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To identify T cell subsets associated with control of tuberculosis, single-cell transcriptome and T cell receptor sequencing were performed on total T cells from patients with tuberculosis and healthy controls. Fourteen distinct subsets of T cells were identified by unbiased UMAP clustering. A GZMK-expressing CD8+ cytotoxic T cell cluster and a SOX4-expressing CD4+ central memory T cell cluster were depleted, while a MKI67-expressing proliferating CD3+ T cell cluster was expanded in patients with tuberculosis compared with healthy controls. The ratio of Granzyme K-expressing CD8+CD161-Ki-67- and CD8+Ki-67+ T cell subsets was significantly reduced and inversely correlated with the extent of TB lesions in patients with TB. In contrast, ratio of Granzyme B-expressing CD8+Ki-67+ and CD4+CD161+Ki-67- T cells and Granzyme A-expressing CD4+CD161+Ki-67- T cells were correlated with the extent of TB lesions. It is concluded that granzyme K-expressing CD8+ T cell subsets might contribute to protection against tuberculosis dissemination.
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Linfocitos T CD8-positivos , Tuberculosis , Humanos , Granzimas , Antígeno Ki-67 , Linfocitos T CD8-positivos/patología , Subgrupos de Linfocitos T , Linfocitos T CD4-Positivos , Factores de Transcripción SOXCRESUMEN
Polar domain walls in centrosymmetric ferroelastics induce inhomogeneity that is the origin of advantageous multifunctionality. In particular, polar domain walls promote charge-carrier separation and hence are promising for energy conversion applications that overcome the hurdles of the rate-limiting step in the traditional photoelectrochemical water splitting processes. Yet, while macroscopic studies investigate the materials at the device scale, the origin of this phenomenon in general and the emergence of polar domain walls during the structural phase transition in particular has remained elusive, encumbering the development of this attractive system. Here, it is demonstrated that twin domain walls arise in centrosymmetric BiVO4 films and they exhibit localized piezoelectricity. It is also shown that during the structural phase transition from the tetragonal to monoclinic, the symmetry reduction is accompanied by an emergence of strain gradient, giving rise to flexoelectric effect and the polar domain walls. These results not only expose the emergence of polar domain walls at centrosymmetric systems by means of direct observation, but they also expand the realm of potential application of ferroelastics, especially in photoelectrochemistry and local piezoelectricity.
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To understand functional role of PD-1-expressing MAIT cells during tuberculosis infection in humans, sorted PD-1+ and PD-1- MAIT cells from pleural effusions of patients with pleural tuberculosis were subjected to transcriptome sequencing. PD-1-expressing MAIT cells were analysed by flow cytometry and their phenotypic and functional features were investigated. Transcriptome sequencing identified 144 genes that were differentially expressed between PD-1+ and PD-1- MAIT cells from tuberculous pleural effusions and CXCL13 was the gene with highest fold difference. The level of PD-1-expressing MAIT cells was associated with extent of TB infection in humans. PD-1-expressing MAIT cells had increased production of CXCL13 and IL-21 as determined by flow cytometry. PD-1high CXCR5- MAIT cells were significantly expanded in pleural effusions from patients with pleural tuberculosis as compared with those from peripheral blood of both patients with tuberculosis and healthy controls. Although PD-1high CXCR5- MAIT cells from tuberculous pleural effusions had reduced IFN-γ level and increased expression of Tim-3 and GITR, they showed activated phenotype and had higher glucose uptake and lipid content. It is concluded that PD-1-expressing MAIT cells had reduced IFN-γ level but increased production of both CXCL13 and IL-21.
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Quimiocina CXCL13/biosíntesis , Células T Invariantes Asociadas a Mucosa/inmunología , Tuberculosis Pleural/inmunología , Adulto , Quimiocina CXCL13/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células T Invariantes Asociadas a Mucosa/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Tuberculosis Pleural/metabolismoRESUMEN
Ferroelectric heterostructures, with capability of storing data at ultrahigh densities, could act as the platform for next-generation memories. The development of new device paradigms has been hampered by the long-standing notion of inevitable ferroelectricity suppression under reduced dimensions. Despite recent experimental observation of stable polarized states in ferroelectric ultrathin films, the out-of-plane polarization components in these films are strongly attenuated compared to thicker films, implying a degradation of device performance in electronic miniaturization processes. Here, in a model system of BiFeO3/La0.7Sr0.3MnO3, we report observation of a dramatic out-of-plane polarization enhancement that occurs with decreasing film thickness. Our electron microscopy analysis coupled with phase-field simulations reveals a polarization-enhancement mechanism that is dominated by the accumulation of oxygen vacancies at interfacial layers. The results shed light on the interplay between polarization and defects in nanoscale ferroelectrics and suggest a route to enhance functionality in oxide devices.
