Impaired M. tuberculosis Antigen-Specific IFN-γ Response without IL-17 Enhancement in Patients with Severe Cavitary Pulmonary Tuberculosis

Fan, Lin; Xiao, Heping; Mai, Guangliang; Su, Bo; Ernst, Joel D.; Hu, Zhongyi

doi:10.1371/journal.pone.0127087

Cited by 17 publications

(22 citation statements)

References 34 publications

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“…Previous studies have indicated that Mtb -specific CD4 T-cell responses differ between TBP and subjects with LTBI, although data on the character of the differences are not uniform ( 18 – 22 ). To immunologically characterize TBP included in our study, we compared Th1 responses in TBP, individuals with LTBI, TBC, and HD groups.…”

Section: Resultsmentioning

confidence: 99%

Severe Tuberculosis in Humans Correlates Best with Neutrophil Abundance and Lymphocyte Deficiency and Does Not Correlate with Antigen-Specific CD4 T-Cell Response

et al. 2017

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It is generally thought that Mycobacterium tuberculosis (Mtb)-specific CD4+ Th1 cells producing IFN-γ are essential for protection against tuberculosis (TB). In some studies, protection has recently been associated with polyfunctional subpopulation of Mtb-specific Th1 cells, i.e., with cells able to simultaneously secrete several type 1 cytokines. However, the role for Mtb-specific Th1 cells and their polyfunctional subpopulations during established TB disease is not fully defined. Pulmonary TB is characterized by a great variability of disease manifestations. To address the role for Mtb-specific Th1 responses during TB, we investigated how Th1 and other immune cells correlated with particular TB manifestations, such as the degree of pulmonary destruction, TB extent, the level of bacteria excretion, clinical disease severity, clinical TB forms, and “Timika X-ray score,” an integrative parameter of pulmonary TB pathology. In comparison with healthy Mtb-exposed controls, TB patients (TBP) did not exhibit deficiency in Mtb-specific cytokine-producing CD4+ cells circulating in the blood and differed by a polyfunctional profile of these cells, which was biased toward the accumulation of bifunctional TNF-α+IFN-γ+IL-2− lymphocytes. Importantly, however, severity of different TB manifestations was not associated with Mtb-specific cytokine-producing cells or their polyfunctional profile. In contrast, several TB manifestations were strongly correlated with leukocyte numbers, the percent or the absolute number of lymphocytes, segmented or band neutrophils. In multiple alternative statistical analyses, band neutrophils appeared as the strongest positive correlate of pulmonary destruction, bacteria excretion, and “Timika X-ray score.” In contrast, clinical TB severity was primarily and inversely correlated with the number of lymphocytes in the blood. The results suggest that: (i) different TB manifestations may be driven by distinct mechanisms; (ii) quantitative parameters and polyfunctional profile of circulating Mtb-specific CD4+ cells play a minor role in determining TB severity; and (iii) general shifts in production/removal of granulocytic and lymphocytic lineages represent an important factor of TB pathogenesis. Mechanisms leading to these shifts and their specific role during TB are yet to be determined but are likely to involve changes in human hematopoietic system.

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Section: Resultsmentioning

confidence: 99%

Severe Tuberculosis in Humans Correlates Best with Neutrophil Abundance and Lymphocyte Deficiency and Does Not Correlate with Antigen-Specific CD4 T-Cell Response

et al. 2017

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“…Patients were included in the study according to the following criteria: (1) diagnosed as newly treated active PTB confirmed by bacteriology with all information regarding bacteriology or pathology, and typical radiological manifestation; (2) patients with severe cavitary PTB with at least one large cavity of ≥3 cm in diameter or at least three cavities regardless of the diameter of cavities or patients with mild lesion PTB without a cavity (patients had mild lesions in ≤two lung fields and no cavity) as reported previously [3], a cavity, or non-cavitary lesions in lungs, which could be observed in a chest computed tomography (CT) scan; (3) patients had never been treated for TB or the anti-TB treatment duration was within 1 week; (4) subjects provided informed consent for the study. During the same period, healthy volunteers were recruited for the control group.…”

Section: Methodsmentioning

confidence: 99%

“…TB cases and tuberculin skin test-positive healthy donors have variant immune responses to MTB ( Mycobacterium tuberculosis ) antigens [2–3]. A large variation has been observed in immune responses of patients with differing severities of active pulmonary tuberculosis (PTB).…”

Section: Introductionmentioning

confidence: 99%

“…We speculated that a critical pathway or molecules might be involved in the change of TB from mild to severe stages. Our previous study [3] showed obvious decreases in MTB antigen-specific interferon (IFN)-γ and CD3+ T cells in the blood of patients with severe cavitary TB compared with mild TB patients. Therefore, the impairment of INF-γ responses when TB lesions become severe needs clarification.…”

