RESUMEN
Non-classical HLA-G*01:46 differs from G*01:01:03:03 at one position in exon 3.
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Alelos , Exones , Antígenos HLA-G , Humanos , Antígenos HLA-G/genética , Brasil , Prueba de Histocompatibilidad , Secuencia de Bases , Análisis de Secuencia de ADN/métodosRESUMEN
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Chronic HCV infection is also an important cause of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCV has the capacity to evade immune surveillance by altering the host immune response. Moreover, variations in immune-related genes can lead to differential susceptibility to HCV infection as well as interfere on the susceptibility to the development of hepatic fibrosis, cirrhosis and HCC. The human leucocyte antigen G (HLA-G) gene codes for an immunomodulatory protein known to be expressed in the maternal-foetal interface and in immune-privileged tissues. The HLA-G 3' untranslated region (3'UTR) is important for mRNA stability, and variants in this region are known to impact gene expression. Studies, mainly focusing in a 14 bp insertion/deletion polymorphism, have correlated HLA-G 3'UTR with susceptibility to viral infections, but other polymorphic variants in the HLA-G 3'UTR might also affect HCV infection as they are inherited as haplotypes. The present study evaluated HLA-G 3'UTR polymorphisms and performed linkage disequilibrium test and haplotype assembly in 286 HCV infected patients who have developed fibrosis, cirrhosis or HCC, as well as in 129 healthy control subjects. Haplotypes UTR-1, UTR-2 and UTR-3 were the most observed in HCV+ patients, in the frequencies of 0.276, 0.255 and 0.121, respectively. No statistically significant difference was observed between HCV+ and control subjects, even when patients were grouped according to outcome (HCC, cirrhosis or fibrosis). Despite that, some trends in the results were observed, and therefore, we cannot rule out the possibility that variants associated to high HLA-G expression can be involved in HCV infection susceptibility.
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Carcinoma Hepatocelular , Hepatitis C , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Regiones no Traducidas 3'/genética , Hepacivirus , Antígenos HLA-G/genética , Haplotipos/genética , Neoplasias Hepáticas/genética , Cirrosis Hepática/genética , Hepatitis C/complicaciones , Hepatitis C/genéticaRESUMEN
As BRAF, TERT, HLA-G, and microRNAs have been individually associated with papillary thyroid carcinoma (PTC), we aimed to evaluate the individual and collaborative role of these markers in PTC in the same patient cohort. HLA-G and BRAF tumor expression was evaluated by immunohistochemistry. Using molecular methods, BRAFV600E and TERT promoter mutations were evaluated in thyroid fine needle aspirates. MicroRNA tumor profiling was investigated using massively parallel sequencing. We observed strong HLA-G (67.96%) while BRAF (62.43%) staining was observed in PTC specimens. BRAF overexpression was associated with poor response to therapy. The BRAFV600E (52.9%) and TERTC228T (13%) mutations were associated with extrathyroidal extension, advanced-age, and advanced-stage cancer. The TERT rs2853669 CC+TC genotypes (38%) were overrepresented in metastatic tumors. Nine modulated microRNAs targeting the BRAF, TERT, and/or HLA-G genes were observed in PTC and involved with cancer-related signaling pathways. The markers were individually associated with PTC features, emphasizing the synergistic effect of BRAFV600E and TERTC228T; however, their collaborative role on PTC outcome was not fully demonstrated. The differentially expressed miRNAs targeting the BRAF and/or HLA-G genes may explain their increased expression in the tumor milieu.