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Germinal centers (GC) are vital to adaptive immunity. BCL6 and miR-155 are implicated in control of GC reaction and lymphomagenesis. FBXO11 causes BCL6 degradation through ubiquitination in B-cell lymphomas. Chronic psychological stress is known to drive immunosuppression. Corticosterone (CORT) is an adrenal hormone expressed in response to stress and can similarly impair immune functions. However, whether GC formation is disrupted by chronic psychological stress and its molecular mechanism remain to be elucidated. To address this issue, we established a GC formation model in vivo, and a GC B cell differentiation model in vitro. Comparing Naive B cells to GC B cells in vivo and in vitro, the differences of BCL6 and FBXO11 mRNA do not match the changes at the protein level and miR-155 levels that were observed. Next we demonstrated that CORT increase, induced by chronic psychological stress, reduced GC response, IgG1 antibody production and miR-155 level in vivo. The effect of chronic psychological stress can be blocked by a glucocorticoid receptor (GR) antagonist. Similarly, impaired GC B cell generation and isotope class switching were observed. Furthermore, we found that miR-155 and BCL6 expression were downregulated, but FBXO11 expression was upregulated in GC B cells treated with CORT in vitro. In addition, we demonstrated that miR-155 directly down-regulated FBXO11 expression by binding to its 3Ì-untranslated region. The subsequent overexpression of miR-155 significantly blocked the stress-induced impairment of GC response, due to changes in FBXO11 and BCL6 expression, as well as increased apoptosis in B cells both in vivo and in vitro. Our findings suggest perturbation of GC reaction may play a role in chronic psychological stress-induced immunosuppression through a glucocorticoid pathway, and miR-155-mediated post-transcriptional regulation of FBXO11 and BCL6 expression may contribute to the impaired GC response.
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Centro Germinal/metabolismo , MicroARNs/metabolismo , Estrés Psicológico/metabolismo , Animales , Apoptosis/fisiología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Diferenciación Celular/inmunología , Proteínas de Unión al ADN/genética , Proteínas F-Box/metabolismo , Femenino , Centro Germinal/fisiología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Estrés Psicológico/fisiopatologíaRESUMEN
The role of MAIT cells in immunity against Mycobacterium tuberculosis infection in humans is still largely unexplored. In this study, we investigated the functional role of 4-1BB on MAIT cells. We found that 4-1BB was highly up-regulated on MAIT cells from tuberculous pleural effusions following Mtb antigen stimulation and its level of expression correlated with IFN-γ and IL-17 production. 4-1BB expression on MAIT cells in response to Mtb antigens was partially dependent on IL-2 and was associated with common γ chain receptor. By transcriptome sequencing, we identified numerous differentially expressed genes between 4-1BB- and 4-1BB+ MAIT cells. GO enrichment and KEGG pathway analysis of differentially expressed genes identified enriched pathways that included T-cell receptor and NF-κB signaling pathways. It is concluded that 4-1BB has the potential to be used as a biomarker to identify MAIT cells with enhanced IFN-γ and IL-17 responses that might be associated with tuberculosis infection control.
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Células T Invariantes Asociadas a Mucosa/fisiología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/fisiología , Adulto , Biomarcadores/sangre , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Interferón gamma/inmunología , Interleucina-17/inmunología , Interleucina-2/inmunología , Masculino , Persona de Mediana Edad , Células T Invariantes Asociadas a Mucosa/metabolismo , Mycobacterium tuberculosis/inmunología , Tuberculosis/fisiopatología , Tuberculosis Pleural/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
Continuous developments in nanotechnology require new approaches to materials synthesis that can produce novel functional structures. Here, we show that nanoscale defects, such as nonstoichiometric nanoregions (NSNRs), can act as nano-building blocks for creating complex electrical polarization structures in the prototypical multiferroic BiFeO_{3}. An array of charged NSNRs are produced in BiFeO_{3} thin films by tuning the substrate temperature during film growth. Atomic-scale scanning transmission electron microscopy imaging reveals exotic polarization rotation patterns around these NSNRs. These polarization patterns resemble hedgehog or vortex topologies and can cause local changes in lattice symmetries leading to mixed-phase structures resembling the morphotropic phase boundary with high piezoelectricity. Phase-field simulations indicate that the observed polarization configurations are mainly induced by charged states at the NSNRs. Engineering defects thus may provide a new route for developing ferroelectric- or multiferroic-based nanodevices.
