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1.
BMC Infect Dis ; 19(1): 1006, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779590

RESUMO

BACKGROUND: Monocytes are the predominant innate immune cells at the early stage of Mycobacterium tuberculosis (M. tb) infection as the host defense against intracellular pathogens. Understanding the profile of different monocyte subpopulations and the dynamics of monocyte-related biomarkers may be useful for the diagnosis and prognosis of tuberculosis. METHODS: We enrolled 129 individuals comprising patients with pulmonary tuberculosis (PTB) (n = 39), tuberculous pleurisy (TBP) (n = 28), malignant pleural effusion (MPE) (n = 21), latent tuberculosis infection (LTBI) (n = 20), and healthy controls (HC) (n = 21). Surface expression of CD14, CD16, and CD163 on monocytes was detected using flow cytometry. In addition, soluble CD163 (sCD163) was determined by enzyme linked immunosorbent assay. RESULTS: Higher frequency of CD14+CD16+ (15.7% vs 7.8%, P < 0.0001) and CD14-CD16+ (5.3% vs 2.5%, P = 0.0011) monocytes and a decreased percentage of CD14+CD16- (51.0% vs 70.4%, P = 0.0110) cells was observed in PTB patients than in HCs. Moreover, PTB patients displayed a higher frequency of CD163+ cells in CD16+ monocytes than those in the HC group (40.4% vs 11.3%, P < 0.0001). The level of sCD163 was elevated in TBP patients and was higher in pleural effusion than in plasma (2116.0 ng/ml vs 1236.0 ng/ml, P < 0.0001). sCD163 levels in pleural effusion and plasma could be used to distinguish TBP from MPE patients (cut-off values: 1950.0 and 934.7 ng/ml, respectively; AUCs: 0.8418 and 0.8136, respectively). Importantly, plasma sCD163 levels in TBP patients decreased significantly after anti-TB treatment. CONCLUSIONS: Higher expression of membrane and soluble CD163 in active tuberculosis patients might provide insights regarding the pathogenesis of tuberculosis, and sCD163 may be a novel biomarker to distinguish TBP from MPE and to predict disease severity.


Assuntos
Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Monócitos/metabolismo , Receptores de Superfície Celular/análise , Tuberculose/diagnóstico , Adulto , Idoso , Antígenos CD/sangue , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/sangue , Antígenos de Diferenciação Mielomonocítica/metabolismo , Área Sob a Curva , Estudos de Casos e Controles , Feminino , Humanos , Imunidade Inata , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/imunologia , Prognóstico , Curva ROC , Receptores de Superfície Celular/sangue , Receptores de Superfície Celular/metabolismo , Receptores de IgG/metabolismo , Índice de Gravidade de Doença , Tuberculose/imunologia , Tuberculose/patologia , Tuberculose Pleural/imunologia , Tuberculose Pleural/patologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia
2.
Medicine (Baltimore) ; 98(38): e17253, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567996

RESUMO

BACKGROUND: Malignant pleural effusion (MPE) and tuberculosis pleural effusion (TPE) are 2 kinds of common pleural diseases. Finding efficient and accurate biomarkers to distinguish the 2 is of benefit to basic and clinical research. In the present study, we carried out the first high-throughput autoantibody chip to screen the beneficial biomarker with samples of MPE and TPE and the corresponding serum. METHODS: We collected pleural effusion and serum of patients with MPE (n = 10) and TPE (n = 10) who had been in Beijing Chao-Yang hospital from June 2013 to August 2014. Using RayBio Human Protein Array-G2 to measure the concentration of 487 defined autoantibodies. RESULTS: Fold changes of Bcl-2-like protein 11 (BIM) autoantibody in MPE-serum/TPE-serum and MPE/TPE groups were 10 (P = .019) and 6 (P = .001); for decorin autoantibody, MPE-serum/TPE-serum ratio was 0.6 (P = .029), and MPE/TPE ratio was 0.3 (P < .001). CONCLUSION: BIM autoantibody is a promising MPE biomarker by high-throughput autoantibody analysis in MPE and TPE.


Assuntos
Autoanticorpos/sangue , Derrame Pleural Maligno/sangue , Derrame Pleural/sangue , Tuberculose Pleural/sangue , Autoanticorpos/imunologia , Proteína 11 Semelhante a Bcl-2/sangue , Proteína 11 Semelhante a Bcl-2/imunologia , Biomarcadores/sangue , Feminino , Ensaios de Triagem em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/diagnóstico , Derrame Pleural/imunologia , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/imunologia , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/imunologia
3.
BMC Immunol ; 20(1): 36, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623558