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Carcinoma Papilar , MicroARNs , Telomerasa , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/patología , Antígenos HLA-G/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Carcinoma Papilar/genética , Carcinoma Papilar/patología , Regiones Promotoras Genéticas , Telomerasa/genética , Telomerasa/metabolismo , Mutación , MicroARNs/genéticaRESUMEN
Human leukocyte antigen (HLA)-G is an immune checkpoint molecule that is highly expressed in papillary thyroid carcinoma (PTC). The HLA-G gene presents several functional polymorphisms distributed across the coding and regulatory regions (5'URR: 5' upstream regulatory region and 3'UTR: 3' untranslated region) and some of them may impact HLA-G expression and human malignancy. To understand the contribution of the HLA-G genetic background in PTC, we studied the HLA-G gene variability in PTC patients in association with tumor morbidity, HLA-G tissue expression, and plasma soluble (sHLA-G) levels. We evaluated 185 PTC patients and 154 healthy controls. Polymorphic sites defining coding, regulatory and extended haplotypes were characterized by sequencing analyses. HLA-G tissue expression and plasma soluble HLA-G levels were evaluated by immunohistochemistry and ELISA, respectively. Compared to the controls, the G0104a(5'URR)G*01:04:04(coding)UTR-03(3'UTR) extended haplotype was underrepresented in the PTC patients, while G0104a(5'URR)G*01:04:01(coding)UTR-03(3'UTR) was less frequent in patients with metastatic and multifocal tumors. Decreased HLA-G tissue expression and undetectable plasma sHLA-G were associated with the G010102a(5'URR)G*01:01:02:01(coding)UTR-02(3'UTR) extended haplotype. We concluded that the HLA-G variability was associated with PTC development and morbidity, as well as the magnitude of the encoded protein expression at local and systemic levels.
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Antígenos HLA-G , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Antígenos HLA-G/genética , Regiones no Traducidas 3' , Morbilidad , Neoplasias de la Tiroides/genética , Proteínas de Unión al GTPRESUMEN
The Human Leukocyte Antigen G (HLA-G) is an immunoregulatory molecule with a critical role in pregnancy success. HLA-G alleles are associated with differential susceptibility to multiple conditions, including gestational problems, infectious diseases, and viral persistence. Of note, both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) can impair HLA-G expression, interfering with HLA-G-associated immunoregulation. On the other hand, the impacts of HLA-G alleles on susceptibility to Herpesviridae infection is a neglected issue. Therefore, this study evaluated HLA-G allele frequencies and their associations with placental Herpesviridae infection in women from southern Brazil. Placenta samples were collected soon after delivery, and detection of viral DNA of HSV-1, HSV-2 and human cytomegalovirus (HCMV) was performed by polymerase chain reaction (PCR). A fragment of HLA-G (exons 2-4) was amplified by PCR, sequenced, and analyzed to allele determination. One hundred and seventy women had their alleles determined. Overall, 25 HLA-G alleles were found, distributed into 56 different genotypes. The most frequent alleles were G* 01:01:01 and G* 01:01:02, found in 37.9 % and 16.5 % of samples, respectively. Among the 170 women, 89 (52.4 %) tested positive for Herpesviridae DNA in the placenta, 55 (32.3 %) tested negative, 3 (1.8 %) were negative for HSV-1 and HSV-2 (with absent HCMV data), and 23 (13.5 %) were undetermined. The G* 01:01:01 allele was significantly associated with an increased risk of placental HSV-1 infection (p = 0.0151; OR=1.837; IC=1.108-3.045). This study describes new information concerning placental HLA-G alleles in women from southern Brazil and helps explain how genetic background can modify susceptibility to placental infections.
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Herpes Simple , Herpesvirus Humano 1 , Embarazo , Femenino , Humanos , Herpesvirus Humano 1/genética , Alelos , Antígenos HLA-G/genética , Brasil/epidemiología , Placenta , Herpesvirus Humano 2/genética , CitomegalovirusRESUMEN
Human Papillomavirus (HPV) persistence leads to the chronification of cervical inflammation, where HLA-G and Foxp3; immunomodulatory molecules, may contribute to the aggravation of the lesion and cancerization. Here, we evaluated the synergic effect of these two molecules in the worsening of the lesion in presence of HPV infection. Hundred and eighty (180) women cervical cells and biopsies were collected for (i) HLAG Sanger sequencing and gene expression, and (ii) HLA-G and Foxp3 molecule expressions by immunohistochemistry. 53 women were HPV+ against 127 women HPV-. HPV+ women were more at risk of having cytological changes (p ≤ 0.0123), histological changes (p < 0.0011), and cervical lesion (p = 0.0004). The HLA-G + 3142CC genotype predisposed women to infection (p = 0.0190), while HLA-G + 3142C and +3035 T alleles were associated with HLA-G5 transcript expression. Both sHLA-G (p = 0.030) and Foxp3 (p = 0.0002) proteins were higher in cervical lesion as well as in high-grade lesion. In addition, sHLA-G+ cells were positively correlated to Foxp3+ cells in presence of HPV infection and in cervical grade II/III injuries. In conclusion, HPV may use HLA-G and Foxp3 as a way of host immune escape contributing to the persistence of infection and inflammation, leading to the cervical lesion and the worsening of lesions.
