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Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome
University of Malaya, Malaysia.
University of Malaya, Malaysia.
University of Malaya, Malaysia; University of Malaya, Malaysia.
Macfarlane Burnet Institute Medical Research and Public Heatlh, Australia.
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2016 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, no 10, 4052-4063 p.Article in journal (Refereed) PublishedText
Abstract [en]

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64(+) monocytes were a marker of increased casp1 expression. Furthermore, IL-1 beta, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18R alpha on CD4(+) T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell-dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.

Place, publisher, year, edition, pages
AMER ASSOC IMMUNOLOGISTS , 2016. Vol. 196, no 10, 4052-4063 p.
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-128934DOI: 10.4049/jimmunol.1502203ISI: 000375831200008PubMedID: 27076678OAI: diva2:934967

Funding Agencies|University of Malaya; Ministry of Higher Education High Impact Research Grant [UM.C/625/1/HIR/MOHE/MED/01]; University of Malaya Research Grants of the Health and Translational Medicine Research Cluster [RP021A-13HTM, RG448-12HTM]; Research Officer Grant Scheme [BR003-2014]; Australian National Health and Medical Research Council; Swedish Research Council [AI52731]; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER from VINNOVA; Linkoping University Hospital research fund; Governmental Funding of Clinical Research within National Health Service; Swedish Society of Medicine; Victorian Operational Infrastructure Support Program

Available from: 2016-06-09 Created: 2016-06-07 Last updated: 2016-06-09

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Ellegård, RadaLarsson, Marie
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