RESUMO

BACKGROUND: A previous study demonstrated pleural fluid (PF) IgA immunodominance for the fused MT10.3:MPT64 protein in pleural tuberculosis (PLTB) cases. However, no clue on the role of IgA and IgG against this and other antigens in PF and serum concerning improved diagnosis is available. Thus, the aim of the present study was to validate PF IgA-MT10.3:MPT64 and evaluate PF and serum IgA and IgG reactivity against this protein, its peptides (F2) and single MPT64, MT10.3 and the PPE59 mycobacterial specific antigens. IgA and IgG ELISA were measured against the antigen in PLTB (n = 29) and other non-TB pleurisy (n = 39) patient samples. RESULTS: The immunodominance of PF IgA-MT10.3:MPT64 was confirmed in PLTB (86.2%) followed by PPE59 (62%), while serum IgA-F2 exhibited 51.7% sensitivity. PF and serum IgG-MT10.3:MPT64 led to 65.5 and 51.7% sensitivity, respectively. However, MT10.3 and MPT64 displayed overall lower sensitivity (≤34.5) for both antibodies. All results at 95% fixed specificity. Combinatory results indicated 93.1% sensitivity for PF IgA-MT10.3:MPT64/-PPE59 and IgA/IgG-MT10.3:MPT64 at 92.3% specificity, followed by IgA-MT10.3:MPT64/-MPT64 or /-F2 (89.6%) without jeopardizing specificity (94.9%). The combinatory results of the PF adenosine deaminase test (ADA) and IgA-MT10.3:MPT64/-F2 demonstrated the highest sensitivity (96.6%), with a specificity of 92.3%. CONCLUSIONS: The PF IgA-MT10:MPT64 immune dominance was validated in PLTB, and its combinatory results with PPE59 or MPT64 or F2 antigens as well as with IgG, are reported herein for the first time, improving their potential to assist diagnosis. Combining PF-ADA and IgA-MT10.3:MPT64/-F2 results achieved better accuracy. Moreover, serum IgG, although less accurate, displays potential beyond microbiological tests.


Assuntos
Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Mycobacterium tuberculosis/imunologia , Derrame Pleural/imunologia , Tuberculose Pleural/imunologia , Biomarcadores , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Derrame Pleural/patologia , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tuberculose Pleural/sangue , Tuberculose Pleural/diagnóstico
4.
Med Hypotheses ; 131: 109319, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443751

RESUMO

We hypothesize that exogenous intrapleural injection of interleukin-27 may improve outcome and prognosis in patients with tuberculous pleural effusion (TPE). Studies have found that the balance of Th1/Th2 determines the development trend of TPE. High concentrations of IFN-γ and TNF-α in pleural effusion are associated with pleural adhesion in patients with TPE. Interleukin-27 is a member of the IL-12 family, and IL-27 has a dual regulatory effect on Th1 immunity. On one hand, IL-27 can promote the initial CD4+ T cell proliferation by inducing the expression of T-bet, IL-12Rß2 and ICAM-1 in the initial CD4+ T cells, and also promote its differentiation into Th1 cells and IFN-γ production in the early infection. On the other hand, in the case of high Th1 polarization, IL-27 induced STAT3 phosphorylation and inhibited TNF and IL-12 production in activated peritoneal macrophages, indicating a novel feedback mechanism by which IL-27 can modulate excessive inflammation, thereby preventing damage to the body caused by excessive immune response. Studies haves confirmed that after stimulation of antigen by mononuclear cells in TPE, the Th1 and Th2 cell subsets and Th1/Th2 ratio markedly increase, and the increase of Th1 is more obvious than that of Th2. Therefore, compared to patients with TPE in the high-level IL-27 group, we hypothesized that pleural effusion is absorbed more slowly, pleural thickening is more obvious, pleural adhesions are more extensive, and the incidence of thoracic collapse is higher in the low-level IL-27 group under the same conditions of anti-tuberculosis treatment. However, exogenous intrapleural injection of IL-27 may induce Stat3 phosphorylation and inhibit TNF and IL-12 production, finally reduces the secretion of IFN-γ and TNF-α. This negative regulation inhibits the excessive inflammatory reaction caused by tuberculosis infection, reduces pleural adhesion, pleural thickening and local pleural tissue damage, thereby improving the prognosis of patients.


Assuntos
Interleucinas/uso terapêutico , Modelos Imunológicos , Derrame Pleural/etiologia , Tuberculose Pleural/tratamento farmacológico , Animais , Retroalimentação Fisiológica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Injeções , Interferon gama/metabolismo , Interleucina-12/biossíntese , Interleucina-12/genética , Interleucinas/administração & dosagem , Interleucinas/fisiologia , Modelos Animais , Fosforilação , Pleura , Prognóstico , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Proteínas Recombinantes/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Resultado do Tratamento , Tuberculose Pleural/complicações , Tuberculose Pleural/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
5.
Tuberculosis (Edinb) ; 116S: S123-S130, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31103419

RESUMO

Tuberculosis is the most common infectious reason for death and a major cause of pleural effusion globally. To understand the role of chemokines in trafficking of cells during TB pleurisy, we studied the responses to MTB, Ag85A in cells from pleural fluids and peripheral blood. Patients with TB pleural effusions, malignant effusions and asymptomatic healthy controls were enrolled. High expression (p < 0.05) of IP-10, MCP-1, MIG, IL-8, IFN-γ and IL-23 were observed in pleural fluids of TB patients compared to their plasma where expression of RANTES was significantly higher (p < 0.05). On specific stimulation of PFMCs with Ag85A, expression of RANTES was significantly lower in TB compared to NTB patients. We also observed increased expression of T regs and PD1 on CD8+T cells in PFMC of TB patients. Though some of the inflammatory chemokine/cytokines were up-regulated in pleura of TB patients, antigenic stimulation failed to induce them indicating poor antigenic responses at the site. Low expression of RANTES might be a reason for decreased trafficking of cells to the site and dissemination of infection into pleural site. The pattern of RANTES expression in pleural fluid vs serum is interesting. The observations necessitate further studies to investigate the levels of RANTES for its potential biological relevance in TB immunity and its use as a biomarker for diagnosis of pleural TB.


