An accurate and reliable real time SNP genotyping assay for the HLA-G +3142 bp C>G polymorphism. ACTA ACUST UNITED AC 2012; 80:259-62. [PMID: 22775767 DOI: 10.1111/j.1399-0039.2012.01926.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Revised: 04/26/2012] [Accepted: 06/13/2012] [Indexed: 12/31/2022]
Abstract
Human leukocyte antigen (HLA)-G is a non classical HLA class I antigen with immuno-modulatory functions. The HLA-G gene is characterized by a +3142C>G variant in the 3' untranslated region which is suggested to control protein production and to be associated with pathological conditions. DNAs form 221 randomly selected healthy subjects were genotyped for HLA-G +3142C>G polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) (BaeGI), real-time PCR and sequencing. The 19% of the PCR-RFLP heterozygous samples were genotyped as 3142GG by real-time PCR and sequencing. This disagreement is caused by digestion efficiency in PCR-RFLP. This real-time PCR method will guarantee an accurate genotyping for future research and clinical purposes, where large cohorts should be tested.
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Affiliation(s)
- D Bortolotti
- Department of Experimental and Diagnostic Medicine, Section of Microbiology, University of Ferrara, Ferrara, 44121, Italy
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27
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Holder BS, Tower CL, Abrahams VM, Aplin JD. Syncytin 1 in the human placenta. Placenta 2012; 33:460-6. [PMID: 22381536 DOI: 10.1016/j.placenta.2012.02.012] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2011] [Revised: 01/27/2012] [Accepted: 02/09/2012] [Indexed: 12/27/2022]
Abstract
This study characterises HERV-W (syncytin 1) expression in normal and pathologic placenta and in BeWo cells. HERV-W mRNA levels were higher in the first trimester than at term, and similar patterns were observed with another retrovirally-derived mRNA species, ERV-3. N-glycosylated syncytin 1 precursor (73 kDa) is cleaved to surface-associated (SU) and transmembrane (TM) subunits. Both were evident in villous trophoblast, where perinuclear and punctate cytoplasmic deposits were observed, and linear TM subunit immunoreactivity was seen at the syncytial microvillous membrane. Punctate immunoreactivity was seen in BeWo cells with antibodies to SU and TM, and the two were co-localised. SU immunoreactivity was observed in association with fetal endothelium, and this effect was increased in tissue from pre-eclamptic placentas, which also showed a higher level of total SU protein. Absence of the TM subunit from endothelium suggests it is not a biosynthetic source. We suggest that SU is released from trophoblast into fetal circulation where it may bind vascular endothelium.
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Affiliation(s)
- B S Holder
- Division of Human Development, Maternal and Fetal Health Research Group, Manchester Academic Health Sciences Centre, Research Floor, St Mary's Hospital, Manchester M13 9WL, UK
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28
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Twito T, Joseph J, Mociornita A, Rao V, Ross H, Delgado DH. The 14-bp deletion in the HLA-G gene indicates a low risk for acute cellular rejection in heart transplant recipients. J Heart Lung Transplant 2011; 30:778-82. [PMID: 21482149 DOI: 10.1016/j.healun.2011.01.726] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2010] [Revised: 12/22/2010] [Accepted: 01/30/2011] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Human leukocyte antigen G (HLA-G) is a non-classical Ib molecule in the major histocompatibility complex. HLA-G has important immunosuppressive properties, and in the context of cardiac transplantation, is associated with a low risk of cellular rejection. A 14-bp insertion/deletion polymorphism in exon 8 of the HLA-G gene is associated with messenger RNA (mRNA) stability and expression of HLA-G. This study analyzed the relationship between HLA-G polymorphisms and serum HLA-G levels in patients after cardiac transplantation to determine if any specific HLA-G genotype is associated with cellular rejection. METHODS Ninety-four heart transplant patients were genotyped for the 14-bp polymorphism. Serum HLA-G levels and cellular rejection grades were evaluated in all patients. RESULTS The 14-bp polymorphism was significantly associated with serum HLA-G expression. Patients with the -14-bp/-14-bp genotype had significantly higher mean serum HLA-G levels (88.2 U/ml) than those patients with the +14-bp/-14-bp (52.8 U/ml) and +14-bp/+14-bp (32.2 U/ml) genotypes (p = 0.004). The -14 bp/-14-bp genotype was significantly associated with fewer episodes of cellular rejection. CONCLUSIONS This study suggests that the 14-bp deletion in the HLA-G gene plays an important role in the expression of HLA-G and thus might be a clinically useful genetic indicator for cellular rejection risk after cardiac transplantation.