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Magnetic domain-wall motion driven by a voltage dissipates much less heat than by a current, but none of the existing reports have achieved speeds exceeding 100 m/s. Here phase-field and finite-element simulations were combined to study the dynamics of strain-mediated voltage-driven magnetic domain-wall motion in curved nanowires. Using a ring-shaped, rough-edged magnetic nanowire on top of a piezoelectric disk, we demonstrate a fast voltage-driven magnetic domain-wall motion with average velocity up to 550 m/s, which is comparable to current-driven wall velocity. An analytical theory is derived to describe the strain dependence of average magnetic domain-wall velocity. Moreover, one 180° domain-wall cycle around the ring dissipates an ultrasmall amount of heat, as small as 0.2 fJ, approximately 3 orders of magnitude smaller than those in current-driven cases. These findings suggest a new route toward developing high-speed, low-power-dissipation domain-wall spintronics.
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T-bet is a T-box transcriptional factor that controls the differentiation and effector functions of CD4 T cells. In this study, we studied the role of T-bet in regulating CD4(+) T cell immunity against tuberculosis (TB). T-bet expression in Mycobacterium tuberculosis antigen-specific CD4(+) T cells was significantly higher in patients with active TB than in individuals with latent TB infection (p<0.0001). Comparison of T-bet expression in TCM and TEM subsets showed that CD4(+)T-bet(+)M. tuberculosis antigen-specific CD4(+) T cells had significantly lower frequency of TCM (p=0.003) and higher frequency of TEM (p=0.003) than CD4(+)T-bet(-) cells. The expression of PD-1 in antigen-specific CD4(+) T cells was significantly higher in patients with TB than in individuals with latent TB infection (p=0.006). CD4(+)CD154(+)T-bet(+) T cells had significantly higher expression of PD-1 than CD4(+)CD154(+)T-bet(-) T cells (p=0.0028). It is concluded that T-bet expression might be associated with differentiation into effector memory cells and PD-1 expression in mycobacterial antigen-specific CD4(+) T cells.
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Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica/inmunología , Tuberculosis Latente/inmunología , Proteínas de Dominio T Box/metabolismo , Tuberculosis Pulmonar/inmunología , Adulto , Antígenos Bacterianos/inmunología , Ligando de CD40/inmunología , Diferenciación Celular , Femenino , Humanos , Interferón gamma/metabolismo , Tuberculosis Latente/metabolismo , Masculino , Mycobacterium tuberculosis/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Tuberculosis Pulmonar/metabolismoRESUMEN
RATIONALE: Mucosal-associated invariant T (MAIT) cells have been proven to play an important role in host defense against mycobacterial infection in animal infection models; however, the functional role of MAIT cells in patients with active tuberculosis (TB) is still largely unknown. OBJECTIVES: To understand the clinical features and functions of MAIT cells in patients with active TB. METHODS: MAIT cells were analyzed in patients with pulmonary TB, tuberculous pleurisy, and tuberculous peritonitis by flow cytometry. The functions of MAIT cells were compared between patients with active TB and healthy control subjects. MEASUREMENTS AND MAIN RESULTS: The frequency of MAIT cells was significantly reduced both in peripheral blood from patients with active pulmonary TB (P < 0.0001) and in tuberculous pleural effusions compared with healthy control subjects but not in ascitic fluids from patients with tuberculous peritonitis. A comparison of bacillus Calmette-Guérin (BCG)-stimulated cytokine production showed that patients with active TB had significantly higher production of IFN-γ (P = 0.0034) and tumor necrosis factor (TNF)-α (P = 0.0399) compared with healthy control subjects. In contrast, when MAIT cells were stimulated with Escherichia coli, patients with active TB had significantly lower production of IFN-γ (P = 0.0007) and TNF-α (P = 0.0032). MAIT cells in patients with active TB exhibited elevated expression of programmed death-1 (PD-1) (P = 0.0015), and blockade of PD-1 signaling resulted in a significantly higher frequency of BCG-stimulated IFN-γ production in MAIT cells (P = 0.0178). CONCLUSIONS: MAIT-cell immune response to antigen stimulation in patients with active TB is regulated by PD-1, which could be a potential target for TB immunotherapy.
