Journal
JOURNAL OF IMMUNOLOGY
Volume 196, Issue 10, Pages 4052-4063Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1502203
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Funding
- 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
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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.
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