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Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Humanos , Femenino , Antígenos HLA-G/genética , Neoplasias del Cuello Uterino/genética , Displasia del Cuello del Útero/genética , Inflamación , Factores de Transcripción Forkhead/genética , Papillomaviridae/genéticaRESUMEN
The physiological expression of HLA-G is mainly observed in the placenta, playing an essential role in maternal-fetal tolerance. Among the HLA-G mRNA alternative transcripts, the one lacking 92 bases at the HLA-G 3' untranslated region (3'UTR), the 92bDel transcript, is more stable, is associated with increased HLA-G soluble levels, and was observed in individuals presenting a 14 bp insertion (14 bp+) at the 3'UTR. We investigated the presence of the 92bDel transcript in placenta samples, correlating its expression levels with the HLA-G polymorphisms at the 3'UTR. The 14 bp+ allele correlates with the presence of the 92bDel transcript. However, the polymorphism triggering this alternative splicing is the + 3010/C allele (rs1710, allele C). Most 14 bp+ haplotypes (UTR-2/-5/-7) present allele + 3010/C. However, 14 bp- haplotypes such as UTR-3 are also associated with + 3010/C, and the 92bDel transcript can be detected in homozygous samples for the 14 bp- allele carrying at least one copy of UTR-3. The UTR-3 haplotype is associated with alleles G*01:04 and the HLA-G lineage HG0104, which is a high-expressing lineage. The only HLA-G lineage that is not likely to produce this transcript is HG010101, associated with the + 3010/G allele. This functional difference may be advantageous, considering the high worldwide frequency of the HG010101 lineage. Therefore, HLA-G lineages are functionally distinct regarding the 92bDel transcript expression, and the 3010/C allele triggers the alternative splicing that produces this shorter and more stable transcript.
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Antígenos HLA-G , Polimorfismo de Nucleótido Simple , Embarazo , Femenino , Humanos , Antígenos HLA-G/genética , Regiones no Traducidas 3'/genética , Genotipo , Nucleótidos , Haplotipos/genética , Frecuencia de los GenesRESUMEN
Vitiligo is the most frequent cause of depigmentation worldwide. Genetic association studies have discovered about 50 loci associated with disease, many with immunological functions. Among them is HLA-G, which modulates immunity by interacting with specific inhibitory receptors, mainly LILRB1 and LILRB2. Here we investigated the LILRB1 and LILRB2 association with vitiligo risk and evaluated the possible role of interactions between HLA-G and its receptors in this pathogenesis. We tested the association of the polymorphisms of HLA-G, LILRB1, and LILRB2 with vitiligo using logistic regression along with adjustment by ancestry. Further, methods based on the multifactor dimensionality reduction (MDR) approach (MDR v.3.0.2, GMDR v.0.9, and MB-MDR) were used to detect potential epistatic interactions between polymorphisms from the three genes. An interaction involving rs9380142 and rs2114511 polymorphisms was identified by all methods used. The polymorphism rs9380142 is an HLA-G 3'UTR variant (+3187) with a well-established role in mRNA stability. The polymorphism rs2114511 is located in the exonic region of LILRB1. Although no association involving this SNP has been reported, ChIP-Seq experiments have identified this position as an EBF1 binding site. These results highlight the role of an epistatic interaction between HLA-G and LILRB1 in vitiligo pathogenesis.
