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Castelli EC, Ramalho J, Porto IOP, Lima THA, Felício LP, Sabbagh A, Donadi EA, Mendes-Junior CT. Insights into HLA-G Genetics Provided by Worldwide Haplotype Diversity. Front Immunol 2014; 5:476. [PMID: 25339953 PMCID: PMC4186343 DOI: 10.3389/fimmu.2014.00476] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 09/18/2014] [Indexed: 12/12/2022] Open
Abstract
Human leukocyte antigen G (HLA-G) belongs to the family of non-classical HLA class I genes, located within the major histocompatibility complex (MHC). HLA-G has been the target of most recent research regarding the function of class I non-classical genes. The main features that distinguish HLA-G from classical class I genes are (a) limited protein variability, (b) alternative splicing generating several membrane bound and soluble isoforms, (c) short cytoplasmic tail, (d) modulation of immune response (immune tolerance), and (e) restricted expression to certain tissues. In the present work, we describe the HLA-G gene structure and address the HLA-G variability and haplotype diversity among several populations around the world, considering each of its major segments [promoter, coding, and 3′ untranslated region (UTR)]. For this purpose, we developed a pipeline to reevaluate the 1000Genomes data and recover miscalled or missing genotypes and haplotypes. It became clear that the overall structure of the HLA-G molecule has been maintained during the evolutionary process and that most of the variation sites found in the HLA-G coding region are either coding synonymous or intronic mutations. In addition, only a few frequent and divergent extended haplotypes are found when the promoter, coding, and 3′UTRs are evaluated together. The divergence is particularly evident for the regulatory regions. The population comparisons confirmed that most of the HLA-G variability has originated before human dispersion from Africa and that the allele and haplotype frequencies have probably been shaped by strong selective pressures.
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Affiliation(s)
- Erick C Castelli
- Department of Pathology, School of Medicine of Botucatu, Universidade Estadual Paulista , Botucatu , Brazil
| | - Jaqueline Ramalho
- Department of Pathology, School of Medicine of Botucatu, Universidade Estadual Paulista , Botucatu , Brazil
| | - Iane O P Porto
- Department of Pathology, School of Medicine of Botucatu, Universidade Estadual Paulista , Botucatu , Brazil
| | - Thálitta H A Lima
- Department of Pathology, School of Medicine of Botucatu, Universidade Estadual Paulista , Botucatu , Brazil
| | - Leandro P Felício
- Biological Sciences Institute, Federal University of Goias , Goiânia , Brazil
| | - Audrey Sabbagh
- UMR 216, Institut de Recherche pour le Développement, MERIT , Paris , France ; Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité , Paris , France
| | - Eduardo A Donadi
- Division of Clinical Immunology, Department of Medicine, School of Medicine of Ribeirão Preto, University of São Paulo , Ribeirão Preto , Brazil
| | - Celso T Mendes-Junior
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, University of São Paulo , Ribeirão Preto , Brazil
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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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Castelli EC, Veiga-Castelli LC, Yaghi L, Moreau P, Donadi EA. Transcriptional and posttranscriptional regulations of the HLA-G gene. J Immunol Res 2014; 2014:734068. [PMID: 24741620 PMCID: PMC3987962 DOI: 10.1155/2014/734068] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Accepted: 01/16/2014] [Indexed: 01/20/2023] Open
Abstract
HLA-G has a relevant role in immune response regulation. The overall structure of the HLA-G coding region has been maintained during the evolution process, in which most of its variable sites are synonymous mutations or coincide with introns, preserving major functional HLA-G properties. The HLA-G promoter region is different from the classical class I promoters, mainly because (i) it lacks regulatory responsive elements for IFN-γ and NF-κB, (ii) the proximal promoter region (within 200 bases from the first translated ATG) does not mediate transactivation by the principal HLA class I transactivation mechanisms, and (iii) the presence of identified alternative regulatory elements (heat shock, progesterone and hypoxia-responsive elements) and unidentified responsive elements for IL-10, glucocorticoids, and other transcription factors is evident. At least three variable sites in the 3' untranslated region have been studied that may influence HLA-G expression by modifying mRNA stability or microRNA binding sites, including the 14-base pair insertion/deletion, +3142C/G and +3187A/G polymorphisms. Other polymorphic sites have been described, but there are no functional studies on them. The HLA-G coding region polymorphisms might influence isoform production and at least two null alleles with premature stop codons have been described. We reviewed the structure of the HLA-G promoter region and its implication in transcriptional gene control, the structure of the HLA-G 3'UTR and the major actors of the posttranscriptional gene control, and, finally, the presence of regulatory elements in the coding region.
