Different immunosuppressive mechanisms in multi-drug-resistant tuberculosis and non-tuberculous mycobacteria patients

Pinheiro, Roberta Olmo; Oliveira, E. B. de; Santos, Gac; Silva, G. M. Sperandio da; Silva, B. J. de Andrade; Teles, Rosane M. B.; Milagres, Alexandre S.; Sarno, Euzenir Nunes; Dalcolmo, Margareth Pretti; Sampaio, E. P.

doi:10.1111/cei.12007

Cited by 27 publications

(17 citation statements)

References 44 publications

(49 reference statements)

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“…Induction of IL-10 expression in effector T-cells is wellestablished in chronic viral infections 17,54 and has also been described in tuberculosis. [55][56][57][58] In general, IL-10 co-expression in effector T-cells is hypothesized to play a role in downregulating immune responses after pathogen eradication to minimize harmful side effects of immune responses. 59,60 Interestingly, the induction of IL-10 in effector T-cells is dependent on IL-6 (or IL-27)-mediated STAT3 activation.…”

Section: Discussionmentioning

confidence: 99%

Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients

et al. 2018

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T-cells critically contribute to protection against Mycobacterium tuberculosis infection, and impaired T-cell responses can lead to disease progression. Pro-inflammatory and immunosuppressive cytokines affect T-cells, and fine-tuned regulation of cytokine signaling via the Jak/STAT signaling pathways is crucial for appropriate T-cell function. Constitutive STAT3 phosphorylation as a consequence of aberrant cytokine signaling has been described to occur in pathognomonic T-cell responses in inflammatory and autoimmune diseases. We characterized blood samples from tuberculosis patients (n=28) and healthy contacts (n=28) from Ghana for M. tuberculosis-specific T-cell responses, constitutive cytokine production, and SOCS3 and pSTAT3 expression. Lentiviral modulation of primary CD4 T-cells was performed to determine the effects of SOCS3 on T-cell functions. T-cells from tuberculosis patients expressed higher levels of IL-10 and IL-6 and lower levels of T helper type (T)17 cytokines after M. tuberculosis-specific stimulation compared to healthy contacts. In addition, tuberculosis patients had higher IL-10 and IL-6 levels in the supernatants of non-stimulated immune cells and plasma samples compared to healthy contacts. Notably, aberrant cytokine expression was accompanied by high constitutive pSTAT3 levels and SOCS3 expression in T-cells. Multivariate analysis identified an IL-6/IL-10 co-expression-based principal component in tuberculosis patients that correlated with high pSTAT3 levels. SOCS3 contributed to a regulatory component, and tuberculosis patients with high SOCS3 expression showed decreased T1 cytokine expression and impaired IL-2-induced STAT5 phosphorylation. SOCS3 over-expression in primary CD4 T-cells confirmed the SOCS3 inhibitory function on IL-2-induced STAT5 phosphorylation. We conclude that constitutive pSTAT3 and high SOCS3 expression are influential factors that indicate impaired T-cell functions in tuberculosis patients.Cellular and Molecular Immunology advance online publication, 19 March 2018; doi:10.1038/cmi.2018.5.

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Section: Discussionmentioning

confidence: 99%

Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients

et al. 2018

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“…The World Health Organization (WHO) estimates that tuberculosis (TB) has become one of the deadliest global emergencies due to the widespread existence of multiple drug resistant strains of Mycobacterium tuberculosis (MTB), frequently caused by limited health care system resources combined with the increasing numbers of HIV/AIDS [1]. In addition, a number of anti-TB drugs may be discontinued in a few years due to the expanding number of multidrug resistant TB (MDR-TB) and extensively drug-resistant (XDR-TB) cases [2].…”

Section: Introductionmentioning

confidence: 99%

Manganese(II) complexes with thiosemicarbazones as potential anti-Mycobacterium tuberculosis agents

Oliveira

Maia

Souza

et al. 2014

Journal of Inorganic Biochemistry

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“…Экспрессия внутриклеточного транскрипционного фактора Foxp3 приводит к индукции генов дифференцировки Тreg и секретируемых ими ингибиторных цитокинов (IL-10 и TGFβ), которые подавляют функциональную активность ýффекторных Т-клеток [10][11][12]. По мнению ряда исследователей, избыточная активация Treg опосредует снижение интенсивности ýффекторных иммунных реакций в борьбе макроорганизма с MBT [2].…”

Section: результаты и обсуждениеunclassified

“…Инфицирование Mycobacterium tuberculosis (MBT) приводит к мобилизации различных популяций миелоидных и лимфоидных клеток иммунной системы, способных посредством межклеточных контактов и секреции иммунорегуляторных биомолекул оказывать влияние на все звенья и ýтапы иммунного ответа, определяя направление его развития, активацию и супрессию. При ýтом факторы врожденного и адаптивного иммунитета при осуществлении иммунологического надзора над антигенами различного происхождения функционируют не изолированно друг от друга, а обладают взаимонаправленной позитивной и негативной регуляцией [1][2][3].…”

Section: Introductionunclassified

Features of immunoregulation in patients with pulmonary tuberculosis with blood eosinophilia

et al. 2018

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The aim of the investigation was to determine the characteristics of the immune response regulation for pulmonary tuberculosis (TB) and to analyze the role of regulatory T cells in the immunopathogenesis of TB with eosinophilia in the blood, depending on the clinical form of the disease and sensitivity of Micobacterium tuberculosis to anti-TB drugs.Materials and methods. 157 patients who were initially diagnosed with infiltrative and disseminated TB were examined. The material of the study was venous blood and culture of mononuclear leukocytes isolated from venous blood. The content of interleukin (IL) 4, IL-10 and transforming factor beta (TGFβ) in culture suspensions of mononuclear leukocytes in vitro and IL-5 in the blood was determined by enzyme-linked immunosorbent assay (ELISA) test. The expression of surface molecules CD4, CD20, CD25 and intracellular transcription factor Foxp3 by lymphocytes of the blood was evaluated by flow cytometry. The obtained results were analyzed by statistical methods.Results. It is shown that excessive generation of regulatory T cells in patients with TB is associated with eosinophilia of the blood and imbalance of immune response regulation mechanisms. In TB with eosinophilia, an increase in the number of Foxp3-positive regulatory T cells in the blood is combined with in vitro hypersecretion of anti-inflammatory cytokines TGFβ, IL-10, IL-4 and an increase in the content of CD20+ B lymphocytes and IL-5 in the blood. These changes are most pronounced in the disseminated form of TB in combination with drug resistance.Conclusion. Characteristics of immunoregulation at TB with blood eosinophilia are associated with activation of immunosuppression mechanisms and polarization of immune response towards Th2-dependent pathway.

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Different immunosuppressive mechanisms in multi-drug-resistant tuberculosis and non-tuberculous mycobacteria patients

Abstract: Summary Previous studies have demonstrated that cells from both multi-drugresistant tuberculosis (MDR-TB

Cited by 27 publications

References 44 publications

Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients

Constitutive STAT3 phosphorylation and IL-6/IL-10 co-expression are associated with impaired T-cell function in tuberculosis patients

Manganese(II) complexes with thiosemicarbazones as potential anti-Mycobacterium tuberculosis agents

Features of immunoregulation in patients with pulmonary tuberculosis with blood eosinophilia

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