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Arnaiz-Villena A, Suarez-Trujillo F, Ruiz-del-Valle V, Juarez I, Vaquero-Yuste C, Martin-Villa JM, Lledo T. The MHC (Major Histocmpatibility Complex) Exceptional Molecules of Birds and Their Relationship to Diseases. Int J Mol Sci 2025; 26:3767. [PMID: 40332403 PMCID: PMC12028091 DOI: 10.3390/ijms26083767] [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: 02/24/2025] [Revised: 03/14/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025] Open
Abstract
There are about 5000 species of Passeriformes birds, which are half of the extant ones. Their class I MHC molecules are found to be different from all other studied vertebrates, including other bird species; i.e., amino acid residues 10 and 96 are not the seven canonic residues extant in all other vertebrate molecules. Thus, the canonic residues in MHC class I vertebrate molecules are reduced to five. These differences have physical effects in MHC (Major Histocompatibility Complex) class I alpha chain interaction with beta-2-microglobulin but have yet unknown functional effects. Also, introns show specific Passeriformes distinction both in size and invariance. The studies reviewed in this paper on MHC structure have been done in wild birds that cover most of the world's passerine habitats. In this context, we are going to expose the most commonly occurring bird diseases with the caveat that MHC and disease linkage pathogenesis is not resolved. In addition, this field is poorly studied in birds; however, common bird diseases like malaria and Marek's disease are linked to MHC. On the other hand, the main established function of MHC molecules is presenting microbial and other antigens to T cells in order to start immune responses, and they also may modulate the immune system through NK receptors and other receptors (non-classical class I MHC molecules). Also, structural and polymorphic differences between classical class I molecules and non-classical class I molecules are at present not clear, and their definition is blurred. These passerine exceptional MHC class I molecules may influence linkage to diseases, transplantation, and other MHC presentation and self-protection functions. Further studies in more Passeriformes species are ongoing and needed.
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Affiliation(s)
- Antonio Arnaiz-Villena
- Department of Immunology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
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Arnaiz-Villena A, Suarez-Trujillo F, Juarez I, Rodríguez-Sainz C, Palacio-Gruber J, Vaquero-Yuste C, Molina-Alejandre M, Fernández-Cruz E, Martin-Villa JM. Evolution and molecular interactions of major histocompatibility complex (MHC)-G, -E and -F genes. Cell Mol Life Sci 2022; 79:464. [PMID: 35925520 PMCID: PMC9352621 DOI: 10.1007/s00018-022-04491-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 07/12/2022] [Accepted: 07/15/2022] [Indexed: 11/30/2022]
Abstract
Classical HLA (Human Leukocyte Antigen) is the Major Histocompatibility Complex (MHC) in man. HLA genes and disease association has been studied at least since 1967 and no firm pathogenic mechanisms have been established yet. HLA-G immune modulation gene (and also -E and -F) are starting the same arduous way: statistics and allele association are the trending subjects with the same few results obtained by HLA classical genes, i.e., no pathogenesis may be discovered after many years of a great amount of researchers' effort. Thus, we believe that it is necessary to follow different research methodologies: (1) to approach this problem, based on how evolution has worked maintaining together a cluster of immune-related genes (the MHC) in a relatively short chromosome area since amniotes to human at least, i.e., immune regulatory genes (MHC-G, -E and -F), adaptive immune classical class I and II genes, non-adaptive immune genes like (C2, C4 and Bf) (2); in addition to using new in vitro models which explain pathogenetics of HLA and disease associations. In fact, this evolution may be quite reliably studied during about 40 million years by analyzing the evolution of MHC-G, -E, -F, and their receptors (KIR-killer-cell immunoglobulin-like receptor, NKG2-natural killer group 2-, or TCR-T-cell receptor-among others) in the primate evolutionary lineage, where orthology of these molecules is apparently established, although cladistic studies show that MHC-G and MHC-B genes are the ancestral class I genes, and that New World apes MHC-G is paralogous and not orthologous to all other apes and man MHC-G genes. In the present review, we outline past and possible future research topics: co-evolution of adaptive MHC classical (class I and II), non-adaptive (i.e., complement) and modulation (i.e., non-classical class I) immune genes may imply that the study of full or part of MHC haplotypes involving several loci/alleles instead of single alleles is important for uncovering HLA and disease pathogenesis. It would mainly apply to starting research on HLA-G extended haplotypes and disease association and not only using single HLA-G genetic markers.
