ORCID Profile
0000-0001-5313-385X
Current Organisations
Saint James's Hospital
,
Trinity College Dublin Faculty of Health Sciences
,
Trinity College Dublin
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Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.IMMUNI.2007.07.022
Abstract: Autophagy is a recently recognized immune effector mechanism against intracellular pathogens. The role of autophagy in innate immunity has been well established, but the extent of its regulation by the adaptive immune response is less well understood. The T helper 1 (Th1) cell cytokine IFN-gamma induces autophagy in macrophages to eliminate Mycobacterium tuberculosis. Here, we report that Th2 cytokines affect autophagy in macrophages and their ability to control intracellular M. tuberculosis. IL-4 and IL-13 abrogated autophagy and autophagy-mediated killing of intracellular mycobacteria in murine and human macrophages. Inhibition of starvation-induced autophagy by IL-4 and IL-13 was dependent on Akt signaling, whereas the inhibition of IFN-gamma-induced autophagy was Akt independent and signal transducer and activator of transcription 6 (STAT6) dependent. These findings establish a mechanism through which Th1-Th2 polarization differentially affects the immune control of intracellular pathogens.
Publisher: Elsevier BV
Date: 03-2009
Publisher: Oxford University Press (OUP)
Date: 15-12-2008
DOI: 10.1086/593174
Abstract: Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine that mediates inflammation in response to various pathogens, including Mycobacterium tuberculosis, but is also a key factor in the pathogenesis of rheumatoid arthritis and other autoimmune diseases. Three TNF-alpha-suppressing drugs have been approved to treat selected autoimmune diseases 2 are monoclonal antibodies against TNF-alpha (adalimumab and infliximab), and the other is a soluble TNF receptor/Fc fusion protein (etanercept). TNF blockers have been shown to increase the risk of reactivation of latent tuberculosis, and this risk is higher in patients treated with the monoclonal antibodies. We studied the effects of TNF-alpha blockers on the maturation of mycobacteria-containing phagosomes in human macrophages. All 3 drugs had an inhibitory effect on IFN-gamma-induced phagosome maturation in phorbolmyristate acetate-differentiated human THP-1 cells. Adalimumab and infliximab, but not etanercept, suppressed phagosome maturation in primary human peripheral blood monocyte-derived macrophages in the presence or absence of IFN-gamma. Treatment of macrophages with TNF-alpha led to increased maturation of phagosomes containing Mycobacterium bovis bacillus Calmette-Guérin or M. tuberculosis H37Rv. These results suggest a role for TNF-alpha in activating phagosome maturation and highlight a mechanism through which TNF-alpha blockade can affect the host response to mycobacteria.
Publisher: Elsevier BV
Date: 10-2007
Publisher: Public Library of Science (PLoS)
Date: 17-11-2011
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.HUMIMM.2016.06.018
Abstract: NKG2D is an important activating receptor expressed on NK cells. Ligands (termed NKG2DL) for this receptor include ULBP1-6, MICA and MICB in humans they are upregulated in stressed, cancerous or infected cells where they engage NKG2D to induce NK cell cytotoxicity and cytokine production. Expression of NKG2DL on effector cells has been described in mice and more recently in human cells. We confirm that NK cell lines and IL-2 stimulated primary human NK cells also express the NKG2DL, ULBP2. However, expression of ULBP2 was not a result of transfer from a non-NK cell to an NK cell and in contrast to recent reports we saw no evidence that ULBP2 expression targeted these NK cells for fratricide or for cytotoxicity by NKG2D-expressing, non-NK effector cells. ULBP2 expression was however linked to expression of mature CD57(+) NK cells. In particular, expression of ULBP2 was strongest on those NK cells that had evidence of recent activation and proliferation. We suggest that ULBP2 could be used to identify recently activated "mature" NK cells. Defining this phenotype would be useful for understanding the ontogeny on human NK cells.
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.VACCINE.2008.07.059
Abstract: Bovine tuberculosis (bTB) is increasing in incidence in the UK. Effective control strategies could involve vaccination BCG, either alone or in prime-boost strategies, remains the most effective vaccine against bovine tuberculosis. However, BCG vaccination of cattle would require development of diagnostic tests able to accurately discriminate Mycobacterium bovis-infected from BCG-vaccinated animals. Herein, we demonstrate that the detection of secreted IFN-gamma following short term culture (4h) of whole blood with purified protein derived from M. bovis (PPD-B) allows such discrimination. This reflects, in part, the differential kinetics of IFN-gamma secretion in infected compared to vaccinated cattle. This is the first study to demonstrate that accurate, rapid distinction of BCG-vaccinated from M. bovis-infected cattle can be achieved in a short time period without the need for production of M. bovis-specific antigens, complex antigen mixtures or extensive laboratory procedures. We were also able to detect PPD-specific IFN-gamma release during short term culture of blood from a number of humans with active TB indicating that this test may have wider application and is potentially useful for the rapid diagnosis of disease in humans.
Publisher: Oxford University Press (OUP)
Date: 25-03-2011
DOI: 10.1111/J.1365-2249.2011.04381.X
Abstract: A growing body of evidence points to autophagy as an essential component in the immune response to tuberculosis. Autophagy is a direct mechanism of killing intracellular Mycobacterium tuberculosis and also acts as a modulator of proinflammatory cytokine secretion. In addition, autophagy plays a key role in antigen processing and presentation. Autophagy is modulated by cytokines it is stimulated by T helper type 1 (Th1) cytokines such as tumour necrosis factor (TNF)-α and interferon (IFN)-γ, and is inhibited by the Th2 cytokines interleukin (IL)-4 and IL-13 and the anti-inflammatory cytokine IL-10. Vitamin D, via cathelicidin, can also induce autophagy, as can Toll-like receptor (TLR)-mediated signals. Autophagy-promoting agents, administered either locally to the lungs or systemically, could have a clinical application as adjunctive treatment of drug-resistant and drug-sensitive tuberculosis. Moreover, vaccines which effectively induce autophagy could be more successful in preventing acquisition or reactivation of latent tuberculosis.
Publisher: American Thoracic Society
Date: 11-2018
Publisher: Massachusetts Medical Society
Date: 21-02-2002
Publisher: Oxford University Press (OUP)
Date: 18-05-2010
DOI: 10.1111/J.1365-2249.2010.04146.X
Abstract: Tumour necrosis factor (TNF) is a potent inflammatory cytokine that plays an important role in immunity to numerous bacterial infections, including Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans. Infliximab, adalimumab, certolizumab pegol and etanercept are anti-TNF agents used to treat a range of inflammatory/autoimmune diseases, such as rheumatoid arthritis. The use of some of these drugs has been linked to reactivation TB. In addition to blocking TNF-mediated immune responses, some anti-TNF drugs have been found to interfere with innate immune responses, such as phagolysosomal maturation and monocyte apoptosis, as well as cell-mediated responses, including interferon-γ secretion by memory T cells, complement-mediated lysis of Mtb-reactive CD8+ T cells and increased regulatory T cell activity. This review summarizes some of the reported effects of TNF blockers on immune cell responses in the context of the observed clinical data on TB reactivation in patients on anti-TNF therapy.
Location: Ireland
Location: United States of America
No related grants have been discovered for Joseph Keane.