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Apoptosis/inmunología , Linfocitos T/inmunología , Tuberculosis/inmunología , Adulto , Estudios de Casos y Controles , Femenino , Citometría de Flujo , Humanos , Inmunidad Mucosa , Masculino , Peritonitis Tuberculosa/inmunología , Estadísticas no Paramétricas , Tuberculosis Pleural/inmunología , Tuberculosis Pulmonar/inmunologíaRESUMEN
OBJECTIVE: To study the effect of Mycobacterium tuberculosis antigens early secretory antigen target 6/culture filtrate protein 10 (ESAT-6/CFP-10) on nuclear factor of activated T-cells 5 (NFAT5) mRNA in monocytes from human peripheral blood. METHODS: Fifteen patients with active pulmonary tuberculosis (age range: 33-42 y, mean: 37 y, male/female: 9/6) were recruited from the Institute of Tuberculosis in 309 Hospital, and 15 healthy subjects (age range: 37-42 y, mean: 40 y, male/female: 9/6) were recruited from Medical Examination Center of the hospital. Monocytes were isolated from peripheral blood and stimulated with whole cell lysate of H37Rv strain and peptide pool of ESAT-6/CFP-10. Fluorescence quantitative PCR was used to detect the mRNA expression of NFAT5, and differences of NFAT5 mRNA between unstimulated and stimulated monocytes were analyzed by paired t test statistic method. RESULTS: The expression of NFAT5 mRNA in monocytes from patients with active pulmonary tuberculosis was significantly decreased when stimulated with peptide pool of ESAT-6/CFP-10 compared with unstimulated monocytes (0.18 ± 0.12 vs. 0.23 ± 0.15) (t = 2.591, P < 0.05). Similarly, the expression of NFAT5 mRNA in monocytes from healthy subjects was also significantly decreased when stimulated with peptide pool of ESAT-6/CFP-10 compared with unstimulated monocytes (0.17 ± 0.09 vs 0.21 ± 0.09) (t = 2.828, P < 0.05). However, the expression of NFAT5 mRNA in monocytes stimulated with whole cell lysate was not significantly changed (t = 1.142, P > 0.05), which was 0.28 ± 0.25 and 0.23 ± 0.15 in stimulated and unstimulated monocytes, respectively. Similarly, the expression of NFAT5 mRNA in monocytes from healthy subjects was also not significantly changed when stimulated with whole cell lysate (t = 0.451 9, P > 0.05), which was 0.20 ± 0.12 and 0.21 ± 0.09 in stimulated and unstimulated monocytes, respectively. CONCLUSIONS: The MTB antigen ESAT-6/CFP-10 can inhibit NFAT5 expression in human monocytes in vitro.