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Affiliation(s)
- Antonio Arnaiz-Villena
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense de Madrid, Pabellón 5, planta 4. Avda. Complutense s/n, 28040, Madrid, Spain.
| | - Fabio Suarez-Trujillo
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense de Madrid, Pabellón 5, planta 4. Avda. Complutense s/n, 28040, Madrid, Spain
| | - Ignacio Juarez
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense de Madrid, Pabellón 5, planta 4. Avda. Complutense s/n, 28040, Madrid, Spain
| | - Carmen Rodríguez-Sainz
- Instituto de Investigaciones Sanitarias Gregorio Marañón, Hospital Gregorio Marañón, Madrid, Spain
| | - José Palacio-Gruber
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense de Madrid, Pabellón 5, planta 4. Avda. Complutense s/n, 28040, Madrid, Spain
| | - Christian Vaquero-Yuste
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense de Madrid, Pabellón 5, planta 4. Avda. Complutense s/n, 28040, Madrid, Spain
| | - Marta Molina-Alejandre
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense de Madrid, Pabellón 5, planta 4. Avda. Complutense s/n, 28040, Madrid, Spain
| | - Eduardo Fernández-Cruz
- Instituto de Investigaciones Sanitarias Gregorio Marañón, Hospital Gregorio Marañón, Madrid, Spain
| | - José Manuel Martin-Villa
- Departamento de Inmunología, Facultad de Medicina, Universidad Complutense de Madrid, Pabellón 5, planta 4. Avda. Complutense s/n, 28040, Madrid, Spain
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Piekarska K, Radwan P, Tarnowska A, Wiśniewski A, Krasiński R, Radwan M, Wilczyński JR, Malinowski A, Nowak I. The Association of HLA-G Gene Polymorphism and Its Soluble Form With Male Infertility. Front Immunol 2022; 12:791399. [PMID: 35111159 PMCID: PMC8801424 DOI: 10.3389/fimmu.2021.791399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/28/2021] [Indexed: 11/25/2022] Open
Abstract
Successful reproduction depends on many factors. Male factors contribute to infertility in approximately 50% of couples who fail to conceive. Seminal plasma consists of secretions from different accessory glands containing a mixture of various cytokines, chemokines, and growth factors, which together can induce a local immune response that might impact on a male’s as well as a female’s fertility. Human leukocyte antigen (HLA)-G expression has been suggested as an immunomodulatory molecule that influences pregnancy outcome. The HLA-G gene encodes either membrane-bound or/and soluble proteins. The aim of this study was the evaluation of HLA-G polymorphisms and their impact on soluble HLA-G (sHLA-G) production. We tested the HLA-G polymorphism in three positions: rs1632947: c.-964G>A; rs1233334: c.-725G>C/T in the promoter region; rs371194629: c.∗65_∗66insATTTGTTCATGCCT in the 3′ untranslated region. We tested two cohorts of men: 663 who participated in in vitro fertilization (test material was blood or sperm), and 320 fertile controls who possessed children born after natural conception (test material was blood). Since 50% of men visiting assisted reproductive clinics have abnormal semen parameters, we wondered if men with normal sperm parameters differ from those with abnormal parameters in terms of HLA-G polymorphism and secretion of sHLA-G into semen. We found that certain rs1632947-rs1233334-rs371194629 HLA-G haplotypes and diplotypes were associated with male infertility, while others were protective. Normozoospermic men with the A-C-del haplotype and A-C-del/A-C-del diplotype secreted the most sHLA-G into semen (574.1 IU/mL and 1047.0 IU/mL, respectively), while those with the G-C-ins haplotype and G-C-ins/G-C-ins diplotype – the least (80.8 IU/mL and 75.7 IU/mL, respectively). Men with the remaining haplotypes/diplotypes secreted sHLA-G at an intermediate level. However, only in one haplotype, namely G-C-ins, did we observe strong significant differences in the concentration of sHLA-G in the semen of men with teratozoospermia compared to men with normal sperm parameters (p = 0.009). In conclusion, fertile men differ in the profile of HLA-G polymorphism from men participating in IVF. Among all HLA-G haplotypes, the most unfavorable for male fertility is the G-C-ins haplotype, which determines the secretion of the lowest concentration of the soluble HLA-G molecule. This haplotype may reduce sperm parameters.