Assuntos
Aciltransferases/imunologia , Antígenos de Bactérias/imunologia , Quimiocina CCL5/metabolismo , Leucócitos Mononucleares/metabolismo , Mycobacterium tuberculosis/imunologia , Derrame Pleural/metabolismo , Tuberculose Pleural/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Estudos de Casos e Controles , Quimiocina CCL5/sangue , Quimiotaxia , Regulação para Baixo , Feminino , Interações Hospedeiro-Patógeno , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/microbiologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural/imunologia , Derrame Pleural/microbiologia , Tuberculose Pleural/imunologia , Tuberculose Pleural/microbiologia , Adulto Jovem
6.
Int J Mol Sci ; 19(7)2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973541

RESUMO

Pleural tuberculosis is one of the most frequent forms of extra-pulmonary tuberculosis observed in patients infected with Mycobacterium tuberculosis. Tumor Necrosis Factor (TNF) is a crucial cytokine needed to control tuberculosis infection that remains a leading cause of morbidity and mortality worldwide. TNF blockade compromises host immunity and may increase the risk of reactivation of latent infection resulting in overt pulmonary, pleural and extra-pulmonary tuberculosis. While TNF signaling is mainly considered pro-inflammatory, its requirement for the anti-inflammation process involved in the resolution of infection and tissue repair is less explored. Our study analyzes the role of TNF and TNF receptors in the control of the inflammatory process associated with Bacillus Calmette-Guérin (BCG)-induced pleurisy. This study shows that the absence of TNF causes exacerbated inflammation in the pleural cavity of BCG-infected mice which is controlled by the transmembrane TNF (tmTNF) expression. The lack of TNF is associated with an impaired cellular expression and shedding of TNFR2 in the pleural cavity. The presence of tmTNF restores the normal expression of TNFR2 on myeloid cells during BCG-induced pleurisy. We also show that absence of TNFR1 affects the expression of TNFR2 on pleural cells and inflammation in the pleural cavity of BCG-infected mice. In conclusion, tmTNF but not soluble TNF prevents pleural cavity inflammation leading to attenuation and the resolution of the inflammatory process caused by mycobacterial pleurisy in association with the expression of TNFR2 on myeloid cells.


Assuntos
Inflamação/imunologia , Receptores do Fator de Necrose Tumoral/metabolismo , Tuberculose Pleural/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium bovis/imunologia , Cavidade Pleural/citologia , Cavidade Pleural/patologia , Receptores do Fator de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/genética
7.
Front Immunol ; 9: 459, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29593722

RESUMO

The ability of Mycobacterium tuberculosis (Mtb) to persist in its human host relies on numerous immune evasion strategies, such as the deregulation of the lipid metabolism leading to the formation of foamy macrophages (FM). Yet, the specific host factors leading to the foamy phenotype of Mtb-infected macrophages remain unknown. Herein, we aimed to address whether host cytokines contribute to FM formation in the context of Mtb infection. Our approach is based on the use of an acellular fraction of tuberculous pleural effusions (TB-PE) as a physiological source of local factors released during Mtb infection. We found that TB-PE induced FM differentiation as observed by the increase in lipid bodies, intracellular cholesterol, and expression of the scavenger receptor CD36, as well as the enzyme acyl CoA:cholesterol acyl transferase (ACAT). Importantly, interleukin-10 (IL-10) depletion from TB-PE prevented the augmentation of all these parameters. Moreover, we observed a positive correlation between the levels of IL-10 and the number of lipid-laden CD14+ cells among the pleural cells in TB patients, demonstrating that FM differentiation occurs within the pleural environment. Downstream of IL-10 signaling, we noticed that the transcription factor signal transducer and activator of transcription 3 was activated by TB-PE, and its chemical inhibition prevented the accumulation of lipid bodies and ACAT expression in macrophages. In terms of the host immune response, TB-PE-treated macrophages displayed immunosuppressive properties and bore higher bacillary loads. Finally, we confirmed our results using bone marrow-derived macrophage from IL-10-/- mice demonstrating that IL-10 deficiency partially prevented foamy phenotype induction after Mtb lipids exposure. In conclusion, our results evidence a role of IL-10 in promoting the differentiation of FM in the context of Mtb infection, contributing to our understanding of how alterations of the host metabolic factors may favor pathogen persistence.


Assuntos
Acetil-CoA C-Acetiltransferase/imunologia , Regulação Enzimológica da Expressão Gênica/imunologia , Interleucina-10/imunologia , Mycobacterium tuberculosis/imunologia , Derrame Pleural/imunologia , Fator de Transcrição STAT3/imunologia , Esterol O-Aciltransferase , Tuberculose Pleural/imunologia , Regulação para Cima/imunologia , Acetil-CoA C-Acetiltransferase/genética , Animais , Feminino , Células Espumosas , Humanos , Interleucina-10/genética , Masculino , Camundongos , Camundongos Knockout , Mycobacterium tuberculosis/genética , Derrame Pleural/genética , Derrame Pleural/patologia , Fator de Transcrição STAT3/genética , Tuberculose Pleural/genética , Tuberculose Pleural/patologia
8.
Tuberculosis (Edinb) ; 109: 69-79, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29559123

