Decreased expression of perforin in CD8+ T lymphocytes in patients with Mycobacterium tuberculosis infection and its potential value as a marker for efficacy of treatment

Huang, Jiang; Gong, Huili; Zhang, Qing; Gu, Jin; Li, Liang; Zhang, Jun

doi:10.21037/jtd.2017.05.74

Cited by 14 publications

(12 citation statements)

References 25 publications

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“…Similarly, lower expression of other immune subset genes (such as NK marker NCAM1) in blood in TB patients may also relate to migration of lymphocytes or natural killer cells from the peripheral blood to the site of infection [32]. Furthermore, GNLY and PRF1 expression levels were also significantly lower in TB patients compared to TST+ and TST- individuals, which is consistent with published data [33,34] and might be explained by rapid consumption of both perforin and granulysin during active disease due to an ongoing effector immune response, or due to migration of the T cell subset responsible for its production [35].…”

Section: Discussionsupporting

confidence: 88%

Gene expression profiles classifying clinical stages of tuberculosis and monitoring treatment responses in Ethiopian HIV-negative and HIV-positive cohorts

et al. 2019

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BackgroundValidation of previously identified candidate biomarkers and identification of additional candidate gene expression profiles to facilitate diagnosis of tuberculosis (TB) disease and monitoring treatment responses in the Ethiopian context is vital for improving TB control in the future.MethodsExpression levels of 105 immune-related genes were determined in the blood of 80 HIV-negative study participants composed of 40 active TB cases, 20 latent TB infected individuals with positive tuberculin skin test (TST+), and 20 healthy controls with no Mycobacterium tuberculosis (Mtb) infection (TST-), using focused gene expression profiling by dual-color Reverse-Transcription Multiplex Ligation-dependent Probe Amplification assay. Gene expression levels were also measured six months after anti-TB treatment (ATT) and follow-up in 38 TB patients.ResultsThe expression of 15 host genes in TB patients could accurately discriminate between TB cases versus both TST+ and TST- controls at baseline and thus holds promise as biomarker signature to classify active TB disease versus latent TB infection in an Ethiopian setting. Interestingly, the expression levels of most genes that markedly discriminated between TB cases versus TST+ or TST- controls did not normalize following completion of ATT therapy at 6 months (except for PTPRCv1, FCGR1A, GZMB, CASP8 and GNLY) but had only fully normalized at the 18 months follow-up time point. Of note, network analysis comparing TB-associated host genes identified in the current HIV-negative TB cohort to TB-associated genes identified in our previously published Ethiopian HIV-positive TB cohort, revealed an over-representation of pattern recognition receptors including TLR2 and TLR4 in the HIV-positive cohort which was not seen in the HIV-negative cohort. Moreover, using ROC cutoff ≥ 0.80, FCGR1A was the only marker with classifying potential between TB infection and TB disease regardless of HIV status.ConclusionsOur data indicate that complex gene expression signatures are required to measure blood transcriptomic responses during and after successful ATT to fully diagnose TB disease and characterise drug-induced relapse-free cure, combining genes which resolve completely during the 6-months treatment phase of therapy with genes that only fully return to normal levels during the post-treatment resolution phase.

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Section: Discussionsupporting

confidence: 88%

Gene expression profiles classifying clinical stages of tuberculosis and monitoring treatment responses in Ethiopian HIV-negative and HIV-positive cohorts

et al. 2019

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“…Cytotoxic molecules, notably granzyme B secreted by cytolytic T cells, contribute in a major way to protection against TB . In order to study the granzyme B as a potential biomarker for TB, we measured by ELISA the granzyme B levels in the supernatants of PBMCs from the LTBI individuals versus aTB patients in response to PPD, ESAT‐6 and Rv0140.…”

Section: Resultsmentioning

confidence: 99%

“…The expression of IFN‐γ, granzyme B, and perforin in CD8+ T lymphocytes during the different disease phases of Mtb infection has been evaluated before and after stimulation with ESAT‐6 and CFP‐10. Positive down‐regulation of perforin and granzyme B after stimulation with ESAT‐6 and CFP‐10 peptides in aTB was seen using ICS . Moreover, it has been shown that protection from reactivation in nonhuman primate model was mainly correlated with enhanced CD8+ T cell‐function and high granzyme B secretion .…”

Section: Discussionmentioning

confidence: 96%

Granzyme B induced by Rv0140 antigen discriminates latently infected from active tuberculosis individuals