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Monocitos , Mycobacterium tuberculosis , Adulto , Antígenos Bacterianos , Proteínas Bacterianas , Femenino , Humanos , Masculino , Péptidos , ARN Mensajero , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Transcripción , Tuberculosis , Tuberculosis PulmonarRESUMEN
OBJECTIVE: To explore the gene expression profiles of severe secondary pulmonary tuberculosis patients. METHODS: From May 2012 to October 2013, a total of 103 eligible patients with secondary pulmonary tuberculosis were recruited from Institution of Tuberculosis Research of PLA Hospital No. 309. They were divided into severe secondary pulmonary tuberculosis (severe group) (n = 57) and mild secondary pulmonary tuberculosis (mild group) (n = 46) by the severity of disease . At the same time age-matched healthy controls (n = 45) were selected from healthy subjects undergoing physical examination. Whole genome expression profiling was performed with Affymetrix Gene expression chips for 4 cases in severe group, 3 in mild group and 5 in healthy group. Cluster and bioinformatics analysies were performed on differentially expressed genes in severe versus mild group. The remainders of three groups were 53, 43 and 40 cases respectively used for verify the results of gene chip by real-time fluorescence quantitative PCR (RT-PCR). And 20 cases in severe group, 20 in mild group and 8 in control group were used to verify the expression level of jun oncogene (JUN) on behalf of differential expressed genes. Analysis of variance and non-parametric tests were used for statistic difference analysis among three groups. RESULTS: There were 406 differentially expressed genes for severe and mild groups. There were 264 down-regulated gene and 142 up-regulated ones. The down-regulated genes were predominant. Cluster analysis show the similarity of gene expression profile in the same group . The result confirmed that the gene chip experiments were both repeatable and reliable. According to gene ontology, the differentially expressed genes were mainly involved in such biological processes as immune response, signal transduction, regulation of transcription (DNA-dependent), inflammatory response, antigen processing and presentation and chemotaxis, etc. Pathway analysis showed differentially expressed genes were involved in 22 pathways of immune response and inflammation. The major pathways included B cell receptor signaling, antigen processing and presentation, Toll-like receptor signaling, MAPK signaling and transforming growth factor-beta (TGF-ß) signaling.Real-time fluorescence quantitative PCR (RT-PCR) analysis showed that the statistics of optical density for JUN was P < 0.001 in severe versus mild group. It was down-regulated in severe group. And the expression of JUN was conformed with the result of gene expression chip. CONCLUSIONS: The patients of severe group have a larger number of differential expressed genes versus those of mild group. And severe lung tissue damage in severe group may be correlated with differences in gene expression.
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Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos , Tuberculosis Pulmonar , Análisis por Conglomerados , Biología Computacional , Regulación hacia Abajo , Expresión Génica , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal , Regulación hacia ArribaRESUMEN
OBJECTIVES: The mechanism that leads to disseminated tuberculosis in HIV-negative patients is still largely unknown. T cell subsets and signaling pathways that were associated with disseminated tuberculosis were investigated. METHODS: Single-cell profiling of whole T cells was performed to identify T cell subsets and enriched signaling pathways that were associated with disseminated tuberculosis. Flow cytometric analysis and blocking experiment were used to investigate the findings obtained by transcriptome sequencing. RESULTS: Patients with disseminated tuberculosis had depleted Th1, Tc1 and Tc17 cell subsets, and IFNG was the most down-regulated gene in both CD4 and CD8 T cells. Gene Ontology analysis showed that non-canonical NF-κB signaling pathway, including NFKB2 and RELB genes, was significantly down-regulated and was probably associated with disseminated tuberculosis. Expression of several TNF superfamily ligands and receptors, such as LTA and TNF genes, were suppressed in patients with disseminated tuberculosis. Blocking of TNF-α and soluble LTα showed that TNF-α was involved in IFN-γ production and LTα influenced TNF-α expression in T cells. CONCLUSIONS: Impaired T cell IFN-γ response mediated by suppression of TNF and non-canonical NF-κB signaling pathways might be responsible for disseminated tuberculosis.
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Interferón gamma , FN-kappa B , Transducción de Señal , Factor de Necrosis Tumoral alfa , Humanos , Masculino , Femenino , Adulto , FN-kappa B/metabolismo , Persona de Mediana Edad , Interferón gamma/metabolismo , Interferón gamma/genética , Interferón gamma/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Tuberculosis/inmunología , Factor de Transcripción ReIB/metabolismo , Factor de Transcripción ReIB/genética , Subunidad p52 de NF-kappa B/metabolismo , Subunidad p52 de NF-kappa B/genética , Análisis de la Célula Individual , Linfocitos T CD8-positivos/inmunología , Linfotoxina-alfa/genética , Linfotoxina-alfa/metabolismo , Adulto Joven , Anciano , Perfilación de la Expresión Génica , Mycobacterium tuberculosis/inmunologíaRESUMEN
Diagnosis of tuberculosis remains a challenge when microbiological tests are negative. Immune cell atlas of patients with tuberculosis and healthy controls were established by single-cell transcriptome. Through integrated analysis of scRNA-seq with microarray and bulk RNA sequencing data, a ferroptosis-related gene signature containing ACSL4, CTSB, and TLR4 genes that were associated with tuberculosis disease was identified. Four gene expression datasets from blood samples of patients with tuberculosis, latent tuberculosis infection, and healthy controls were used to assess the diagnostic value of the gene signature. The areas under the ROC curve for the combined gene signature were 1.000, 0.866, 0.912, and 0.786, respectively, in differentiating active tuberculosis from latent infection. During anti-tuberculosis treatment, the expression of the gene signature decreased significantly in cured patients with tuberculosis. In conclusion, the ferroptosis-related gene signature was associated with tuberculosis treatment efficacy and was a promising biomarker for differentiating active tuberculosis from latent infection.