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Affiliation(s)
- Tal Twito
- Department of Medicine, Division of Cardiology, Toronto General Hospital, Toronto, Ontario, Canada
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29
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Gonzalez A, Alegre E, Torres MI, Díaz-Lagares A, Lorite P, Palomeque T, Arroyo A. Evaluation of HLA-G5 plasmatic levels during pregnancy and relationship with the 14-bp polymorphism. Am J Reprod Immunol 2011; 64:367-74. [PMID: 20482523 DOI: 10.1111/j.1600-0897.2010.00855.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
PROBLEM Plasmatic HLA-G levels increase during pregnancy, but the contribution of each different isoform has not been elucidated yet. METHOD OF STUDY HLA-G5 was analyzed by ELISA in 19 controls, 79 women in the first 8 weeks of pregnancy and in nine women monthly until delivery. Genotyping for the 14-bp polymorphism was performed by PCR amplification of exon 8. RESULTS HLA-G5 was detected in plasma from 80% of pregnant women. The levels did not change during pregnancy, and there were no differences compared to control non-pregnant women. There was a high interindividual variation that was maintained throughout the pregnancy. The presence of +14-bp allele was associated with HLA-G5 positivity. Pregnant women who were heterozygotic to 14-bp polymorphism had significantly higher levels of HLA-G5 compared to -14 bp/-14-bp homozygotic. CONCLUSION Plasmatic HLA-G5 levels do not change during pregnancy and its concentration depends on 14-bp polymorphism.
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Affiliation(s)
- Alvaro Gonzalez
- Department of Biochemistry, University Clinic of Navarra, Pamplona, Spain.
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30
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Deschaseaux F, Delgado D, Pistoia V, Giuliani M, Morandi F, Durrbach A. HLA-G in organ transplantation: towards clinical applications. Cell Mol Life Sci 2011; 68:397-404. [PMID: 21103908 PMCID: PMC11114658 DOI: 10.1007/s00018-010-0581-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Accepted: 10/22/2010] [Indexed: 11/28/2022]
Abstract
HLA-G plays a particular role during pregnancy in which its expression at the feto-maternal barrier participates into the tolerance of the allogenic foetus. HLA-G has also been demonstrated to be expressed in some transplanted patients, suggesting that it regulates the allogenic response. In vitro data indicate that HLA-G modulates NK cells, T cells, and DC maturation through its interactions with various inhibitory receptors. In this paper, we will review the data reporting the HLA-G involvement of HLA-G in human organ transplantation, then factors that can modulate HLA-G, and finally the use of HLA-G as a therapeutic tool in organ transplantation.
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Affiliation(s)
| | - Diego Delgado
- Heart Transplant Program, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, ON Canada
| | - Vito Pistoia
- Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy
| | - Massimo Giuliani
- INSERM U1014, Département de Néphrologie, Hôpital du Kremlin-Bicêtre, IFRNT, Université Paris XI, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France
| | - Fabio Morandi
- Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy
| | - Antoine Durrbach
- INSERM U1014, Département de Néphrologie, Hôpital du Kremlin-Bicêtre, IFRNT, Université Paris XI, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France
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31
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Carosella ED, Gregori S, Rouas-Freiss N, LeMaoult J, Menier C, Favier B. The role of HLA-G in immunity and hematopoiesis. Cell Mol Life Sci 2011; 68:353-68. [PMID: 21116680 PMCID: PMC11114977 DOI: 10.1007/s00018-010-0579-0] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Accepted: 10/22/2010] [Indexed: 12/14/2022]
Abstract
The non-classical HLA class I molecule HLA-G was initially shown to play a major role in feto-maternal tolerance. Since this discovery, it has been established that HLA-G is a tolerogenic molecule which participates to the control of the immune response. In this review, we summarize the recent advances on (1) the multiple structures of HLA-G, which are closely associated with their role in the inhibition of NK cell cytotoxicity, (2) the factors that regulate the expression of HLA-G and its receptors, (3) the mechanism of action of HLA-G at the immunological synapse and through trogocytosis, and (4) the generation of suppressive cells through HLA-G. Moreover, we also review recent findings on the non-immunological functions of HLA-G in erythropoiesis and angiogenesis.