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Affiliation(s)
- Karolina Piekarska
- Department of Clinical Immunology, Laboratory of Immunogenetics and Tissue Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Paweł Radwan
- Department of Reproductive Medicine, Gameta Hospital, Rzgów, Poland
| | - Agnieszka Tarnowska
- Department of Clinical Immunology, Laboratory of Immunogenetics and Tissue Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Andrzej Wiśniewski
- Department of Clinical Immunology, Laboratory of Immunogenetics and Tissue Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Rafał Krasiński
- Department of Reproductive Medicine, Gameta Hospital, Rzgów, Poland
| | - Michał Radwan
- Department of Reproductive Medicine, Gameta Hospital, Rzgów, Poland.,Faculty of Health Sciences, The State University of Applied Sciences in Płock, Płock, Poland
| | - Jacek R Wilczyński
- Department of Surgical and Oncological Gynecology, Medical University of Łódź, Łódź, Poland
| | - Andrzej Malinowski
- Department of Surgical, Endoscopic and Oncologic Gynecology, Polish Mothers' Memorial Hospital-Research Institute, Łódź, Poland
| | - Izabela Nowak
- Department of Clinical Immunology, Laboratory of Immunogenetics and Tissue Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
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Duygu B, Olieslagers TI, Groeneweg M, Voorter CEM, Wieten L. HLA Class I Molecules as Immune Checkpoints for NK Cell Alloreactivity and Anti-Viral Immunity in Kidney Transplantation. Front Immunol 2021; 12:680480. [PMID: 34295330 PMCID: PMC8290519 DOI: 10.3389/fimmu.2021.680480] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 06/14/2021] [Indexed: 12/12/2022] Open
Abstract
Natural killer (NK) cells are innate lymphocytes that can kill diseased- or virally-infected cells, mediate antibody dependent cytotoxicity and produce type I immune-associated cytokines upon activation. NK cells also contribute to the allo-immune response upon kidney transplantation either by promoting allograft rejection through lysis of cells of the transplanted organ or by promoting alloreactive T cells. In addition, they protect against viral infections upon transplantation which may be especially relevant in patients receiving high dose immune suppression. NK cell activation is tightly regulated through the integrated balance of signaling via inhibitory- and activating receptors. HLA class I molecules are critical regulators of NK cell activation through the interaction with inhibitory- as well as activating NK cell receptors, hence, HLA molecules act as critical immune checkpoints for NK cells. In the current review, we evaluate how NK cell alloreactivity and anti-viral immunity are regulated by NK cell receptors belonging to the KIR family and interacting with classical HLA class I molecules, or by NKG2A/C and LILRB1/KIR2DL4 engaging non-classical HLA-E or -G. In addition, we provide an overview of the methods to determine genetic variation in these receptors and their HLA ligands.