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Tissue-resident MAIT cells in tuberculous pleural effusions, the site of tuberculosis infection, were investigated in the study. Tim-3+CD69+CD103+ and CD39+CD69+CD103+ tissue-resident MAIT cell subsets were identified in tuberculous pleural effusions. Tim-3 expression in MAIT cells was greatly induced and CD39 expression was elevated following ex vivo stimulation with Mycobacterium tuberculosis antigens. Mycobacterial antigen-stimulated Tim-3+CD69+CD103+ tissue-resident MAIT cells had higher frequency of IFN-γ- and granzyme B-producing cells than Tim-3-CD69+CD103+ subset, while CD39+CD69+CD103+ MAIT cells had similar frequency of IFN-γ-positive cells but higher ratio of granzyme B-producing cells than CD39-CD69+CD103+ subset. Blocking of IL-2, IL-12p70 or IL-18 but not IL-15 led to significantly reduced expression of Tim-3 compared with isotype antibody control. In contrast, CD39 expression was not influenced by any of the cytokines tested. Tim-3+ MAIT cells had higher levels of lipid uptake and lipid content than Tim-3- cells. It is concluded that Tim-3+CD69+CD103+ tissue-resident MAIT cells were elevated in tuberculous pleural effusions and had higher capacity to produce effector molecules of IFN-γ and granzyme B.
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Células T Invariantes Asociadas a Mucosa , Derrame Pleural , Tuberculosis , Humanos , Células T Invariantes Asociadas a Mucosa/metabolismo , Granzimas/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Derrame Pleural/metabolismo , LípidosRESUMEN
The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays an important role in the pathogenesis of immune diseases. High levels of MIF have been detected in the sera of patients with tuberculosis (TB), and it has been proposed that MIF gene polymorphisms may influence the risk of developing TB. The aim of this study was to evaluate the potential relationship between functional polymorphisms of MIF and TB in a Han population from Southwestern China. TB patients (n=215) and healthy unrelated controls (n=245) were recruited for this study. Genomic DNA was isolated from all the participants. The MIF-173 G/C SNP was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The MIF-794 CATT(5-8) microsatellite was evaluated by direct sequencing of the subsequent PCR products. Association analysis of the two polymorphisms showed that the frequency of -173 (GC+CC) in TB patients and controls was 49.3% and 31.4%, respectively, which was statistically significant (OR=2.12, 95% CI=1.45-3.10, P<0.001); the frequencies of -794 (7/X+8/X) were 56.7% and 45.3%, respectively, also statistically significant between the TB and healthy controls (OR=1.58, 95% CI=1.10-2.29, P=0.015). In summary, Genetic variation in the MIF gene is closely associated with tuberculosis. Both the 173 (GC+CC) SNP and -794 (7/X+8/X) microsatellite increased the risk of Chinese Han developing TB.