RESUMO

Human Leukocyte Antigen-G (HLA-G), a non-classical, class Ib molecule, has been shown to mediate immunoregulatory functions by inducing apoptosis, inhibits cytotoxicity and differentiation by modulating cytokine secretion. Due to its immune-suppressive function, it facilitates tolerance in feto-maternal interface and transplantation. In contrary, it favours immune evasion of microbes and tumors by inhibiting immune and inflammatory responses. In Tuberculosis (TB), we previously reported differential expression of HLA-G and its receptor Ig-like transcript -2 (ILT-2) in disseminated vs. localized Tuberculosis. The present study explores the impact of HLA-G inhibition on the function of T cells and monocytes, in TB Pleural Effusion (PE), a localized form of TB. Blocking of HLA-G resulted in significant increase in IFN-γ and TNF-α production by CD3+ T cells. Additionally, we observed that HLA-G influences the apoptosis and cytotoxic effect of T cells from TB- PE patients. Next, we checked the impact of interaction between HLA-G and ILT-4 receptor in monocytes derived from TB-PE patients upon blocking and observed significant increase in IFN-γ production. The present study reveals for the first time HLA-G mediated suppression of Th1 cytokines, especially, IFN-γ and TNF-α in TB-PE patients.


Assuntos
Anticorpos Bloqueadores/farmacologia , Antígenos HLA-G/imunologia , Interferon gama/imunologia , Mycobacterium tuberculosis/imunologia , Derrame Pleural/imunologia , Células Th1/efeitos dos fármacos , Tuberculose Pleural/imunologia , Fator de Necrose Tumoral alfa/imunologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Apoptose/efeitos dos fármacos , Células Cultivadas , Antígenos HLA-G/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Interferon gama/metabolismo , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/imunologia , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/metabolismo , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/microbiologia , Perforina/imunologia , Perforina/metabolismo , Derrame Pleural/metabolismo , Derrame Pleural/microbiologia , Derrame Pleural/patologia , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/microbiologia , Tuberculose Pleural/metabolismo , Tuberculose Pleural/microbiologia , Tuberculose Pleural/patologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Int J Tuberc Lung Dis ; 22(3): 321-327, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29471911

RESUMO

BACKGROUND: Tuberculosis (TB) is a major health problem worldwide. In TB, the immune and central nervous systems modulate each other. The two main components of this network are the hypothalamic-pituitary-adrenal axis (HPA) and autonomic nervous system (ANS). OBJECTIVE: To elucidate neuro-endocrine-immune (NEI) interactions in pulmonary (PTB) or pleural (PLTB) TB, we analysed the relationship among compounds from these systems. METHODS: We quantified levels of catecholamines, hormones and cytokines in plasma from patients with PTB (n = 46) or PLTB (n = 12) and controls (n = 32), and in the pleural fluid from PLTB patients. Transcript expression for genes involved in glucocorticoid-related function (quantitative real-time polymerase chain reaction) was also analysed in mononuclear cells (MCs) from peripheral blood (PBMC) or pleural effusion (PEMC) compartments. RESULTS: Both patient groups had increased plasma levels of pro- and anti-inflammatory cytokines, cortisol, growth hormone (GH) and dopamine, whereas insulin-like growth factor 1 (IGF-1) and dehydroepiandrosterone levels were decreased. The pleural fluid contained increased levels of pro-inflammatory cytokines, GH and IGF-1 and reduced levels of steroid hormones compared with their plasma counterparts. PBMCs from PTB patients had increased expression of transcripts for 11ß-hydroxysteroid dehydrogenase (11ßHSD1) and a decreased glucocorticoid receptor (GR) ratio (GRα/GRß). In PLTB cases, expression of 11ßHSD1 and GRα transcripts was higher in PEMCs. CONCLUSION: PTB patients seem to display adverse NEI dysregulation. Changes in pleural fluid are compatible with a more effective NEI reaction.


Assuntos
Sistemas Neurossecretores/imunologia , Tuberculose Pleural/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Estudos de Coortes , Citocinas/análise , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Derrame Pleural/metabolismo , Receptores de Glucocorticoides/metabolismo , Tuberculose Pleural/sangue , Tuberculose Pulmonar/sangue , Adulto Jovem
10.
Int J Tuberc Lung Dis ; 22(12): 1514-1522, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30606326

RESUMO

BACKGROUND: Chemokine receptors and their ligands play a prominent role in regulating leucocyte migration. In the local milieu of inflammation, a high concentration of chemokines can recruit different chemokine receptor-expressing lymphocytes. OBJECTIVE: To understand the distinct immunological functions of CXC chemokine receptor 3 (CXCR3+) and CC chemokine receptor 4 (CCR4+) cluster of differentiation 4 (CD4+) T-cells accumulated in human tuberculosis (TB) pleural fluid after tuberculous antigen stimulation. METHODS: Mononuclear cells were isolated from the peripheral blood of healthy donors, cord blood and TB pleural fluid, and expression of CXCR3 and CC chemokine receptor 4 (CCR4), cytokines and cytolytic molecules by CD4+ T-cells with or without stimulation were analysed using fluorescence-activated cell sorting. RESULTS: CXCR3 and CCR4 expression on CD4+ T-cells from pleural fluid mononuclear cells (PFMCs) was significantly higher than in peripheral blood mononuclear cells (PBMCs). T-cell receptor signalling resulted in the upregulation of CXCR3 and CCR4 expression on CD4+ T-cells from cord blood mononuclear cells (CBMCs) and PBMCs in a time-dependent manner, but not from PFMCs. After stimulation with Mycobacterium tuberculosis antigens, CXCR3+CCR4-CD4+ T-cells were dominated by multifunctional T-helper 1 cells; however, CXCR3+CCR4+CD4+ T-cells exhibited cytotoxicity and degranulation by expressing granzyme B, perforin, CD107a/b and tumour necrosis factor-related apoptosis-inducing ligand. CONCLUSION: Our results indicated that CXCR3 or CCR4 expression on CD4+ T-cells had different biological activities against tuberculous infection, and could be a potential marker for the diagnosis of TB.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Receptores CCR4/metabolismo , Receptores CXCR3/metabolismo , Tuberculose Pleural/imunologia , Adulto , Idoso , Estudos de Casos e Controles , China , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Receptores CCR4/genética , Receptores CXCR3/genética , Células Th1/imunologia , Tuberculose Pleural/genética
11.
BMC Pulm Med ; 17(1): 180, 2017 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-29216864