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Affiliation(s)
- Edgardo D Carosella
- CEA, I2BM, Service de Recherches en Hemato-Immunologie, 75475 Paris, France.
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32
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Kyurkchiev DS, Ivanova-Todorova E, Kyurkchiev SD. Effect of Progesterone on Human Mesenchymal Stem Cells. STEM CELL REGULATORS 2011; 87:217-37. [DOI: 10.1016/b978-0-12-386015-6.00040-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Frequency of HLA-G exon 8 polymorphisms and kidney allograft outcome in Iranian population. Mol Biol Rep 2010; 38:3593-7. [DOI: 10.1007/s11033-010-0470-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Accepted: 11/09/2010] [Indexed: 10/18/2022]
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34
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Cervera I, Herraiz MA, Peñaloza J, Barbolla ML, Jurado ML, Macedo J, Vidart JA, Martinez-Laso J. Human leukocyte antigen–G allele polymorphisms have evolved following three different evolutionary lineages based on intron sequences. Hum Immunol 2010; 71:1109-15. [DOI: 10.1016/j.humimm.2010.07.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2010] [Revised: 06/24/2010] [Accepted: 07/12/2010] [Indexed: 10/19/2022]
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35
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van Beekhuizen HJ, Joosten I, Lotgering FK, Bulten J, van Kempen LC. Natural killer cells and HLA-G expression in the basal decidua of human placenta adhesiva. Placenta 2010; 31:1078-84. [PMID: 20952056 DOI: 10.1016/j.placenta.2010.09.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2009] [Revised: 09/25/2010] [Accepted: 09/27/2010] [Indexed: 11/26/2022]
Abstract
Retained placenta is caused by abnormal adherence of the placenta to the uterine wall, leading to delayed expulsion of the placenta and causing postpartum haemorrhage. The mildest form of retained placenta is the placenta adhesiva (PA), of which the cause is unknown. The aim of our study was to explore possible differences in immune response in the basal decidua between PA and control placentas (CP). We performed a descriptive analysis of immunohistochemical differences in 17 PA and 10 CP. Our results show that in PA the amount of uterine natural killer (uNK) cells is significantly reduced (0.2 uNK cell/standardised area) as compared to CP (9.8 uNK cell/standardised area, p < 0.001) whereas the number of trophoblast cells and the expression of HLA-G by trophoblast are similar in the decidua of PA and CP. We speculate that adequate numbers of uNK cells in the basal decidua are needed for normal expulsion of the placenta.
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Affiliation(s)
- H J van Beekhuizen
- Department of Obstetrics & Gynaecology, Erasmus Medical Center, Rotterdam, The Netherlands.
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Kyurkchiev D, Ivanova-Todorova E, Kyurkchiev SD. New target cells of the immunomodulatory effects of progesterone. Reprod Biomed Online 2010; 21:304-11. [PMID: 20638907 DOI: 10.1016/j.rbmo.2010.04.014] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Revised: 04/01/2010] [Accepted: 04/07/2010] [Indexed: 01/08/2023]
Abstract
It is well known that the reproductive steroid hormones, particularly progesterone, in addition to its widely recognized effects on endometrial epithelial and stromal cells and spiral arteries, affect the activities of T cells and natural killer cells in the deciduas, thus inducing active immune tolerance against the fetal antigens. The immunomodulatory effects of progesterone on T cells, B cells and natural killer cells have been discussed extensively in the literature. The aim of the present review is to sum up and discuss the results from this and other laboratories of investigations on the effects of progesterone on dendritic cells and adult stem cells, which are some of the other cell populations present at the fetal-maternal interface and possibly are related to the immunoregulation during pregnancy. These cells have been shown to have a number of specific functions but their involvement in the entire process of regulation of the immune response in pregnancy is still under discussion. The present review focuses on facts showing that the progesterone is a kind of 'regulator of regulators' in the decidua, thus creating the most favourable conditions for the development of the semi-allogeneic fetus in successful pregnancy.
