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HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling.

Lai RP, Meintjes G, Wilkinson KA, Graham CM, Marais S, Van der Plas H, Deffur A, Schutz C, Bloom C, Munagala I, Anguiano E, Goliath R, Maartens G, Banchereau J, Chaussabel D, O'Garra A, Wilkinson RJ - Nat Commun (2015)

Bottom Line: Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB.Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients.These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

View Article: PubMed Central - PubMed

Affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.

ABSTRACT
Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

No MeSH data available.


Related in: MedlinePlus

Inhibition of the MyD88 adaptor results in reduced cytokine productions.PBMC from TB-IRIS patients (week 2) were treated with MyD88 inhibitor (MYD88-Inh), control peptide or RPMI medium (mock), followed by stimulation with heat-inactivated H37Rv and the supernatant cytokine concentration was determined. An unstimulated background control was included for each treatment per sample. Data are shown as background subtracted (stimulated minus unstimulated) with a value of zero assigned to those negative after background subtraction. The Wilcoxon signed rank test was used for statistical comparisons. The median value of each group was shown and P-value was designated: *P≤0.05, **P≤0.01 and ***P≤0.001.
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f6: Inhibition of the MyD88 adaptor results in reduced cytokine productions.PBMC from TB-IRIS patients (week 2) were treated with MyD88 inhibitor (MYD88-Inh), control peptide or RPMI medium (mock), followed by stimulation with heat-inactivated H37Rv and the supernatant cytokine concentration was determined. An unstimulated background control was included for each treatment per sample. Data are shown as background subtracted (stimulated minus unstimulated) with a value of zero assigned to those negative after background subtraction. The Wilcoxon signed rank test was used for statistical comparisons. The median value of each group was shown and P-value was designated: *P≤0.05, **P≤0.01 and ***P≤0.001.

Mentions: Among the analytes measured, concentrations of IL-12p40, IFN-γ and TNF-α in PBMC culture supernatant from TB-IRIS patients significantly decreased following treatment with MyD88 inhibitor, but not with the control peptide, compared with the RPMI mock (Fig. 6). The same experiments were also performed in the PBMCs from non-IRIS patients, but analytes were below the limits of detection. Similar observations have also been previously reported in the PBMCs from non-IRIS patients28. Although IL-1 was predicted to be activated downstream of the TLR-MyD88 signalling cascade, we failed to detect any difference in the level of IL-1β following MyD88 inhibition (Fig. 6), suggesting other immunological pathways are also involved in mediating the inflammatory response in TB-IRIS.


HIV-tuberculosis-associated immune reconstitution inflammatory syndrome is characterized by Toll-like receptor and inflammasome signalling.

Lai RP, Meintjes G, Wilkinson KA, Graham CM, Marais S, Van der Plas H, Deffur A, Schutz C, Bloom C, Munagala I, Anguiano E, Goliath R, Maartens G, Banchereau J, Chaussabel D, O'Garra A, Wilkinson RJ - Nat Commun (2015)

Inhibition of the MyD88 adaptor results in reduced cytokine productions.PBMC from TB-IRIS patients (week 2) were treated with MyD88 inhibitor (MYD88-Inh), control peptide or RPMI medium (mock), followed by stimulation with heat-inactivated H37Rv and the supernatant cytokine concentration was determined. An unstimulated background control was included for each treatment per sample. Data are shown as background subtracted (stimulated minus unstimulated) with a value of zero assigned to those negative after background subtraction. The Wilcoxon signed rank test was used for statistical comparisons. The median value of each group was shown and P-value was designated: *P≤0.05, **P≤0.01 and ***P≤0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4595995&req=5

f6: Inhibition of the MyD88 adaptor results in reduced cytokine productions.PBMC from TB-IRIS patients (week 2) were treated with MyD88 inhibitor (MYD88-Inh), control peptide or RPMI medium (mock), followed by stimulation with heat-inactivated H37Rv and the supernatant cytokine concentration was determined. An unstimulated background control was included for each treatment per sample. Data are shown as background subtracted (stimulated minus unstimulated) with a value of zero assigned to those negative after background subtraction. The Wilcoxon signed rank test was used for statistical comparisons. The median value of each group was shown and P-value was designated: *P≤0.05, **P≤0.01 and ***P≤0.001.
Mentions: Among the analytes measured, concentrations of IL-12p40, IFN-γ and TNF-α in PBMC culture supernatant from TB-IRIS patients significantly decreased following treatment with MyD88 inhibitor, but not with the control peptide, compared with the RPMI mock (Fig. 6). The same experiments were also performed in the PBMCs from non-IRIS patients, but analytes were below the limits of detection. Similar observations have also been previously reported in the PBMCs from non-IRIS patients28. Although IL-1 was predicted to be activated downstream of the TLR-MyD88 signalling cascade, we failed to detect any difference in the level of IL-1β following MyD88 inhibition (Fig. 6), suggesting other immunological pathways are also involved in mediating the inflammatory response in TB-IRIS.

Bottom Line: Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB.Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients.These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

View Article: PubMed Central - PubMed

Affiliation: The Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, UK.

ABSTRACT
Patients with HIV-associated tuberculosis (TB) initiating antiretroviral therapy (ART) may develop immune reconstitution inflammatory syndrome (TB-IRIS). No biomarkers for TB-IRIS have been identified and the underlying mechanisms are unclear. Here we perform transcriptomic profiling of the blood samples of patients with HIV-associated TB. We identify differentially abundant transcripts as early as week 0.5 post ART initiation that predict downstream activation of proinflammatory cytokines in patients who progress to TB-IRIS. At the characteristic time of TB-IRIS onset (week 2), the signature is characterized by over-representation of innate immune mediators including TLR signalling and TREM-1 activation of the inflammasome. In keeping with the transcriptional data, concentrations of plasma cytokines and caspase-1/5 are elevated in TB-IRIS. Inhibition of MyD88 adaptor and group 1 caspases reduces secretion of cytokines including IL-1 in TB-IRIS patients. These data provide insight on the pathogenesis of TB-IRIS and may assist the development of specific therapies.

No MeSH data available.


Related in: MedlinePlus