RESUMO

BACKGROUND: The ability of interleukins (ILs) to differentiate tuberculous pleural effusion from other types of effusion is controversial. The aim of our study was to summarize the evidence for its use of ruling out or in tuberculous pleural effusion. METHODS: Two investigators independently searched PubMed, EMBASE, Web of Knowledge, CNKI, WANFANG, and WEIPU databases to identify studies assessing diagnostic role of ILs for tuberculous pleural effusion published up to January, 2017. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. The pooled diagnostic sensitivity and specificity of ILs were calculated by using Review Manager 5.3. Area under the summary receiver operating characteristic curve (AUC) was used to summarize the overall diagnostic performance of individual markers. RESULTS: Thirty-eight studies met our inclusion criteria. Pooled sensitivity, specificity and AUC for chosen ILs were as follows: IL-2, 0.67,0.76 and 0.86; IL-6, 0.86, 0.84 and 0.90; IL-12, 0.78, 0.83 and 0.86; IL-12p40, 0.82,0.65 and 0.76; IL-18, 0.87, 0.92 and 0.95; IL-27, 0.93, 0.95 and 0.95; and IL-33, 0.84, 0.80 and 0.88. CONCLUSIONS: Some of these ILs may assist in diagnosing tuberculous pleural effusion, though no single IL is likely to show adequate sensitivity or specificity on its own. Further studies on a large scale with better study design should be performed to assess the diagnostic potential of ILs.


Assuntos
Exsudatos e Transudatos/imunologia , Interleucinas/imunologia , Derrame Pleural/imunologia , Tuberculose Pleural/imunologia , Área Sob a Curva , Humanos , Derrame Pleural/diagnóstico , Derrame Pleural/etiologia , Sensibilidade e Especificidade , Tuberculose Pleural/complicações , Tuberculose Pleural/diagnóstico
12.
Tuberculosis (Edinb) ; 107: 95-103, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29050778

RESUMO

Despite evidence suggesting an anti-Mycobacterium tuberculosis effector function of CD4+ T cells that produce and retain IL-22 in macaques, the general role of IL-22 in tuberculosis infection is still poorly characterized. To explore the immune mechanism in the pathogenesis of tuberculosis in humans, here we evaluated different forms of IL-22 in populations with different tuberculosis infection statuses. We enrolled 156 subjects including 49 patients with pulmonary tuberculosis, 27 patients with tuberculous pleurisy (TPE), 38 individuals with latent tuberculous infection (LTBI) and 42 healthy controls (HC). We found significantly higher IL-22 levels at the tuberculosis infection site than in the peripheral blood as well as higher antigen-specific IL-22 levels in the culture supernatant for patients with active tuberculosis than in healthy controls. The proportions of IL-22 + CD4+ T and IL-22 + CD8+ T cells in patients with active tuberculosis were significantly higher than those in the latent tuberculosis infection group and the healthy control group, based on intracellular cytokine staining. However, surprisingly, we found membrane-bound IL-22+ T cells, including CD4+ T cells and CD8+ T cells, by surface staining, especially in patients with active tuberculosis. Furthermore, the expression of membrane-bound IL-22 significantly decreased after drug therapy. In conclusion, our results suggest that IL-22 has various roles in tuberculosis immune responses. In particular, membrane-bound IL-22+ T cells may play important roles in the human immune response to Mycobacterium.


Assuntos
Interleucinas/imunologia , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pleural/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/uso terapêutico , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/microbiologia , Estudos de Casos e Controles , Membrana Celular/imunologia , Membrana Celular/metabolismo , Membrana Celular/microbiologia , Células Cultivadas , Feminino , Interações Hospedeiro-Patógeno , Humanos , Interleucinas/sangue , Tuberculose Latente/sangue , Tuberculose Latente/tratamento farmacológico , Tuberculose Latente/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pleural/sangue , Tuberculose Pleural/tratamento farmacológico , Tuberculose Pleural/microbiologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Adulto Jovem
13.
Clin Sci (Lond) ; 131(15): 1859-1876, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28588103