Ouni

Gharsalli

Dirix

et al. 2018

Journal of Leukocyte Biology

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Nearly two billion people are latently infected with Mtb (LTBI). Detection of LTBI with high risk to develop active tuberculosis (aTB) is considered the cornerstone to control the disease. The current challenge is to identify markers that better classify LTBI versus aTB. It has been previously shown that Rv0140, a reactivation-associated antigen of Mtb, induces significantly higher IFN-γ production in LTBI individuals as compared to aTB patients. Herein, we show that Rv0140 induces high granzyme B level by PBMCs derived from LTBI (n = 34) as compared to aTB (n = 18). Receiving operator characteristic (ROC) curves were used to evaluate the capacity of Rv0140 to discriminate between LTBI and aTB by measuring IFN-γ and granzyme B secretion. Our results show that, in response to Rv0140, granzyme B seems to allow better discrimination of LTBI from aTB with areas under the curve (AUC) of 0.88 (95% CI 0.79-0.98) as compared to IFN-γ with AUC of 0.85 (95% CI 0.74-0.96) even though CI overlap. Intracellular staining (ICS) experiments and the use of anti-MHC I antibody showed that granzyme B is mainly produced by CD8+ T cells in response to Rv0140. Thus, we propose granzyme B as a host marker to help identify LTBI individuals.

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“…Our results support the recent findings on the higher IFN-γ production by stimulated PBMCs with PPD in patients with infiltrative TB compared to other clinical features of TB and healthy controls [24]. Moreover, the increased IFN-γ production from PBMCs of pulmonary TB patients upon stimulation with either early secretory antigenic target of 6 kDa (ESAT6) or culture filtrated protein 10 (CFP10), and the high expression of IFN-γ by CD4+ T cells and CD8+ T cells have been recently demonstrated [39].…”

Section: Discussionmentioning

confidence: 96%

Coordinated In Vitro Release of Granulysin, Perforin and IFN-γ in TB and HIV/TB Co-Infection Associated with Clinical Outcomes before and after Anti-TB Treatment

et al. 2020

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Granule-associated killing molecules released from cytotoxic T lymphocytes participate as a crucial step in immunity against tuberculosis (TB), but the role of coordinated production remains controversial. Coordinated release of effector molecules in vitro after stimulating peripheral blood mononuclear cells (PBMCs) of active TB or HIV/TB coinfection patients with PPD, purified protein derivative of tuberculin and avirulent Mtb, H37Ra, an attenuated strain were investigated in association with clinical outcomes. Perforin, granzyme-B, granulysin and IFN-γ were measured using ELISA. Before anti-TB treatment, PBMCs of TB stimulated with PPD or H37Ra released higher perforin, granzyme-B, and granulysin levels than in HIV/TB and released significantly higher IFN-γ (p = 0.045, p = 0.022). Granulysin positively correlated with perforin in TB (p = 0.042, r = 0.385), HIV/TB coinfection (p = 0.003, r = 0.941) after PPD stimulation, and after H37Ra stimulation in TB (p = 0.005, r = 0.549), but negatively correlated with granzyme B in TB (p = 0.042, r = −0.386), HIV/TB coinfection (p = 0.042, r = 0.754) were noted. After anti-TB treatment, increased levels of perforin, granulysin and IFN-γ in TB or HIV/TB upon PPD or H37Ra stimulation, and decreased granzyme-B levels after PPD (p = 0.003) or H37Ra (p = 0.028) stimulation in TB were observed. These results suggest that granulysin may act synergistic with perforin and IFN-γ in TB, indicating its crucial function in host immunity to tuberculosis. Future studies with larger numbers of patients ought to be conducted in the future.

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Decreased expression of perforin in CD8+ T lymphocytes in patients with Mycobacterium tuberculosis infection and its potential value as a marker for efficacy of treatment

Cited by 14 publications

References 25 publications

Gene expression profiles classifying clinical stages of tuberculosis and monitoring treatment responses in Ethiopian HIV-negative and HIV-positive cohorts

Gene expression profiles classifying clinical stages of tuberculosis and monitoring treatment responses in Ethiopian HIV-negative and HIV-positive cohorts

Granzyme B induced by Rv0140 antigen discriminates latently infected from active tuberculosis individuals

Coordinated In Vitro Release of Granulysin, Perforin and IFN-γ in TB and HIV/TB Co-Infection Associated with Clinical Outcomes before and after Anti-TB Treatment

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