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Antígenos CD , Antígenos HLA-G , Receptor Leucocitario Tipo Inmunoglobulina B1 , Vitíligo , Humanos , Antígenos HLA-G/genética , Receptor Leucocitario Tipo Inmunoglobulina B1/genética , Polimorfismo Genético , Receptores Inmunológicos/genética , Vitíligo/metabolismoRESUMEN
Mesenchymal stromal cells (MSCs) have been used in immunosuppressive therapy due to their therapeutic effects, with the HLA-G molecule seeming to play a fundamental role. This work evaluated alternative MSC sources to bone marrow (BM), namely, umbilical cord tissue (UC), adipose tissue (AD) and dental pulp tissue (DP), and the influence of interferon-γ (IFN-γ) and hypoxia on the cultivation of these cells for use in immunosuppression therapies. Expression of costimulatory markers CD40, CD80 and CD86 and immunosuppressive molecules CD152 and HLA-G was analyzed. Lymphocyte inhibition assays were also performed. Sequencing of the HLA-G gene from exons 1 to 5 was performed using next-generation sequencing to determine the presence of alleles. UC-derived MSCs (UCMSCs) expressed higher CD152 and HLA-G1 under standard cultivation. UCMSCs and DP-derived MSCs (DPSCs) secreted similar levels of HLA-G5. All MSC sources inhibited the proliferation of peripheral blood mononuclear cells (PBMCs); growth under regular versus hypoxic conditions resulted in similar levels of inhibition. When IFN-γ was added, PBMC growth was inhibited to a lesser extent by UCMSCs. The HLA-G*01:04:01:01 allele appears to generate a more efficient MSC response in inhibiting lymphocyte proliferation. However, the strength of this conclusion was limited by the small sample size. UCMSCs are an excellent alternative to BM in immunosuppressive therapy: they express high concentrations of inhibitory molecules and can be cultivated without stimuli, which minimizes cost.
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Antígenos HLA-G , Células Madre Mesenquimatosas , Proliferación Celular , Células Cultivadas , Antígenos HLA-G/genética , Antígenos HLA-G/metabolismo , Terapia de Inmunosupresión , Interferón gamma/metabolismo , Interferón gamma/farmacología , Leucocitos Mononucleares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Cordón Umbilical/metabolismoRESUMEN
OBJECTIVES: Investigate polymorphisms and expressions of human leukocyte antigen-G (HLA-G), galectin-1 (Gal-1), and interleukin-10 (IL-10) in people living with HIV (PLHIV) with and without comorbidities to help understanding the mechanisms involved in triggering these disorders in PLHIV and in their prognosis. DESIGN: Here we evaluated the potential correlation between the genetic polymorphism and/or protein levels of HLA-G, Gal-1, and IL-10 with and without comorbidities of PLHIV. METHODS: Two hundred HIV patients under antiretroviral treatment (83 with comorbidities and 117 without comorbidities) and 200 healthy individuals (controls) were genotyped, using PCR, for HLA-G 14-base pair polymorphism located at the 3' untranslated region in exon 8âinsertion/insertion (Ins/Ins: low HLA-G expression) or deletion/deletion (Del/Del: high HLA-G expression). Soluble levels of HLA-G (sHLA-G), Gal-1, and IL-10 were quantified by enzyme-linked immunosorbet assay. RESULTS: HIV patients without comorbidities exhibited higher frequency of 14-base pair Del/Del genotype than HIV patients with comorbidities. As expected, HIV patients Ins/Ins with and without comorbidities produced less sHLA-G than controls. However, HIV patients Del/Del with comorbidities expressed sHLA-G more than controls and HIV patients Del/Del without comorbidities. Interestingly, patients that showed low levels sHLA-G, and presence of comorbidities, exhibited high Gal-1 serum levels. However, an increase in soluble levels of IL-10 in PLHIV was observed when compared to controls, especially in the PLHIV group without comorbidities suggesting, a protective role of IL-10 in the development of comorbidities. CONCLUSIONS: These data suggested that the high expression of sHLA-G and IL-10 or Gal-1 could be associated and could be associated with the development or not of comorbidities in PLHIV.