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Affiliation(s)
- Dobroslav Kyurkchiev
- Laboratory of Clinical Immunology, University Hospital St. Ivan Rilski, Medical University Sofia, 15 Acad. Ivan Geshov, 1431 Sofia, Bulgaria.
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Kyurkchiev S, Shterev A, Dimitrov R. Assessment of presence and characteristics of multipotent stromal cells in human endometrium and decidua. Reprod Biomed Online 2010; 20:305-13. [DOI: 10.1016/j.rbmo.2009.12.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2009] [Revised: 09/07/2009] [Accepted: 11/27/2009] [Indexed: 11/26/2022]
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Bijen CBM, Bantema-Joppe EJ, de Jong RA, Leffers N, Mourits MJE, Eggink HF, van der Zee AGJ, Hollema H, de Bock GH, Nijman HW. The prognostic role of classical and nonclassical MHC class I expression in endometrial cancer. Int J Cancer 2010; 126:1417-27. [PMID: 19728333 DOI: 10.1002/ijc.24852] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The aim of this study was to investigate classical MHC class I and nonclassical MHC (human leukocyte antigen-G [HLA-G]) expression in a large cohort of patients with endometrial cancer, to determine the prognostic value of these cell surface markers and their relation with clinicopathological variables. Tissue microarrays containing epithelial endometrial carcinoma tissue from 554 patients were stained for classical and nonclassical MHC class I using the following monoclonal antibodies: 4H84 (anti-HLA-G), beta2-m (anti-beta-2-microglobulin) and HC-10 (MHC class I antigen heavy chain). Expression data were linked to known clinicopathological characteristics and survival. HLA-G upregulation and MHC class I downregulation in neoplastic cells was observed in 40% and 48%, respectively. Nonendometrioid tumor type, advanced stage disease (FIGO stage > or = II) and poorly or undifferentiated tumors were associated with MHC class I downregulation. Absence of HLA-G expression was independently associated with MHC class I downregulation. In univariate analysis, MHC class I downregulation was a predictor of worse disease-specific survival. Prognostic unfavorable tumor characteristics were correlated with downregulation of MHC class I expression in endometrial cancer cells. Furthermore, downregulated MHC class I has a negative impact on disease-specific survival, observed in a large cohort of patients with endometrial cancer. As there seems to be a relation between classical and nonclassical MHC class I molecules (HLA-G), further research is warranted to unravel this regulatory mechanism.
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Affiliation(s)
- Claudia B M Bijen
- Department of Gynecologic Oncology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
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The structure and stability of the monomorphic HLA-G are influenced by the nature of the bound peptide. J Mol Biol 2010; 397:467-80. [PMID: 20122941 DOI: 10.1016/j.jmb.2010.01.052] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2009] [Revised: 01/22/2010] [Accepted: 01/22/2010] [Indexed: 11/21/2022]
Abstract
The highly polymorphic major histocompatibility complex class Ia (MHC-Ia) molecules present a broad array of peptides to the clonotypically diverse alphabeta T-cell receptors. In contrast, MHC-Ib molecules exhibit limited polymorphism and bind a more restricted peptide repertoire, in keeping with their major role in innate immunity. Nevertheless, some MHC-Ib molecules do play a role in adaptive immunity. While human leukocyte antigen E (HLA-E), the MHC-Ib molecule, binds a very restricted repertoire of peptides, the peptide binding preferences of HLA-G, the class Ib molecule, are less stringent, although the basis by which HLA-G can bind various peptides is unclear. To investigate how HLA-G can accommodate different peptides, we compared the structure of HLA-G bound to three naturally abundant self-peptides (RIIPRHLQL, KGPPAALTL and KLPQAFYIL) and their thermal stabilities. The conformation of HLA-G(KGPPAALTL) was very similar to that of the HLA-G(RIIPRHLQL) structure. However, the structure of HLA-G(KLPQAFYIL) not only differed in the conformation of the bound peptide but also caused a small shift in the alpha2 helix of HLA-G. Furthermore, the relative stability of HLA-G was observed to be dependent on the nature of the bound peptide. These peptide-dependent effects on the substructure of the monomorphic HLA-G are likely to impact on its recognition by receptors of both innate and adaptive immune systems.