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Affiliation(s)
- Burcu Duygu
- Department of Transplantation Immunology, Maastricht University Medical Center, Maastricht, Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Timo I Olieslagers
- Department of Transplantation Immunology, Maastricht University Medical Center, Maastricht, Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Mathijs Groeneweg
- Department of Transplantation Immunology, Maastricht University Medical Center, Maastricht, Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Christina E M Voorter
- Department of Transplantation Immunology, Maastricht University Medical Center, Maastricht, Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Lotte Wieten
- Department of Transplantation Immunology, Maastricht University Medical Center, Maastricht, Netherlands.,GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
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Nowak I, Wilczyńska K, Radwan P, Wiśniewski A, Krasiński R, Radwan M, Wilczyński JR, Malinowski A, Kuśnierczyk P. Association of Soluble HLA-G Plasma Level and HLA-G Genetic Polymorphism With Pregnancy Outcome of Patients Undergoing in vitro Fertilization Embryo Transfer. Front Immunol 2020; 10:2982. [PMID: 31993049 PMCID: PMC6971053 DOI: 10.3389/fimmu.2019.02982] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 12/04/2019] [Indexed: 01/31/2023] Open
Abstract
Infertility is currently a growing problem observed around the world and is estimated to affect between 8 and 12% of reproductive-aged couples worldwide. Artificial reproductive techniques are the last chance for couples seeking their own child. Human leukocyte antigen (HLA)-G expression has been suggested as an immunomodulatory molecule that influences pregnancy outcome. The HLA-G gene encodes either membrane-bound or/and soluble proteins. The aim of this study was the evaluation of the role of soluble HLA-G (sHLA-G) and its gene polymorphism in successful implantation after in vitro fertilization embryo transfers (IVF-ETs) in different clinical protocols. We tested the HLA-G polymorphism in three positions: rs1632947: c.-964G>A; rs1233334: c.-725G>C/T in promoter region; rs371194629: c.*65_*66insATTTGTTCATGCCT in 3′ untranslated region of exon 8, in 389 patients who underwent IVF-ETs and 320 women with healthy children born after natural conception. Among the patient group, 239 women were with recurrent implantation failure and 117 women had an ongoing pregnancy or a child born after IVF-ET. We found that certain rs1632947-rs1233334-rs371194629 HLA-G haplotypes and diplotypes were associated with infertility, while others were protective. The lowest secretors of sHLA-G were G-C-ins haplotype carriers (37.21 IU/ml), while the highest -G-C-del carriers (73.80 IU/ml). Other haplotype carriers were intermediate secretors. In our study, regardless of possessed haplotype by the patient, 59.73 IU/ml sHLA-G was the threshold value with the best sensitivity (58.82%) and specificity (66.10%) to discriminate patients who achieved and maintained pregnancy from those who did not conceive or they had miscarriage (p = 0.0085; likelihood ratio, 1.74; 95% CI = 0.55–0.78). However, we do not exclude that factors other than sHLA-G may also contribute to complications in pregnancy. In addition, we found that IVF patients in cycles when frozen/thawed embryo was transferred secreted higher soluble HLA-G levels than patients with fresh embryo transferred (p = 0.021). Moreover, correlation analysis of sHLA-G concentration measured before and after embryo transfer for particular patients indicated short ovarian stimulation with gonadotropin-releasing hormone antagonist as more beneficial than long protocol with gonadotropin-releasing hormone agonist. Our study confirms a role of HLA-G polymorphism in infertility and soluble HLA-G in the early stages of pregnancy.