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Affiliation(s)
- Erick C. Castelli
- Departamento de Patologia, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), 18618-970 Botucatu, SP, Brazil
| | - Luciana C. Veiga-Castelli
- Division of Clinical Immunology, Department of Medicine, School of Medicine of Ribeirao Preto, University of São Paulo (USP), 14049-900 Ribeirão Preto, SP, Brazil
| | - Layale Yaghi
- Alternative Energies and Atomic Energy Commission, Institute of Emerging Diseases and Innovative Therapies, Department of Hematology and Immunology Research, Saint-Louis Hospital, 75010 Paris, France
- Paris-Diderot University, Sorbonne Paris-Cité, UMR E5, University Institute of Hematology, Saint-Louis Hospital, 75010 Paris, France
| | - Philippe Moreau
- Alternative Energies and Atomic Energy Commission, Institute of Emerging Diseases and Innovative Therapies, Department of Hematology and Immunology Research, Saint-Louis Hospital, 75010 Paris, France
- Paris-Diderot University, Sorbonne Paris-Cité, UMR E5, University Institute of Hematology, Saint-Louis Hospital, 75010 Paris, France
| | - Eduardo A. Donadi
- Division of Clinical Immunology, Department of Medicine, School of Medicine of Ribeirao Preto, University of São Paulo (USP), 14049-900 Ribeirão Preto, SP, Brazil
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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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Menendez L, Walker LD, Matyunina LV, Totten KA, Benigno BB, McDonald JF. Epigenetic changes within the promoter region of the HLA-G gene in ovarian tumors. Mol Cancer 2008; 7:43. [PMID: 18498645 PMCID: PMC2429914 DOI: 10.1186/1476-4598-7-43] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2008] [Accepted: 05/22/2008] [Indexed: 12/05/2022] Open
Abstract
Background Previous findings have suggested that epigenetic-mediated HLA-G expression in tumor cells may be associated with resistance to host immunosurveillance. To explore the potential role of DNA methylation on HLA-G expression in ovarian cancer, we correlated differences in HLA-G expression with methylation changes within the HLA-G regulatory region in an ovarian cancer cell line treated with 5-aza-deoxycytidine (5-aza-dC) and in malignant and benign ovarian tumor samples and ovarian surface epithelial cells (OSE) isolated from patients with normal ovaries. Results A region containing an intact hypoxia response element (HRE) remained completely methylated in the cell line after treatment with 5-aza-dC and was completely methylated in all of the ovarian tumor (malignant and benign) samples examined, but only variably methylated in normal OSE samples. HLA-G expression was significantly increased in the 5-aza-dC treated cell line but no significant difference was detected between the tumor and OSE samples examined. Conclusion Since HRE is the binding site of a known repressor of HLA-G expression (HIF-1), we hypothesize that methylation of the region surrounding the HRE may help maintain the potential for expression of HLA-G in ovarian tumors. The fact that no correlation exists between methylation and HLA-G gene expression between ovarian tumor samples and OSE, suggests that changes in methylation may be necessary but not sufficient for HLA-G expression in ovarian cancer.
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Affiliation(s)
- Laura Menendez
- Department of Genetics, University of Georgia, Athens, GA 30605, USA.
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Abstract
HLA-G belongs to the non-classical HLA class-I family of genes presently designated as class-Ib genes. There are four membrane-bound (HLA-G1 to -G4) and three soluble forms (HLA-G5 to -G7) generated by alternative splicing of the primary transcript. HLA-G in the soluble form is found in the plasma, amniotic fluid, and cord blood of healthy individuals. Quantitative determination suggested that HLA-G levels are genetically controlled. While quantifying soluble HLA-G by ELISA, we observed that when plasma and serum levels were measured for the same individual, HLA-G plasma values were almost invariably higher than those from serum. Our results suggest that HLA-G is trapped and/or consumed during clot formation. The amount trapped within the clot is variable and inconsistent. To obtain values which reflect the true biological levels, it is therefore recommended that HLA-G should be determined in the plasma. If serum levels are determined, they should be compared with matched control sera. It should always be borne in mind that conclusions concerning sera levels might be erroneous, because the true plasma level of the protein can be significantly higher.