Section: Introductionmentioning

confidence: 99%

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Impairment of Wnt/β-catenin signaling in blood cells of patients with severe cavitary pulmonary tuberculosis

et al. 2017

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Tuberculosis (TB) remains as a leading infectious disease worldwide. Our previous study showed interferon (IFN)-γ and CD3 T cell impairment in patients with severe cavitary pulmonary TB (PTB). However, the cause of the change in immune responses during the progression of TB is still poorly understood. In this study, eight newly diagnosed patients with severe cavitary and mild lesion non-cavity PTB were recruited, and three healthy volunteers were recruited as the control. RNA extracted from blood was tested by whole genome oligo microarrays. A PCR array was used to further test the same samples. Two additional groups of patients were recruited according to the same criteria with healthy control(HC) recruited as well and subjected to peripheral blood mononuclear cell isolation (PBMC)and analysis of TCF-7, β-catenin, cyclin D2, IFN-γ, and tumor necrosis factor (TNF)-α expression in CD14- cells (lymphocytes) and CD14+ cells by quantitative PCR. The changes of expression of β-catenin, CD69+ and IFN-γ by CD3+, CD14- and CD14+ cells in vitro with stimulation of LiCl were tested by flow cytometry. Whole genome oligo microarrays showed a significant decrease in expression of the Wnt signaling pathway in severe PTB patients. Further analysis of the Wnt pathway by PCR array indicated that TCF-7, β-catenin, and cyclin D2 expression was significantly reduced in severe PTB patients compared with mild PTB patients. In the additionally recruited patients, TCF-7, β-catenin, and cyclin D2 were expressed in both CD14+ and CD14- cells, while β-catenin was decreased significantly in CD14- cells compared with CD14+ cells in severe PTB patients, and IFN-γ and TNF-α expression in CD14- cells was also reduced significantly in severe PTB patients. β-catenin can directly trigger T cell activation and IFN-γsecretion in PBMCs stimulated for 24 hours. These findings indicate that Wnt pathway and its key genes, such as β-catenin, were impaired in blood cells of patients with severe PTB. Therefore, Wnt/β-catenin pathway is closely associated with T cell proliferation and TB lesion deterioration.

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“…In 2013, there were 9 million new cases of TB diagnosed and 1.5 million deaths due to the disease [ 1 ]. Adaptive immune responses mediated by CD4 + T cells and CD8 + T cells, and T helper (Th) 1 cytokines characterized by interferon (IFN)-γ production are associated with a good prognosis and play an important role in countering the progression of MTB infection [ 2 – 4 ]. However, Th1 cells (primarily CD4 + cells producing IFN-γ) alone are not capable of controlling the infection [ 3 , 5 ] and other factors, including Th2 cells, Th17 cells and regulatory T cells (Treg cells), are also involved in the progression of MTB infection.…”

Section: Introductionmentioning

confidence: 99%

Decreased IL-17 during treatment of sputum smear-positive pulmonary tuberculosis due to increased regulatory T cells and IL-10

Cui

Jia

et al. 2016

J Transl Med

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BackgroundTuberculosis (TB) remains a major public health concern worldwide. Previous studies have demonstrated that IL-17 plays an important role in initial immune response and is involved in both immune-mediated protection and pathology following infection with Mycobacterium tuberculosis (MTB). However, the alterations and regulation of plasma IL-17 level during TB treatment remain unclear. Moreover, the cell type responsible for the production of IL-17 in TB patients requires further study.MethodsA total of 20 acid-fast bacilli smear-positive (AFB-positive) pulmonary TB patients and 20 age- and gender-matched healthy volunteers were included in our study. Blood samples were collected in heparinized tubes at the time of diagnosis (AFB-positive group) and 3 weeks after the initiation of therapy, when the sputum smear conversion (AFB-negative group) occurred, followed by symptomatic improvement. IL-17 levels and IL-17-producing cells in PBMCs were detected. Lymphocyte populations in the peripheral blood between the AFB-positive and AFB-negative groups were compared by flow-cytometry. A549 cells, a cell line of alveolar epithelial cells, were applied to determine the extent of the pathological damage mediated by IL-17 following MTB infection. Recombinant human IL-10 was used to investigate the regulation of IL-17 expression after sputum smear conversion in AFB-positive pulmonary TB patients.ResultsPlasma IL-17 level were elevated in patients with sputum AFB-positive pulmonary TB, but substantially decreased after TB treatment and smear conversion. Our data indicate that NKT-like cells might be the main source of IL-17, in addition to conventional T cells in AFB-positive pulmonary TB patients. The secretion of IL-17 may be suppressed by regulatory T (Treg) cells and IL-10 during TB treatment. Moreover, the IL-17 levels were positively correlated to both the C-reactive protein and erythrocyte sedimentation rate. Therefore, IL-17 was capable of alveolar epithelial cell damage following MTB infection.ConclusionThe increase in the frequency of Treg cells and IL-10 levels was associated with a decrease in IL-17 in patients receiving TB treatment. Thus, IL-10 and Tregs may function to inhibit immune-mediated pathology in TB patients.

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Impaired M. tuberculosis Antigen-Specific IFN-γ Response without IL-17 Enhancement in Patients with Severe Cavitary Pulmonary Tuberculosis

Cited by 17 publications

References 34 publications

Severe Tuberculosis in Humans Correlates Best with Neutrophil Abundance and Lymphocyte Deficiency and Does Not Correlate with Antigen-Specific CD4 T-Cell Response

Severe Tuberculosis in Humans Correlates Best with Neutrophil Abundance and Lymphocyte Deficiency and Does Not Correlate with Antigen-Specific CD4 T-Cell Response

Impairment of Wnt/β-catenin signaling in blood cells of patients with severe cavitary pulmonary tuberculosis

Decreased IL-17 during treatment of sputum smear-positive pulmonary tuberculosis due to increased regulatory T cells and IL-10

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