Augmentation of Apoptosis and Interferon‐γ Production at Sites of Active<i>Mycobacterium tuberculosis</i>Infection in Human Tuberculosis

Hirsch, Christina S.; Toossi, Zahra; Johnson, John L.; Luzze, Henry; Ntambi, L.; Peters, Pierre; McHugh, Michael J.; Okwera, Alphonse; Joloba, Moses; Mugyenyi, Peter; Mugerwa, Roy D.; Terebuh, Pauline; Ellner, Jerrold J.

doi:10.1086/318817

Cited by 96 publications

(87 citation statements)

References 38 publications

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“…Successful chemotherapy resulted in 50% reduction in apoptosis, coinciding with 3-to 8-fold increases in levels of mycobacteria-stimulated IL-2 and IFN-␥, respectively. In another study based on examination of pleural fluid from patients with pleural tuberculosis, the loss of IFN-␥-producing cells is limited specifically to M. tuberculosis-responsive cells (35). These studies provide evidence that T cell apoptosis is biologically significant in the disease process.…”

Section: Discussionmentioning

confidence: 88%

IL-4 Influences Apoptosis of Mycobacterium-Reactive Lymphocytes in the Presence of TNF-α

Seah

Rook

2001

The Journal of Immunology

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T cell apoptosis is associated with defective cell-mediated effector functions in several infectious diseases. In tuberculosis, there is evidence that T cell apoptosis may be cytokine mediated, but the mechanisms are not clearly understood. Type 2 cytokines have recently been associated with disease extent in human tuberculosis, but they have not previously been linked to apoptosis in mycobacterium-reactive T cells. This study presents evidence that PBLs from healthy donors respond to sonicated Mycobacterium tuberculosis Ags with increased IL-4 gene activation, CD30 expression, and apoptosis. The changes were significantly greater than those observed when cells were stimulated with Ags from nonpathogenic Mycobacterium vaccae. A hypothesis linking these observations was tested. CD30 expression and TNF-α-mediated lymphocyte apoptosis were both down-regulated by inhibiting IL-4 in this model. TNFR-associated factor 2 (TRAF2) expression was down-regulated in CD30+ cells, and addition of anti-TNF-α Ab significantly reduced apoptosis in the CD30+ but not the CD30− population. These observations support the hypothesis that increased IL-4 expression in M. tuberculosis-activated lymphocytes promotes CD30 expression, which sensitizes the lymphocytes to TNF-α-mediated apoptosis via TRAF2 depletion. This may be one mechanism by which IL-4 is associated with immunopathological consequences in human tuberculosis.

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Section: Discussionmentioning

confidence: 88%

IL-4 Influences Apoptosis of Mycobacterium-Reactive Lymphocytes in the Presence of TNF-α

Seah

Rook

2001

The Journal of Immunology

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“…Indeed, IFN-γ was shown to induce apoptosis of monocytic cells in vitro (55,56), and high levels of this cytokine were also associated with a high level of apoptosis and tissue immunopathology in vivo during intracellular infection (57). Caseous necrosis in human tuberculosis was also recently found to be associated with enhanced IFN-γ and apoptosis (58,59). It is important to point out that the nature and regulation of immune responses in human TB could be more complicated than what we have learned from our current model system.…”

Section: Figurementioning

confidence: 98%

TNF-α is a critical negative regulator of type 1 immune activation during intracellular bacterial infection

Zganiacz

Santosuosso²,

Wang³

et al. 2004

J. Clin. Invest.

170

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TNF-α has long been regarded as a proimmune cytokine involved in antimicrobial type 1 immunity. However, the precise role of TNF-α in antimicrobial type 1 immunity remains poorly understood. We found that TNF-α-deficient (TNF -/-) mice quickly succumbed to respiratory failure following lung infection with replication-competent mycobacteria, because of apoptosis and necrosis of granuloma and lung structure. Tissue destruction was a result of an uncontrolled type 1 immune syndrome characterized by expansion of activated CD4 and CD8 T cells, increased frequency of antigen-specific T cells, and overproduction of IFN-γ and IL-12. Depletion of CD4 and CD8 T cells decreased IFN-γ levels, prevented granuloma and tissue necrosis, and prolonged the survival of TNF -/-hosts. Early reconstitution of TNF-α by gene transfer reduced the frequency of antigen-specific T cells and improved survival. TNF-α controlled type 1 immune activation at least in part by suppressing T cell proliferation, and this suppression involved both TNF receptor p55 and TNF receptor p75. Heightened type 1 immune activation also occurred in TNF -/-mice treated with dead mycobacteria, live replication-deficient mycobacteria, or mycobacterial cell wall components. Our study thus identifies TNF-α as a type 1 immunoregulatory cytokine whose primary role, different from those of other type 1 cytokines, is to keep an otherwise detrimental type 1 immune response in check.

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“…After centrifugation, bronchial washing cells were resuspended in FACS buffer (PBS 1Â, pH 7.2, 1% BSA), and counted. Cell surface labeling was performed prior to apoptosis detection, incubating 10 …”

Section: In Situ Detection Of Apoptotic Cells By Colorimetric Tunelmentioning

confidence: 99%

“…Most of these cells are eliminated by apoptosis to restore the T cell compartment to homeostasis [1]. Several experimental observations have suggested that apoptosis of mycobacteriaresponsive T cells, particularly Th1 lymphocytes, decreases production of interferon-gamma (IFN-c), and so reduces the protective immune response in progressive tuberculosis [9][10][11]. Indeed, Th1 cells, which are essential for the control of the infection, are more susceptible than Th0 or Th2 cells to Fasmediated apoptosis [12].…”

Section: Introductionmentioning

confidence: 99%

Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: their relationship to mycobacterial virulence

et al. 2006

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The kinetics of macrophage and T lymphocyte apoptosis were determined in a wellcharacterized mouse model of pulmonary tuberculosis, comparing strains of intermediate (H37Rv) and high virulence (Beijing strain, code 9501000). Both strains induced a high percentage of apoptotic activated macrophages at days 1 and 3 post infection, although this was twofold lower in Beijing-infected mice. Progressive pneumonia started at day 14 (Beijing) or 21 (H37Rv) post infection. Pneumonic areas contained numerous macrophages with vacuolated cytoplasm (VM). In H37Rv infection few VM were apoptotic (8.7% at day 60), and the percentage was even lower in Beijing infection (1.4% at day 28). A high percentage of VM expressed the anti-apoptotic molecule Bcl-2 (H37Rv, 83%; Beijing, 95%). Both strains induced a progressive increase of apoptotic Th1 lymphocytes, peaking at day 60 in H37Rv infection, or 28 in Beijing infection. The peak was twofold higher in the latter. VM had strong FasL immunostaining, and confocal microscopy showed numerous apoptotic Th1 cells closely associated with them, suggesting that VM might induce apoptosis of Th1 cells. These results support the hypothesis that apoptosis of macrophages is associated with protection, while apoptosis of Th1 cells favors disease progression, and is related to the virulence of the mycobacterial strain.

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Augmentation of Apoptosis and Interferon‐γ Production at Sites of ActiveMycobacterium tuberculosisInfection in Human Tuberculosis

Cited by 96 publications

References 38 publications

IL-4 Influences Apoptosis of Mycobacterium-Reactive Lymphocytes in the Presence of TNF-α

IL-4 Influences Apoptosis of Mycobacterium-Reactive Lymphocytes in the Presence of TNF-α

TNF-α is a critical negative regulator of type 1 immune activation during intracellular bacterial infection

Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: their relationship to mycobacterial virulence

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