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Galectina 1 , Infecciones por VIH , Antígenos HLA-G , Interleucina-10 , Regiones no Traducidas 3' , Estudios de Casos y Controles , Comorbilidad , Galectina 1/genética , Genotipo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Antígenos HLA-G/genética , Humanos , Interleucina-10/genética , Polimorfismo GenéticoRESUMEN
Human Leukocyte Antigen (HLA)-G participates in several biological processes, including reproduction, vascular remodeling, immune tolerance, and hypoxia response. HLA-G is a potential candidate gene for high altitude adaptation since its expression is modulated in both micro and macro environment under hypoxia and constant cellular stress. Besides the promoter region, the HLA-G 3'untranslated region (UTR) influences HLA-G expression patterns through several post-transcriptional mechanisms. Currently, the 3'UTR genetic diversity in terms of altitude adaptation of Native American populations is still unexplored, particularly at high altitude ecoregions. Here, we evaluated 288 Native Americans from 9 communities located in the Andes [highland (HL); ≥2,500 m (range = 2,838-4,433 m)] and 8 populations located in lowland (LL) regions [<2,500 m (range = 80-431 m); Amazonian tropical forest, Brazilian central plateau, and Chaco] of South America. In total, nine polymorphic sites and ten haplotypes were observed. The most frequent haplotypes (UTR-1, UTR-2, and UTR-3) accounted for â¼ 77% of haplotypes found in LL, while in the HL, the same haplotypes reach â¼ 93%. Also, a remarkable high frequency of putative ancestral UTR-5 haplotype was observed in LL (21.5%), while in HL UTR-2 reaches up to 47%. Further, UTR-2 frequency positively correlates with altitude-related variables, while a negative correlation for UTR-5 was observed. From an evolutionary perspective, we observed a tendency towards balancing selection in HL and LL populations thus suggesting that haplotypes of ancient and more derived alleles may have been co-opted for relatively recent adaptations such as those experienced by modern humans in the highland and lowland of South America. We also discuss how long-term balancing selection can be a reservoir of genetic variants that can be positively selected. Finally, our study provides some pieces of evidence that HLA-G 3'UTR haplotypes may have contributed to high altitude adaptation in the Andes.
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Indio Americano o Nativo de Alaska , Antígenos HLA-G , Regiones no Traducidas 3'/genética , Brasil , Frecuencia de los Genes , Genotipo , Antígenos HLA-G/genética , Haplotipos , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
Human Antigen Leukocyte-G (HLA-G) gene encodes an immune checkpoint molecule that has restricted tissue expression in physiological conditions; however, the gene may be induced in hypoxic conditions by the interaction with the hypoxia inducible factor-1 (HIF1). Hypoxia regulatory elements (HRE) located at the HLA-G promoter region and at exon 2 are the major HIF1 target sites. Since the G allele of the -964G > A transversion induces higher HLA-G expression when compared to the A allele in hypoxic conditions, here we analyzed HIF1-HRE complex interaction at the pair-atom level considering both -964G > A polymorphism alleles. Mouse HIF2 dimer crystal (Protein Data Bank ID: 4ZPK) was used as template to perform homology modelling of human HIF1 quaternary structure using MODELLER v9.14. Two 3D DNA structures were built from 5'GCRTG'3 HRE sequence containing the -964G/A alleles using x3DNA. Protein-DNA docking was performed using the HADDOCK v2.4 server, and non-covalent bonds were computed by DNAproDB server. Molecular dynamic simulation was carried out per 200 ns, using Gromacs v.2019. HIF1 binding in the HRE containing -964G allele results in more hydrogen bonds and van der Waals contact formation than HRE with -964A allele. Protein-DNA complex trajectory analysis revealed that HIF1-HRE-964G complex is more stable. In conclusion, HIF1 binds in a more stable and specific manner at the HRE with G allele.