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Shaikly V, Shakhawat A, Withey A, Morrison I, Taranissi M, Dealtry GB, Jabeen A, Cherry R, Fernández N. Cell bio-imaging reveals co-expression of HLA-G and HLA-E in human preimplantation embryos. Reprod Biomed Online 2010; 20:223-33. [PMID: 20113960 DOI: 10.1016/j.rbmo.2009.11.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2009] [Revised: 05/06/2009] [Accepted: 10/29/2009] [Indexed: 01/07/2023]
Abstract
The non-classical major histocompatibility complex (MHC) class Ib antigens, termed HLA-G and HLA-E, have been associated with fetal maternal tolerance. The role of HLA-G in the preimplantation embryo remains unclear although immunoprotection, adhesion and cell signalling mechanisms have been suggested. Unlike HLA-G, HLA-E protein expression has not been previously studied in preimplantation embryos. Embryos and model trophoblast cell lines JEG-3 and BeWo were labelled with the HLA-G- and HLA-E-specific monoclonal antibodies MEMG9 and MEME07. Flow cytometry, confocal microscopy and single particle fluorescence imaging techniques were employed to investigate the spatial and temporal expression of these receptors. Lipid raft analysis and adhesion assays were performed to investigate the role of these receptors in cell membrane domains and in promoting adhesion by cell-to-cell contact. HLA-E and HLA-G were co-localized in the trophectoderm of day 6 blastocysts. Analysis on trophoblast cell lines revealed that 37% of HLA-G and 41% of HLA-E receptors were co-localized as tetramers or higher order homodimer clusters. HLA-G receptors did not appear to play a role in either cell adhesion or immunoreceptor signalling via lipid raft platforms on the cell membrane. A possible role of HLA-G and HLA-E in implantation via immunoregulation or modulation of uterine maternal leukocytes is discussed.
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Affiliation(s)
- Valerie Shaikly
- Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO43SQ, UK
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Kusanovic JP, Romero R, Jodicke C, Mazaki-Tovi S, Vaisbuch E, Erez O, Mittal P, Gotsch F, Chaiworapongsa T, Edwin SS, Pacora P, Hassan SS. Amniotic fluid soluble human leukocyte antigen-G in term and preterm parturition, and intra-amniotic infection/inflammation. J Matern Fetal Neonatal Med 2009; 22:1151-66. [PMID: 19916713 PMCID: PMC3424396 DOI: 10.3109/14767050903019684] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE Circulating soluble human leukocyte antigen-G (sHLA-G) has been associated with pregnancy complications, and determination of sHLA-G concentrations in amniotic fluid (AF) has been reported in normal pregnancies. Our aim was to determine if the AF concentrations of sHLA-G change with advancing gestation, spontaneous labor at term, and in patients with spontaneous preterm labor (PTL) with intact membranes, as well as in those with preterm prelabor rupture of membranes (PROM), in the presence or absence of intra-amniotic infection/inflammation (IAI). STUDY DESIGN This cross-sectional study included the following groups: (1) mid-trimester (n = 55); (2) normal pregnancy at term with (n = 50) and without (n = 50) labor; (3) spontaneous PTL with intact membranes divided into: (a) PTL who delivered at term (n = 153); (b) PTL who delivered preterm without IAI (n = 108); and (c) PTL with IAI (n = 84); and (4) preterm PROM with (n = 46) and without (n = 44) IAI. sHLA-G concentrations were determined by ELISA. Non-parametric statistics were used for analysis. RESULTS (1) Among patients with PTL, the median AF sHLA-G concentration was higher in patients with IAI than in those without IAI or women that delivered at term (p < 0.001 for both comparisons); (2) Similarly, patients with preterm PROM and IAI had higher median AF sHLA-G concentrations than those without IAI (p = 0.004); (3) Among patients with PTL and delivery, those with histologic chorioamnionitis and/or funisitis had a higher median AF sHLA-G concentration than those without histologic inflammation (p < 0.001); and (4) The median AF sHLA-G concentration did not change with advancing gestational age. CONCLUSIONS AF sHLA-G concentrations are elevated in preterm parturition associated to IAI as well as in histologic chorioamnionitis. We propose that sHLA-G may participate in the regulation of the host immune response against intra-amniotic infection.