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Affiliation(s)
- N Rudstein-Svetlicky
- Tissue Typing Laboratory, Sheba Medical Center, and Tel Aviv University, Ramat Gan, Tel Aviv, Israel
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Langat DK, Morales PJ, Fazleabas AT, Hunt JS. Potential regulatory sequences in the untranslated regions of the baboon MHC class Ib gene, Paan-AG, more closely resemble those in the human MHC class Ia genes than those in the class Ib gene, HLA-G. Immunogenetics 2004; 56:657-66. [PMID: 15578264 DOI: 10.1007/s00251-004-0727-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2003] [Revised: 09/09/2004] [Indexed: 10/26/2022]
Abstract
The baboon major histocompatibility complex (MHC) class Ib gene, Paan-AG, is structurally similar to the human MHC class Ia gene, HLA-A, but exhibits characteristics similar to those of the class Ib gene HLA-G. These include limited polymorphism, alternative splicing of a single message, and restricted tissue distribution, with high expression in the placenta. In order to determine whether regulatory elements controlling expression of Paan-AG resemble those of HLA-A or HLA-G, we cloned the 5' and 3' untranslated regions of Paan-AG. Unexpectedly, sequence comparisons showed that potential regulatory elements in Paan-AG strikingly resembled those in HLA-A and differed in major respects from those in HLA-G. Unlike HLA-G, Paan-AG contained an intact interferon-gamma stimulated response element (ISRE) in the promoter. Studies using luciferase reporter assays showed that the Paan-AG ISRE was functional. The basal activity of the Paan-AG ISRE and its response to interferon-gamma was similar to that of class Ia MHC genes. Further, we identified an ISRE in the 3' untranslated region of Paan-AG that is known to be functional in HLA-A2 but is deleted in HLA-G. These experiments predict that functional studies may demonstrate differences in regulation of expression of Paan-AG and HLA-G genes, which could restrict the use of the baboon as a primate model for studying HLA-G expression and function.
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Affiliation(s)
- Daudi K Langat
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160-7400, USA
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Gazit E, Slomov Y, Goldberg I, Brenner S, Loewenthal R. HLA-G is associated with pemphigus vulgaris in Jewish patients. Hum Immunol 2004; 65:39-46. [PMID: 14700594 DOI: 10.1016/j.humimm.2003.09.019] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Pemphigus is a group of life-threatening autoimmune blistering diseases of the skin and mucous membranes. The etiology and pathogenesis of this destructive autoimmune process remains unknown, but significant association with human leukocyte antigen (HLA) factors have been described in pemphigus vulgaris (PV) patient cohorts worldwide. We have recently analyzed DNA samples obtained from pemphigus patients and matched controls with a set of microsatellite markers, and found that markers mapped to HLA class I region are significantly associated with the disease. In order to narrow the region that is associated with the disease single nucleotide polymorphism (SNP) technology was used. In this study, a set of 26 SNP markers, which span a chromosomal region of about 600,000 bp, were used to screen DNA samples of the patients and their matched controls. Of the 26 SNPs, four markers were found informative, all mapped to HLA-G. Typing patients and controls for HLA-G polymorphism revealed significant differences in the exon 8 deletion/insertion variant. The latter is probably associated with the efficiency of transcription of this gene. Taken together, the results suggest that HLA-G is associated with PV in Jewish patients.
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Affiliation(s)
- Ephraim Gazit
- Tissue Typing Laboratory, Sheba Medical Center, Tel-Hashomer, Israel.