RESUMO

T-cell responses have been demonstrated to be essential for preventing Mycobacterium tuberculosis infection. The Th1-cytokines produced by T cells, such as INF-γ, IL-2, and TNF-α, not only limit the invasion of M. tuberculosis but also eliminate the pathogen at the site of infection. Bacillus Calmette-Guérin (BCG) is known to induce Th1-type responses but the protection is inadequate. Identification of immunogenic components, in addition to those expressed in BCG, and induction of a broad spectrum of Th1-type responses provide options for generating sufficient adaptive immunity. Here, we studied human pulmonary T-cell responses induced by the M. tuberculosis-specific antigen Rv3615c, a protein with a similar size and sequence homology to ESAT-6 and CFP-10, which induced dominant CD4+ T-cell responses in human tuberculosis (TB) models. We characterized T-cell responses including cytokine profiling, kinetics of activation, expansion, differentiation, TCR usage, and signaling of activation induced by Rv3615c compared with other M. tuberculosis-specific antigens. The expanded CD4+ T cells induced by Rv3615c predominately produced Th1, but less Th2 and Th17, cytokines and displayed effector/memory phenotypes (CD45RO+CD27-CD127-CCR7-). The magnitude of expansion and cytokine production was comparable to those induced by well-characterized the 6 kDa early secreted antigenic target (ESAT-6), the 10 kDa culture filtrate protein (CFP-10) and BCG. Rv3615c contained multiple epitopes Rv3615c1-15, Rv3615c6-20, Rv3615c66-80, Rv3615c71-85 and Rv3615c76-90 that activated CD4+ T cells. The Rv3615c-specific CD4+ T cells shared biased of T-cell receptor variable region of ß chain (TCR Vß) 1, 2, 4, 5.1, 7.1, 7.2 and/or 22 chains to promote their differentiation and proliferation respectively, by triggering a signaling cascade. Our data suggest that Rv3615c is a major target of Th1-type responses and can be a highly immunodominant antigen specific for M. tuberculosis infection.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Epitopos Imunodominantes/imunologia , Mycobacterium tuberculosis/imunologia , Células Th1/imunologia , Tuberculose Pleural/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Células Cultivadas , Citocinas/biossíntese , Feminino , Humanos , Memória Imunológica/imunologia , Imunofenotipagem , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Adulto Jovem
14.
Lung ; 195(4): 517-521, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28551717

RESUMO

The cellular immune response to Mycobacterium tuberculosis infection has been well characterized, while the humoral antibody response remains underexplored. We aimed to examine the total and anti-phospholipid IgM levels in the pleural lavage from mice with Mycobacterium bovis BCG extrapulmonary infection. We found that the levels of total and anti-phosphatidylcholine IgM antibodies remained significantly higher in infected mice as compared to non-infected mice up to day 90 after BCG infection, while the anti-cardiolipin IgM antibody levels decreased with bacteria clearance. Our findings suggest that IgM antibodies are secreted and their composition vary during early and late immune response to BCG pleurisy.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Imunidade Humoral , Imunoglobulina M/imunologia , Mycobacterium tuberculosis/imunologia , Fosfatidilcolinas/imunologia , Tuberculose Pleural/imunologia , Animais , Anticorpos Anticardiolipina/imunologia , Carga Bacteriana , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno , Masculino , Camundongos Endogâmicos C57BL , Fatores de Tempo , Tuberculose Pleural/microbiologia
15.
Medicine (Baltimore) ; 96(47): e8412, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29381918

RESUMO

The aim of this study was to identify the optimal cut-off value of T cell enzyme-linked immunospot assay for tuberculosis (T-SPOT.TB) and evaluate its diagnostic performance alone (in the peripheral blood) or in combination with the adenosine deaminase (ADA) activity test (in peripheral blood and the pleural fluid) in patients with tuberculous pleurisy.Adult patients presenting with pleural effusion were included in this prospective cohort study. Tuberculous pleurisy was diagnosed by T-SPOT.TB in peripheral blood and a combination of T-SPOT.TB and ADA activity test in pleural fluid and peripheral blood. Receiver operating characteristic (ROC) curve in combination with multivariate logistic regression was used to evaluate the diagnostic performance of the assays.Among a total of 189 patients with suspected tuberculous pleurisy who were prospectively enrolled in this study, 177 patients were validated for inclusion in the final analysis. ROC analysis revealed that the area under the ROC curve (AUC) for T-SPOT.TB in pleural fluid and peripheral blood was 0.918 and 0.881, respectively, and for the ADA activity test in pleural fluid was 0.944. In addition, 95.5 spot-forming cells (SFCs)/2.5 × 10 cells were determined as the optimal cut-off value for T-SPOT.TB in pleural fluid. Parallel combination of T-SPOT.TB and ADA activity test in pleural fluid showed increased sensitivity (96.9%) and specificity (87.5%), whereas serial combination showed increased specificity (97.5%). The combination of 3 assays had the highest sensitivity at 97.9%, with an AUC value of 0.964.T-SPOT.TB in pleural fluid performed better than that in peripheral blood and the ADA activity test in pleural fluid for tuberculous pleurisy diagnosis. The optimal cut-off value of T-SPOT.TB in pleural fluid was 95.5 SFCs/2.5 × 10 cells. Combination of 3 assays might be a promising approach for tuberculous pleurisy diagnosis.