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Antígenos HLA-G/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Elementos de Respuesta/genética , Alelos , Sitios de Unión , Exones , Antígenos HLA-G/química , Antígenos HLA-G/genética , Humanos , Enlace de Hidrógeno , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Simulación del Acoplamiento Molecular , Regiones Promotoras Genéticas , Unión Proteica , TermodinámicaRESUMEN
HLA-G is a promiscuous immune checkpoint molecule. The HLA-G gene presents substantial nucleotide variability in its regulatory regions. However, it encodes a limited number of proteins compared to classical HLA class I genes. We characterized the HLA-G genetic variability in 4640 individuals from 88 different population samples across the globe by using a state-of-the-art method to characterize polymorphisms and haplotypes from high-coverage next-generation sequencing data. We also provide insights regarding the HLA-G genetic diversity and a resource for future studies evaluating HLA-G polymorphisms in different populations and association studies. Despite the great haplotype variability, we demonstrated that: (1) most of the HLA-G polymorphisms are in introns and regulatory sequences, and these are the sites with evidence of balancing selection, (2) linkage disequilibrium is high throughout the gene, extending up to HLA-A, (3) there are few proteins frequently observed in worldwide populations, with lack of variation in residues associated with major HLA-G biological properties (dimer formation, interaction with leukocyte receptors). These observations corroborate the role of HLA-G as an immune checkpoint molecule rather than as an antigen-presenting molecule. Understanding HLA-G variability across populations is relevant for disease association and functional studies.
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Antígenos HLA-G/genética , Polimorfismo Genético , Regiones no Traducidas 3' , Alelos , Biología Computacional , Dimerización , Evolución Molecular , Frecuencia de los Genes , Genes MHC Clase I , Variación Genética , Genética de Población , Genotipo , Salud Global , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteínas de Punto de Control Inmunitario/genética , Inmunogenética , Intrones , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido SimpleRESUMEN
Cancer immunotherapies based mainly on the blockade of immune-checkpoint (IC) molecules by anti-IC antibodies offer new alternatives for treatment in oncological diseases. However, a considerable proportion of patients remain unresponsive to them. Hence, the development of novel clinical immunotherapeutic approaches and/or targets are crucial.W In this context, targeting the immune-checkpoint HLA-G/ILT2/ILT4 has caused great interest since it is abnormally expressed in several malignancies generating a tolerogenic microenvironment. Here, we used CRISPR/Cas9 gene editing to block the HLA-G expression in two tumor cell lines expressing HLA-G, including a renal cell carcinoma (RCC7) and a choriocarcinoma (JEG-3). Different sgRNA/Cas9 plasmids targeting HLA-G exon 1 and 2 were transfected in both cell lines. Downregulation of HLA-G was reached to different degrees, including complete silencing. Most importantly, HLA-G - cells triggered a higher in vitro response of immune cells with respect to HLA-G + wild type cells. Altogether, we demonstrated for the first time the HLA-G downregulation through gene editing. We propose this approach as a first step to develop novel clinical immunotherapeutic approaches in cancer.
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Edición Génica/métodos , Antígenos HLA-G/genética , Antígenos HLA-G/metabolismo , Sistemas CRISPR-Cas , Línea Celular Tumoral , Antígenos HLA-G/inmunología , Humanos , Inmunoterapia/métodos , ARN Guía de Kinetoplastida , TransfecciónRESUMEN
HLA-G allele frequencies were studied in Yucatán (Mexico) Maya Amerindians by a direct exon DNA sequencing technique. It is described that Mayas are probably one of the first populations together with Olmecs that populated Meso America and that important HLA genetic differences between Mexican and Guatemalan Mayas support that Maya languages were imposed to several neighbouring Amerindian groups. HLA-G*01:01:02, HLA-G*01:01:01 and HLA-G*01:04:01 are the most frequent alleles in this population. It is remarkable that HLA-G*01:05N allele was not found in the population in accordance with similar results found in another Amerindians. Also, protein allele HLA-G*01:04 frequency is found not to differ to those found in another far or close living Amerindians in contrast to other World populations. It seems that while high HLA-G*01:05N frequency is found in Iran and Middle East populations, probably where this allele appeared within an ancestral HLA-A*19 group of alleles haplotype and it is maintained by unknown evolutionary forces, Amerindians do not have a high frequency because a founder effect or because required natural evolutionary forces do not exist in America. Finally, we believe useful to study HLA-G evolution for its physiopathology understanding in addition to the many papers on statistics on HLA-G and in vitro models that are yearly published.