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Affiliation(s)
- Izabela Nowak
- Laboratory of Immunogenetics and Tissue Immunology, Department of Clinical Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Karolina Wilczyńska
- Laboratory of Immunogenetics and Tissue Immunology, Department of Clinical Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Paweł Radwan
- Department of Reproductive Medicine, Gameta Hospital, Rzgów, Poland.,Biogeno-Regional Science-Technology Centre, Podzamcze, Poland
| | - Andrzej Wiśniewski
- Laboratory of Immunogenetics and Tissue Immunology, Department of Clinical Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Rafał Krasiński
- Department of Reproductive Medicine, Gameta Hospital, Rzgów, Poland
| | - Michał Radwan
- Department of Reproductive Medicine, Gameta Hospital, Rzgów, Poland.,Faculty of Health Sciences, The State University of Applied Sciences in Płock, Płock, Poland
| | - Jacek R Wilczyński
- Department of Surgical and Oncological Gynecology, Medical University of Łódź, Łódź, Poland
| | - Andrzej Malinowski
- Department of Surgical, Endoscopic and Oncologic Gynecology, Polish Mothers' Memorial Hospital-Research Institute, Łódź, Poland
| | - Piotr Kuśnierczyk
- Laboratory of Immunogenetics and Tissue Immunology, Department of Clinical Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
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Arnaiz-Villena A, Enriquez-de-Salamanca M, Palacio-Gruber J, Juarez I, Muñiz E, Nieto J, Campos C, Martin-Villa JM. HLA-G in Amerindians: Epidemiology and Worldwide Population Comparison. ACTA ACUST UNITED AC 2018. [DOI: 10.2174/1874220301805010001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:HLA-G molecules are immunosuppressive and avoid fetal rejection by giving negative signals to maternal immune system from fetal trophoblast cell surface. HLA-G genes have been associated to different pathologies: Spontaneous abortions, autoimmunity, tumor progression, transplant rejection and infection. In addition, different World populations show remarkable different HLA-G allele frequencies in the allele that does not produce a full HLA-G molecule (HLA-G*05N); this allele is almost absent in studied Amerindians.Objectives:The aim is to study HLA-A.-B,-DRB1 and –G alleles and extended haplotypes in Amerindians for the first time. This may be useful to asses HLA-G epidemiology, association to disease and Preventive Medicine in Amerindians.Methods:HLA-A,-B and -DRB1 have been typed by using standard automatic protocols. HLA-G alleles have been detected by direct HLA-G exon 2, exon 3 and exon 4 DNA sequencing. Computer calculations have been done by specific standard methods.Results:HLA-A,-B,-DRB1 and –G extended haplotypes have been calculated in Amerindians for the first time. Also, their HLA-G frequencies have been compared with worldwide populations.Conclusion:Low frequencies of null HLA-G*01:05N allele are found in Amerindians. The extended haplotypes with this allele bear other typical Amerindian HLA-DRB1 alleles and its origin is discussed. HLA-G allele frequency profile is closer to that of Europeans than to that of Far East Asians. Our findings are useful to Preventive Medicine and Epidemiology associated to Fertility and HLA-G associated pathology and transplantation.
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Poras I, Yaghi L, Martelli-Palomino G, Mendes-Junior CT, Muniz YCN, Cagnin NF, Sgorla de Almeida B, Castelli EC, Carosella ED, Donadi EA, Moreau P. Haplotypes of the HLA-G 3' Untranslated Region Respond to Endogenous Factors of HLA-G+ and HLA-G- Cell Lines Differentially. PLoS One 2017; 12:e0169032. [PMID: 28045999 PMCID: PMC5207740 DOI: 10.1371/journal.pone.0169032] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 12/09/2016] [Indexed: 12/11/2022] Open
Abstract
The immune checkpoint HLA-G prevents maternal rejection of the fetus and contributes in cancer invasion and acceptance of allografts. The 5’ and 3’ regulatory regions of the HLA-G gene are polymorphic and balancing selection probably maintains this variability. It is proposed that nucleotide variations may affect the level of HLA-G expression. To investigate this issue we aimed to analyze how haplotypes of the 3’ untranslated region (3’UTR) with highest worldwide frequencies, namely UTR-1, UTR-2, UTR-3, UTR-4, UTR-5, UTR-18 and UTR-7, impact the expression of a luciferase reporter gene in vitro. Experiments performed with the HLA-G positive cell lines JEG-3 (choricarcinoma) and FON (melanoma), and with the HLA-G negative cell lines M8 (melanoma) and U251MG (glioblastoma) showed that the HLA-G 3’UTR polymorphism influences the response to endogenous cellular factors and may vary according to the cell type. UTR-5 and UTR-7 impact the activity of luciferase the most whereas UTR-2, UTR-3, UTR-4, and UTR-18 have intermediate impact, and UTR-1 has the lowest impact. These results corroborate the previous associations between amounts of plasma sHLA-G levels and 3’UTR haplotypes in healthy individuals and reinforce that 3’UTR typing may be a predictor of the genetic predisposition of an individual to express different levels of HLA-G.