Assuntos
Adenosina Desaminase/imunologia , ELISPOT/métodos , Interferon gama/imunologia , Tuberculose Pleural/diagnóstico , Tuberculose Pleural/imunologia , Adulto , Idoso , ELISPOT/normas , Feminino , Testes Hematológicos , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/imunologia , Estudos Prospectivos , Curva ROC , Valores de Referência , Sensibilidade e Especificidade
16.
PLoS One ; 11(10): e0165428, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27788218

RESUMO

Pleural tuberculosis (TB), a form of extrapulmonary TB, can be difficult to diagnose. High numbers of lymphocytes in pleural fluid have been considered part of the diagnostic criteria for pleural TB; however, in many cases, neutrophils rather than lymphocytes are the predominant cell type in pleural effusions, making diagnosis more complicated. Additionally, there is limited information on the clinical and laboratory characteristics of neutrophil-predominant pleural effusions caused by Mycobacterium tuberculosis (MTB). To investigate clinical and laboratory differences between lymphocyte- and neutrophil-predominant pleural TB, we retrospectively analyzed 200 patients with the two types of pleural TB. Of these patients, 9.5% had neutrophil-predominant pleural TB. Patients with lymphocyte-predominant and neutrophil-predominant pleural TB showed similar clinical signs and symptoms. However, neutrophil-predominant pleural TB was associated with significantly higher inflammatory serum markers, such as white blood cell count (P = 0.001) and C-reactive protein (P = 0.001). Moreover, MTB was more frequently detected in the pleural fluid from patients in the neutrophil-predominant group than the lymphocyte-predominant group, with the former group exhibiting significantly higher rates of positive results for acid-fast bacilli in sputum (36.8 versus 9.4%, P = 0.003), diagnostic yield of MTB culture (78.9% versus 22.7%, P < 0.001) and MTB detected by polymerase chain reaction (31.6% versus 5.0%, P = 0.001). Four of seven patients with repeated pleural fluid analyses revealed persistent neutrophil-predominant features, which does not support the traditional viewpoint that neutrophil-predominant pleural TB is a temporary form that rapidly develops into lymphocyte-predominant pleural TB. In conclusion, neutrophil-predominant pleural TB showed a more intense inflammatory response and a higher positive rate in microbiological testing compared to lymphocyte-predominant pleural TB. Pleural TB should be considered in neutrophil-predominant pleural effusions, and microbiological tests are warranted.


Assuntos
Laboratórios , Linfócitos/citologia , Neutrófilos/citologia , Tuberculose Pleural/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cavidade Pleural/microbiologia , Escarro/microbiologia , Tuberculose Pleural/diagnóstico
17.
Sci Rep ; 6: 32320, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27586092

RESUMO

The functions of MAIT cells at the site of Mycobacterium tuberculosis infection in humans are still largely unknown. In this study, the phenotypes and immune response of MAIT cells from tuberculous pleural effusions and peripheral blood were investigated. MAIT cells in tuberculous pleural effusions had greatly enhanced IFN-γ, IL-17F and granzyme B response compared with those in peripheral blood. The level of IFN-γ response in MAIT cells from tuberculous pleural effusions was inversely correlated with the extent of tuberculosis infection (p = 0.0006). To determine whether cytokines drive the immune responses of MAIT cells at the site of tuberculosis infection, the role of IL-1ß, IL-2, IL-7, IL-12, IL-15 and IL-18 was investigated. Blockade of IL-2, IL-12 or IL-18 led to significantly reduced production of IFN-γ and/or granzyme B in MAIT cells from tuberculous pleural effusions. Majority of IL-2-producing cells (94.50%) in tuberculous pleural effusions had phenotype of CD3(+)CD4(+), and most IL-12p40-producing cells (91.39%) were CD14(+) cells. MAIT cells had significantly elevated expression of γc receptor which correlated with enhanced immune responses of MAIT cells. It is concluded that MAIT cells from tuberculous pleural effusions exhibited highly elevated immune response to Mtb antigens, which are controlled by cytokines produced by innate/adaptive immune cells.


Assuntos
Imunidade Celular , Células T Invariáveis Associadas à Mucosa/imunologia , Mycobacterium tuberculosis/imunologia , Derrame Pleural/imunologia , Transdução de Sinais/imunologia , Tuberculose Pleural/imunologia , Adulto , Anticorpos Bloqueadores/farmacologia , Feminino , Regulação da Expressão Gênica , Granzimas/genética , Granzimas/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/antagonistas & inibidores , Interleucina-12/genética , Interleucina-12/imunologia , Subunidade p40 da Interleucina-12/genética , Subunidade p40 da Interleucina-12/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-18/antagonistas & inibidores , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-2/antagonistas & inibidores , Interleucina-2/genética , Interleucina-2/imunologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Masculino , Células T Invariáveis Associadas à Mucosa/microbiologia , Mycobacterium tuberculosis/patogenicidade , Derrame Pleural/microbiologia , Derrame Pleural/patologia , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Tuberculose Pleural/microbiologia , Tuberculose Pleural/patologia
18.
Emerg Microbes Infect ; 5(8): e83, 2016 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-27485497

RESUMO

The differential diagnosis of tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) remains difficult despite the availability of numerous diagnostic tools. The current study aimed to evaluate the performance of the whole blood QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and conventional laboratory biomarkers in differential diagnosis of TPE and MPE in high tuberculosis prevalence areas. A total of 117 patients with pleural effusions were recruited, including 91 with TPE and 26 with MPE. All of the patients were tested with QFT-GIT, and the conventional biomarkers in both blood and pleural effusion were detected. The level of antigen-stimulated QFT-GIT in the whole blood of TPE patients was significantly higher than that of MPE (2.89 vs 0.33 IU/mL, P<0.0001). The sensitivity and specificity of QFT-GIT for the diagnosis of TPE were 93.0% and 60.0%, respectively. Among the biomarkers in blood and pleural effusion, pleural adenosine deaminase (ADA) was the most prominent biomarker, with a cutoff value of 15.35 IU/L. The sensitivity and specificity for the diagnosis of TPE were 93.4% and 96.2%, respectively. The diagnostic classification tree from the combination of these two biomarkers was 97.8% sensitive and 92.3% specific. Ultimately, the combination of whole blood QFT-GIT with pleural ADA improved both the specificity and positive predictive value to 100%. Thus, QFT-GIT is not superior to pleural ADA in the differential diagnosis of TPE and MPE. Combined whole blood QFT-GIT and pleural ADA detection can improve the diagnosis of TPE.