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Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N. HLA-G Molecules: from Maternal–Fetal Tolerance to Tissue Acceptance. Adv Immunol 2003; 81:199-252. [PMID: 14711057 DOI: 10.1016/s0065-2776(03)81006-4] [Citation(s) in RCA: 257] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Over the past few years, HLA-G, the non-classical HLA class I molecule, has been the center of investigations that have led to the description of its specific structural and functional properties. Although located in the HLA class I region of chromosome six, the HLA-G gene may be distinguished from other HLA class I genes by its low polymorphism and alternative splicing that generates seven HLA-G proteins, whose tissue-distribution is restricted to normal fetal and adult tissues that display a tolerogeneic function toward both innate and acquired immune cells. We review these points, with special emphasis on the role of HLA-G in human pathologies, such as cancer, viral infection, and inflammatory diseases, as well as in organ transplantation.
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Affiliation(s)
- Edgardo D Carosella
- Service de Recherches en Hémato-Immunologie, Direction des Sciences du Vivant, Département de Recherche Médicale, CEA Commissariat à l'Energie Atomique, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 75010 Paris, France.
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Drénou B, Le Friec G, Bernard M, Pangault C, Grosset JM, Lamy T, Fauchet R, Amiot L. Major histocompatibility complex abnormalities in non-Hodgkin lymphomas. Br J Haematol 2002; 119:417-24. [PMID: 12406080 DOI: 10.1046/j.1365-2141.2002.03814.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
An optimal antitumoral immune response requires the participation of both CD8 and CD4 T lymphocytes, which are activated by peptide antigen presentation via human leucocyte antigen (HLA) class I and class II molecules respectively. Loss of HLA molecules has been observed in different malignancies, and provides a mechanism for escape from immune surveillance. Furthermore, HLA-G, a class Ib molecule, is considered to be an immune tolerance-inducing molecule. HLA-G expression on tumour cells could provide a further mechanism for immune escape. To determine the frequency and the pattern of HLA defects in non-Hodgkin lymphomas (NHL), HLA expression was prospectively studied in 614 NHL cases, using flow cytometry. Furthermore, HLA-G expression was tested in 50 cases, including 20 cases selected on the basis of their defective HLA class I expression. In 64 cases (10.4%), lymphomatous cells exhibited lower HLA class I mean fluorescence intensity compared with reactive cells. Their characteristics were (1) the diversity of histological entities; (2) the significant frequency of relapse or transformation; (3) the increased incidence of high-grade NHL compared with low-grade; and (4) the severity of the class I defect in 50% of the cases, mainly in high-grade NHL. A defect in HLA-DR expression was always associated with a severe class I defect (12 cases; 2%). The HLA-G protein was detected in three class I defective cases. These HLA alterations frequently appeared as a secondary event at relapse or at transformation, suggesting a direct role in lymphomagenesis.
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Affiliation(s)
- Bernard Drénou
- Laboratoire Universitaire d'Hématologie et de la Biologie des Cellules Sanguines, UPRES EA 22.33, Rennes, France.
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Gobin SJ, van den Elsen PJ. Transcriptional regulation of the MHC class Ib genes HLA-E, HLA-F, and HLA-G. Hum Immunol 2000; 61:1102-7. [PMID: 11137213 DOI: 10.1016/s0198-8859(00)00198-1] [Citation(s) in RCA: 102] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The restricted tissue expression of the MHC class Ib molecules HLA-E, HLA-F, and HLA-G has suggested specialized functions and tight transcriptional control of their genes. Transactivation of classical MHC class I genes is mediated by two groups of juxtaposed cis-acting elements, which can be viewed as regulatory modules. The most upstream module consists of the enhancer A and ISRE, and mediates constitutive and cytokine induced expression, whereas the SXY module is important for the constitutive and CIITA-mediated transactivation of MHC class I genes. Nucleotide sequence divergence in these regulatory elements in the promoters of HLA-E, HLA-F, or HLA-G determines their differential responsiveness to NF-kappaB, IRF1, and CIITA-mediated induction. HLA-E is not inducible by NF-kappaB or IRF1, but is responsive to IFN-gamma through an upstream STAT1 binding site. Furthermore, HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA. Both regulatory modules are divergent in HLA-G rendering this gene unresponsive to NF-kappaB, IRF1, and CIITA-mediated induction. This implies a unique regulation of HLA-G transcription amongst the MHC class Ib genes.
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Affiliation(s)
- S J Gobin
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
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