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Predisposición Genética a la Enfermedad/genética , Factores Inhibidores de la Migración de Macrófagos/genética , Polimorfismo Genético , Regiones Promotoras Genéticas/genética , Tuberculosis/genética , Adulto , Alelos , Pueblo Asiatico/genética , Secuencia de Bases , China , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Tuberculosis/etnologíaRESUMEN
Objective To investigate the relationship between the CD160 expression and anti-tuberculosis immunity. Methods Fluorescence quantitative real-time PCR was used to detect the expression of CD160 in peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze the expression of CD160 on main subtypes of PBMCs, such as T cells, B cells, NK cells and monocytes. The relationship among CD160 and perforin, granzyme B, granulysin, CD69, CD107 and IFN-γ in NK cells was analyzed by flow cytometry. Results CD160 mRNAs in the PBMCs from patients with active tuberculosis was significantly down-regulated, and the levels of CD160 expression in Mycobacterium tuberculosis (MTB)-positive patients was significantly lower than in MTB-negative patients. The expression of CD160 on B cells and monocytes was lower in patients with active tuberculosis as compared with normal controls, while no significant difference was observed on CD3+ T cells. NK cells from patients with active tuberculosis had significantly lower CD160 expression than those from normal controls. In vitro culture with MTB antigens led to down-regulated expression of CD160 on NK cells. The activation marker CD69 on NK in patients with active tuberculosis was significantly lower than that in normal controls. The expression of perforin, granzyme B, granulysin, CD69 and CD107 in CD160+ NK cells was significantly higher than that of CD160- NK cells. However, the expression of IFN-γ in CD160+ NK cells was significantly lower than that of CD160- NK cells. Conclusion The mRNA and protein expression of CD160 was significantly down-regulated in patients with active tuberculosis. CD160 promotes the activation and degranulation of NK cells associated with tuberculosis antigens, but suppresses the expression of IFN-γ of NK cells. CD160 may become a new target for the diagnosis and treatment of tuberculosis.
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Leucocitos Mononucleares , Tuberculosis , Antígenos CD/genética , Antígenos CD/metabolismo , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Granzimas/genética , Granzimas/metabolismo , Humanos , Células Asesinas Naturales , Leucocitos Mononucleares/metabolismo , Perforina/genética , Perforina/metabolismo , ARN Mensajero/metabolismo , Receptores InmunológicosRESUMEN
OBJECTIVE: Current commercially available immunological tests cannot be used for discriminating active tuberculosis (TB) from latent TB infection. To evaluate the value of biomarker candidates in the diagnosis of active TB, this study aimed to identify differentially expressed genes in peripheral blood mononuclear cells (PBMCs) between patients with active TB and individuals with latent TB infection by transcriptome sequencing. METHODS: The differentially expressed genes in unstimulated PBMCs and in Mycobacterium tuberculosis (Mtb) antigen-stimulated PBMCs from patients with active TB and individuals with latent TB infection were identified by transcriptome sequencing. Selected candidate genes were evaluated in cohorts consisting of 110 patients with TB, 30 individuals with latent TB infections, and 50 healthy controls by quantitative real-time RT-PCR. Receiver operating characteristic (ROC) curve analysis was performed to calculate the diagnostic value of the biomarker candidates. RESULTS: Among the differentially expressed genes in PBMCs without Mtb antigen stimulation, interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) had the highest area under curve (AUC) value (0.918, 95% CI: 0.852-0.984, P<0.0001) in discriminating patients with active TB from individuals with latent TB infection, with a sensitivity of 91.86% and a specificity of 84.00%. In Mtb antigen-stimulated PBMCs, orosomucoid 1 (ORM1) had a high AUC value (0.833, 95% CI: 0.752-0.915, P<0.0001), with a sensitivity of 81.94% and a specificity of 70.00%. CONCLUSION: IFIT3 and ORM1 might be potential biomarkers for discriminating active TB from latent TB infection.
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Tuberculosis Latente , Tuberculosis , Humanos , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/genética , Orosomucoide/metabolismo , Leucocitos Mononucleares/química , Leucocitos Mononucleares/metabolismo , Tuberculosis/diagnóstico , Tuberculosis/genética , Biomarcadores/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismoRESUMEN
Dielectric capacitors are emerging energy-storage components that require both high energy-storage density and high efficiency. The conventional approach to energy-storage enhancement is polar nanodomain engineering via chemical modification. Here, a new approach of domain engineering is proposed by exploiting the tunable polar topologies that have been observed recently in ferroelectric/paraelectric multilayer films. Using phase-field simulations, it is demonstrated that vortex, spiral, and in-plane polar structures can be stabilized in BiFeO3 /SrTiO3 (BFO/STO) multilayers by tailoring the strain state and layer thickness. Various switching dynamics are realized in these polar topologies, resulting in relaxor-ferroelectric-, antiferroelectric-, and paraelectric-like polarization behaviors, respectively. Ultrahigh energy-storage densities above 170 J cm-3 and efficiencies above 95% are achievable in STO/BFO/STO trilayers. This strategy should be generally implementable in other multilayer dielectrics and offers a new avenue to enhancing energy storage by tuning the polar topology and thus the polarization characteristics.