Assuntos
Adenosina Desaminase/análise , Biomarcadores/sangue , Testes de Liberação de Interferon-gama , Interferon gama/sangue , Derrame Pleural Maligno/diagnóstico , Derrame Pleural/enzimologia , Tuberculose Pleural/diagnóstico , Adolescente , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Interferon gama/imunologia , Masculino , Derrame Pleural/imunologia , Derrame Pleural Maligno/imunologia , Kit de Reagentes para Diagnóstico , Sensibilidade e Especificidade , Tuberculose Pleural/imunologia , Tuberculose Pleural/microbiologia , Adulto Jovem
19.
Tuberculosis (Edinb) ; 99: 92-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27450010

RESUMO

T-helper (Th) 17 cells are a pro-inflammatory subset of CD4(+) effector T-cells critical in mucosal immunity. Imbalances in Th17 cell proportion have been implicated in the pathogenesis of several diseases; however, this has not been adequately explored in tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection. Since Th17 cells are predominantly mucosally associated, we assessed Th17 proportion and associated microenvironment in pleural effusions from patients co-infected with TB/HIV. Our results show that TB(+)HIV(+) pleurisy results in significantly reduced frequency of CD4(+)IL-17(+)RORC(+)STAT3(+) Th17 cells compared to TB(-)HIV(-)ex vivo (p = 0.0054) and was confirmed in conditioned media studies in vitro (p = 0.0001). This was not associated with alterations in Th17 polarising cytokines IL-6, IL-21 and IL-23 or changes in Th17 signature cytokines IL-17A and F. However, the mRNA expression of Th17 signalling molecules, IL-6 (p = 0.0022), IL-6R (p = 0.0247), IL-1ß (p = 0.0022) and signal transducer and activator (STAT) 3 (p = 0.0022) were significantly upregulated. Notably, TB(+)HIV(+) pleural fluid contained significantly higher concentrations of IL-1ß (p = 0.0008), IL-22 (p = 0.0115), IL-31 (p = 0.0210), TNF-α (p = 0.0251) and IFN-γ (p = 0.0026) than TB(-)HIV(-) pleural fluid ex vivo. Taken together, this suggests a reduced portion of Th17 lymphocytes in TB/HIV pleurisy is independent of locally mediated cytokine polarisation.


Assuntos
Microambiente Celular , Coinfecção , Citocinas/imunologia , Infecções por HIV/imunologia , Células Th17/imunologia , Tuberculose Pleural/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Idoso , Contagem de Linfócito CD4 , Estudos de Casos e Controles , Células Cultivadas , Citocinas/genética , Feminino , Regulação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Derrame Pleural/imunologia , Derrame Pleural/microbiologia , Derrame Pleural/virologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Th17/microbiologia , Células Th17/virologia , Tuberculose Pleural/genética , Tuberculose Pleural/microbiologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/microbiologia , Adulto Jovem
20.
Am J Pathol ; 186(9): 2364-77, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27456129

RESUMO

Tumor necrosis factor (TNF) is crucial to control Mycobacterium tuberculosis infection, which remains a leading cause of morbidity and mortality worldwide. TNF blockade compromises host immunity and may cause reactivation of latent infection, resulting in overt pulmonary, pleural, and extrapulmonary tuberculosis. Herein, we investigate the roles of TNF and TNF receptors in the control of Mycobacterium bovis bacillus Calmette-Guerin (BCG) pleural infection in a murine model. As controls, wild-type mice and those with a defective CCR5, a receptor that is crucial for control of viral infection but not for tuberculosis, were used. BCG-induced pleural infection was uncontrolled and progressive in absence of TNF or TNF receptor 1 (TNFR1)/TNFR2 (TNFR1R2) with increased inflammatory cell recruitment and bacterial load in the pleural cavity, and heightened levels of pleural and serum proinflammatory cytokines and chemokines, compared to wild-type control mice. The visceral pleura was thickened with chronic inflammation, which was prominent in TNF(-/-) and TNFR1R2(-/-) mice. The parietal pleural of TNF(-/-) and TNFR1R2(-/-) mice exhibited abundant inflammatory nodules containing mycobacteria, and these mice developed nonresolving inflammation and succumbed from disseminated BCG infection. By contrast, CCR5(-/-) mice survived and controlled pleural BCG infection as wild-type control mice. In conclusion, BCG-induced pleurisy was uncontrolled in the absence of TNF or TNF receptors with exacerbated inflammatory response, impaired bacterial clearance, and defective mesothelium repair, suggesting a critical role of TNF to control mycobacterial pleurisy.


Assuntos
Receptores do Fator de Necrose Tumoral/imunologia , Tuberculose Pleural/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mycobacterium bovis , Tuberculose Pleural/patologia
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