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Affiliation(s)
- Juan Pedro Kusanovic
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Roberto Romero
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, USA
| | - Cristiano Jodicke
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Shali Mazaki-Tovi
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Edi Vaisbuch
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Offer Erez
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Pooja Mittal
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Francesca Gotsch
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
| | - Tinnakorn Chaiworapongsa
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
| | - Sam S. Edwin
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
| | - Percy Pacora
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
| | - Sonia S. Hassan
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA
- Wayne State University School of Medicine, Department of Obstetrics and Gynecology, Detroit, Michigan, USA
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Erikci AA, Karagoz B, Ozyurt M, Ozturk A, Kilic S, Bilgi O. HLA-G expression in B chronic lymphocytic leukemia: a new prognostic marker? ACTA ACUST UNITED AC 2009; 14:101-5. [PMID: 19298722 DOI: 10.1179/102453309x385197] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by a malignant clonal population of lymphocytes, which are usually of the B cell lineage. Classical Rai and Binet staging of CLL is being superseded by new prognostic markers. The mutational status of the immunoglobulin variable region heavy-chain genes segregates the disease into more benign and more malignant versions, and has been confirmed as an important prognostic marker in prospective clinical trials. A search for surrogate markers for this assay has led to flow cytometric assays for CD38 and ZAP-70 expression. The human leukocyte antigen G (HLA-G) molecule exhibits limited tissue distribution and a low polymorphism that generate seven HLA-G isoforms. HLA-G exerts multiple immunoregulatory functions. Recent studies indicate an ectopic up-regulation in tumor cells that may favor their escape from anti-tumor immune responses. For this report we studied HLA-G in parallel with CD38 and ZAP-70 in B-cell chronic lymphocytic leukemia (B-CLL) patients. HLA-G expression was studied retrospectively in circulating B-CLL cells from 20 patients by flow cytometry using the anti-HLA-G specific monoclonal antibody MEM/G9. The proportion of leukemic cells expressing HLA-G varied from 1 to 34%. We detected a statistically significant correlation between HLA-G positive (>12%) expression and progression free survival (p=0.045), but no correlation with CD38 and ZAP-70. We also detected a statistically significant difference between Binet stage A; B and C (p=0.046) and a positive correlation between IL-10 and HLA-G (p=0.044). We conclude that positive HLA-G has an effect on progression - free survival, when compared with CD38 and ZAP-70.
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Affiliation(s)
- Alev Akyol Erikci
- Department of Hematology, Gulhane Military Hospital, Istanbul/Ankara, Turkey.
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Torres MI, Luque J, Lorite P, Isla-Tejera B, Palomeque T, Aumente MD, Arizon J, Peña J. 14-Base pair polymorphism of human leukocyte antigen-G as genetic determinant in heart transplantation and cyclosporine therapy monitoring. Hum Immunol 2009; 70:830-5. [PMID: 19638290 DOI: 10.1016/j.humimm.2009.07.012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2009] [Revised: 07/17/2009] [Accepted: 07/17/2009] [Indexed: 10/20/2022]
Abstract
The 14-base pair (bp) polymorphism within the HLA-G gene has been investigated in heart transplant patients for the first time. The 14-bp polymorphism is associated with HLA-G mRNA stability and the patterns of alternative isoforms splicing, and therefore may influence the functionality of the HLA-G molecule. In heart transplantation, the highest production of soluble HLA-G was related to the -14/-14-bp genotype in the pre- and post-transplantation periods. Our study findings showed that the 14-bp polymorphism of the HLA-G gene influenced the expression of soluble HLA-G in heart transplantation and accordingly resulted in low rejection rates, being a possible marker of genetic variability associated with heart transplantation. In addition, the 14-bp polymorphism of the HLA-G gene is related to the absorber status of cyclosporine of each individual patient, and is useful for determining the oral dose of cyclosporine to manage patients (to adjust immunosuppressive protocols) so as to minimize the risk of a low or high immunosuppression and the side effects in the early stages of heart transplantation.
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Affiliation(s)
- M I Torres
- Department of Experimental Biology, University of Jaen, Jaen, Spain.