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Genes MHC Clase I , Antígenos HLA-G , Alelos , Frecuencia de los Genes , Antígenos HLA-G/genética , Haplotipos , Humanos , MéxicoRESUMEN
BACKGROUND: Since HLA-G is an immune checkpoint molecule and since Crohn's disease (CD) and ulcerative colitis (UC) exhibit deregulated immune-mediated mechanisms, we aimed to evaluate intestinal HLA-G expression and soluble HLA-G (sHLA-G) levels in CD/UC patients stratified according to the CD phenotype/localization and UC extension. METHODS: HLA-G tissue expression was assessed by immunohistochemistry in biopsies collected from 151 patients (90 CD, 61 UC) and in surgical resection specimens (28 CD, 12 UC). Surgical material from 24 healthy controls was also assessed. Plasma sHLA-G levels (97 CD, 81 UC, and 120 controls) were evaluated using ELISA. RESULTS: HLA-G expression was similarly observed in the intestinal epithelial cells of control and CD/UC specimens. However, in biopsies, the plasma cells/lymphocytes infiltrating the lamina propria in CD/UC presented (1) increased HLA-G expression compared to controls (P < 0.0001), (2) greater cell staining in UC cells than in CD cells irrespective of disease extent (P = 0.0011), and (3) an increased number of infiltrating cells in the inflammatory CD phenotype compared to that in the stenosing and fistulizing phenotypes (P = 0.0407). In surgical specimens, CD/UC patients exhibited higher infiltrating cell HLA-G expression in lesion areas than in margins. sHLA-G levels were higher in UC/CD patients (P < 0.0001) than in controls, but no difference was observed between diseases. CONCLUSIONS: Increased infiltrating cell HLA-G expression associated with increased sHLA-G levels in CD/UC patients may reflect ongoing host strategies to suppress chronic inflammation.
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Colitis Ulcerosa/patología , Enfermedad de Crohn/patología , Regulación de la Expresión Génica/inmunología , Antígenos HLA-G/metabolismo , Adolescente , Adulto , Femenino , Antígenos HLA-G/genética , Humanos , Inflamación , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
HLA-G is considered to be an immune checkpoint molecule, a function that is closely linked to the structure and dynamics of the different HLA-G isoforms. Unfortunately, little is known about the structure and dynamics of these isoforms. For instance, there are only seven crystal structures of HLA-G molecules, being all related to a single isoform, and in some cases lacking important residues associated to the interaction with leukocyte receptors. In addition, they lack information on the dynamics of both membrane-bound HLA-G forms, and soluble forms. We took advantage of in silico strategies to disclose the dynamic behavior of selected HLA-G forms, including the membrane-bound HLA-G1 molecule, soluble HLA-G1 dimer, and HLA-G5 isoform. Both the membrane-bound HLA-G1 molecule and the soluble HLA-G1 dimer were quite stable. Residues involved in the interaction with ILT2 and ILT4 receptors (α3 domain) were very close to the lipid bilayer in the complete HLA-G1 molecule, which might limit accessibility. On the other hand, these residues can be completely exposed in the soluble HLA-G1 dimer, due to the free rotation of the disulfide bridge (Cys42/Cys42). In fact, we speculate that this free rotation of each protomer (i.e., the chains composing the dimer) could enable alternative binding modes for ILT2/ILT4 receptors, which in turn could be associated with greater affinity of the soluble HLA-G1 dimer. Structural analysis of the HLA-G5 isoform demonstrated higher stability for the complex containing the peptide and coupled ß2-microglobulin, while structures lacking such domains were significantly unstable. This study reports for the first time structural conformations for the HLA-G5 isoform and the dynamic behavior of HLA-G1 molecules under simulated biological conditions. All modeled structures were made available through GitHub (https://github.com/KavrakiLab/), enabling their use as templates for modeling other alleles and isoforms, as well as for other computational analyses to investigate key molecular interactions.