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Affiliation(s)
- Isabelle Poras
- Commissariat à l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- Université Paris-Diderot, Sorbonne Paris-Cité, UMR_E5, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France
| | - Layale Yaghi
- Commissariat à l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- Université Paris-Diderot, Sorbonne Paris-Cité, UMR_E5, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France
- Lebanese University, School of Medicine, Hadath, Lebanon
| | - Gustavo Martelli-Palomino
- Commissariat à l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- Université Paris-Diderot, Sorbonne Paris-Cité, UMR_E5, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France
- Programa de Pós-graduação em Ciências da Saúde, Centro de Ciências da Saúde. Universidade Federal do Rio Grande do Norte, Natal, Rio Grande do Norte, Brasil
| | - Celso T. Mendes-Junior
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Yara Costa Netto Muniz
- Commissariat à l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- Université Paris-Diderot, Sorbonne Paris-Cité, UMR_E5, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France
- Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, Brasil
| | - Natalia F. Cagnin
- Commissariat à l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- Université Paris-Diderot, Sorbonne Paris-Cité, UMR_E5, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Bibiana Sgorla de Almeida
- Commissariat à l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- Université Paris-Diderot, Sorbonne Paris-Cité, UMR_E5, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France
- Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, Brasil
- Divisão de Imunologia Clínica, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - Erick C. Castelli
- Department of Pathology, School of Medicine, Universidade Estadual Paulista, Unesp, Botucatu, São Paulo, Brazil
| | - Edgardo D. Carosella
- Commissariat à l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- Université Paris-Diderot, Sorbonne Paris-Cité, UMR_E5, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France
| | - Eduardo A. Donadi
- Divisão de Imunologia Clínica, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil
| | - Philippe Moreau
- Commissariat à l’Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France
- Université Paris-Diderot, Sorbonne Paris-Cité, UMR_E5, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France
- * E-mail:
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Gineau L, Luisi P, Castelli EC, Milet J, Courtin D, Cagnin N, Patillon B, Laayouni H, Moreau P, Donadi EA, Garcia A, Sabbagh A. Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G. Genes Immun 2014; 16:57-70. [DOI: 10.1038/gene.2014.63] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 10/04/2014] [Accepted: 10/06/2014] [Indexed: 12/28/2022]
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Garziera M, Toffoli G. Inhibition of host immune response in colorectal cancer: Human leukocyte antigen-G and beyond. World J Gastroenterol 2014; 20:3778-3794. [PMID: 24744572 PMCID: PMC3983436 DOI: 10.3748/wjg.v20.i14.3778] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 01/22/2014] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most diffuse cancers worldwide and is still a clinical burden. Increasing evidences associate CRC clinical outcome to immune contexture represented by adaptive immune cells. Their type, density and location are summarized in the Immune Score that has been shown to improve prognostic prediction of CRC patients. The non-classical MHC class I human leukocyte antigen-G (HLA-G), is a crucial tumor-driven immune escape molecule involved in immune tolerance. HLA-G and soluble counterparts are able to exert inhibitory functions by direct interactions with inhibitory receptors present on both innate cells such as natural killer cells, and adaptive immune cells as cytotoxic T and B lymphocytes. HLA-G may play a prominent role in CRC strategies to avoid host immunosurveillance. This review highlights the current knowledge on HLA-G contribution in CRC, in related inflammatory diseases and in other type of cancers and disorders. HLA-G genetic setting (specific haplotypes, genotypes and alleles frequencies) and association with circulating/soluble profiles was highlighted. HLA G prognostic and predictive value in CRC was investigated in order to define a novel prognostic immune biomarker in CRC.
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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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Santos KE, Lima THA, Felicio LP, Massaro JD, Palomino GM, Silva ACA, Oliveira SF, Sabbagh A, Garcia A, Moreau P, Donadi EA, Mendes-Junior CT, Castelli EC. Insights on the HLA-G Evolutionary History Provided by a Nearby Alu Insertion. Mol Biol Evol 2013; 30:2423-34. [DOI: 10.1093/molbev/mst142] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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