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Ivanova-Todorova E, Mourdjeva M, Kyurkchiev D, Bochev I, Stoyanova E, Dimitrov R, Timeva T, Yunakova M, Bukarev D, Shterev A, Tivchev P, Kyurkchiev S. ORIGINAL ARTICLE: HLA-G Expression Is Up-Regulated by Progesterone in Mesenchymal Stem Cells. Am J Reprod Immunol 2009; 62:25-33. [DOI: 10.1111/j.1600-0897.2009.00707.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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Abstract
Human leucocyte antigen-G (HLA-G) plays a key role in maternal–foetal tolerance and allotransplantation acceptance and is also implicated in tumour escape from the immune system. The modulation of HLA-G expression can prove to be very important to therapeutic goals in some pregnancy complications, transplantation, cancer and possibly autoimmune diseases. In spite of substantial similarities with classical HLA-class I genes, HLA-G is characterized by a restricted tissue-specific expression in non-pathological situations. HLA-G expression is mainly controlled at the transcriptional level by a unique gene promoter when compared with classical HLA-class I genes, and at the post-transcriptional level including alternative splicing, mRNA stability, translation and protein transport to the cell surface. We focus on the characteristics of the HLA-G gene promoter and the factors which are involved in HLA-G transcriptional modulation. They take part in epigenetic mechanisms that control key functions of the HLA-G gene in the regulation of immune tolerance.
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Affiliation(s)
- Philippe Moreau
- Commissariat à l'Energie Atomique, Direction des Sciences du Vivant, I2BM, Service de Recherches en Hémato-Immunologie, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
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Can soluble human leucocyte antigen-G predict successful pregnancy in assisted reproductive technology? Curr Opin Obstet Gynecol 2009; 21:285-90. [DOI: 10.1097/gco.0b013e32832924cd] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Heterogeneous expression of HLA-G1, -G2, -G5, -G6, and -G7 in myeloid and plasmacytoid dendritic cells isolated from umbilical cord blood. Hum Immunol 2009; 70:104-9. [DOI: 10.1016/j.humimm.2008.12.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2008] [Revised: 11/17/2008] [Accepted: 12/04/2008] [Indexed: 11/21/2022]
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A critical look at HLA-G. Trends Immunol 2008; 29:313-21. [DOI: 10.1016/j.it.2008.02.012] [Citation(s) in RCA: 170] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2008] [Revised: 02/04/2008] [Accepted: 02/19/2008] [Indexed: 01/10/2023]
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The HLA-G 14bp gene polymorphism and decidual HLA-G 14bp gene expression in pre-eclamptic and normal pregnancies. J Reprod Immunol 2008; 78:158-65. [DOI: 10.1016/j.jri.2008.03.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2007] [Revised: 01/30/2008] [Accepted: 03/03/2008] [Indexed: 11/17/2022]
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Novel HLA-G-binding leukocyte immunoglobulin-like receptor (LILR) expression patterns in human placentas and umbilical cords. Placenta 2008; 29:631-8. [PMID: 18538388 DOI: 10.1016/j.placenta.2008.04.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2008] [Revised: 04/16/2008] [Accepted: 04/19/2008] [Indexed: 11/22/2022]
Abstract
Human placentas are sources of cytokines, hormones and other substances that program receptive cells. One of these substances is HLA-G, which influences the functioning of both leukocytes and endothelial cells. In this study, we investigated the possibility that these and/or other types of cells in extraembryonic fetal tissues might respond to HLA-G by interacting with one or another of the leukocyte immunoglobulin-like receptors (LILR). LILRB1 is expressed by most leukocytes and LILRB2 is expressed primarily by monocytes, macrophages and dendritic cells. Analysis of term placentas by immunohistochemistry and Real Time PCR demonstrated that LILRB1 and LILRB2 protein and specific messages are produced in the mesenchyme of term villous placenta but are differently localized. LILRB1 was abundant in stromal cells and LILRB2 was prominent perivascularly. Neither receptor was identified in trophoblast. Further investigation using double label immunofluorescence indicated that placental vascular smooth muscle but not endothelia exhibit LILRB2. Term umbilical cord exhibited the same LILRB2 patterns as term placenta. Samples obtained by laser capture dissection of vascular smooth muscle in umbilical cords demonstrated LILRB2 mRNA, and double label immunofluorescence showed that cord vascular smooth muscle but not endothelium exhibited LILRB2 protein. The presence of LILRB1 in placental stromal cells and LILRB2 in vascular smooth muscle strongly suggest that HLA-G has novel functions in these tissues that could include regulation of placental immunity as well as development and function of the extraembryonic vasculature.
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