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Membrana Celular/metabolismo , Antígenos HLA-G/metabolismo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Antígenos HLA-G/química , Antígenos HLA-G/genética , Humanos , Membrana Dobles de Lípidos , Dominios y Motivos de Interacción de Proteínas , Isoformas de Proteínas , Multimerización de Proteína , Estabilidad Proteica , Relación Estructura-ActividadRESUMEN
Cytomegalovirus retinochoroiditis (CMV-R) is the primary cause of blindness among AIDS patients. Since HLA-G is associated with the modulation of the immune response, we hypothesized that variability at the 3' untraslated region (3'UTR) of the gene could be implicated on the predisposition to CMV-R. We evaluated whether HLA-G 3'UTR influences CMV-R development in Brazilian AIDS patients. Peripheral blood DNA was obtained from two groups of patients: (1) AIDS exhibiting CMV-R (n = 40) and (2) AIDS without CMV-R (n = 147). HLA-G 3'UTR typing was performed using sequencing analysis. Allele, genotype and haplotype frequencies were evaluated using Fisher's exact test accompanied by the calculation of the odds ratio and its 95% confidence interval (95% CI). The etiologic (EF) and preventive fractions were also estimated. Compared to AIDS patients without CMV-R, AIDS patients with CMV-R showed increased frequencies of the: (1) + 3001T allele, (2) the + 3001C/T genotype and (3) the UTR-17 (InsTTCCGTGACG) haplotype (EFs = 0.02-0.04). The UTR-3 (DelTCCGCGACG) haplotype was associated with protection against CMV-R development. Although the risk for developing CMR-V at the population level was relatively low (EF), the identification of HLA-G 3'UTR variation sites may help to further evaluate the role of post-transcriptional factors that may contribute to the existent immunosuppresion caused by HIV per se.
Asunto(s)
Regiones no Traducidas 3' , Síndrome de Inmunodeficiencia Adquirida/genética , Coroiditis/genética , Retinitis por Citomegalovirus/genética , Antígenos HLA-G/genética , Humanos , Proteínas de Punto de Control Inmunitario/genéticaRESUMEN
Chronic hepatitis C virus (HCV) infection induces liver damage and the HCV/Human Immunodeficiency Virus (HIV)-coinfection may further contribute to its progression. The HLA-G molecule inhibits innate and adaptive immunity and may be deleterious for chronically virus-infected cells. Thus we studied 204 HCV-mono-infected patients, 142 HCV/HIV-coinfected patients, 104 HIV-mono-infected patients and 163 healthy subjects. HLA-G liver expression was similarly induced in HCV and HCV/HIV specimens, increasing with advanced fibrosis and necroinflammatory activity, and with increased levels of liver function-related enzymes. Plasma soluble HLA-G (sHLA-G) levels were higher in HCV/HIV patients compared to HCV, HIV and to healthy individuals. sHLA-G continued to be higher in coinfected patients even after stratification of samples according to degree of liver fibrosis and necroinflammatory activity when compared to mono-infected patients. Some HLA-G gene haplotypes differentiated patient groups and presented few associations with liver and plasma HLA-G expression. HLA-G thus may help to distinguish patient groups.
Asunto(s)
Infecciones por VIH/inmunología , Antígenos HLA-G/genética , Antígenos HLA-G/metabolismo , Hepatitis C Crónica/inmunología , Hígado/metabolismo , Adulto , Coinfección , Femenino , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , VIH-1/inmunología , Haplotipos/genética , Hepacivirus/inmunología , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética , Estudios RetrospectivosRESUMEN
Hematopoietic stem-cell transplantation is widely performed for the treatment of hematologic diseases and is increasingly being used for the experimental treatment of various autoimmune diseases. Despite the rapid evolution of this therapy, the mortality rate of patients undergoing this procedure is still high, mainly due to the development of graft versus host disease (GvHD). Even with the administration of immunosuppressive therapy, some patients manifest the chronic form of the disease. For these cases, infusion of mesenchymal stem cells (MSCs) was proposed as a therapeutic strategy, considering the immunosuppressive potential of these cells. This review describes the main results obtained in cell therapy with MSCs for the treatment of GvHD. Despite the encouraging results found, some points differed among the studies. Although the factors that influence the different results are uncertain, some investigators have suggested that variations in immunosuppressive molecules are responsible for these divergences. We highlight the key role of the HLA-G gene in modulating the immune response, and the importance of the polymorphisms and alleles of this gene associated with the outcome of the transplants. We suggest that the HLA-G gene and its polymorphisms be analyzed as a factor in selecting the MSCs to be used in treating GvHD, given its strong immunosuppressive role.