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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

Cytokine production at week 2 of TB-IRIS reflects the transcriptomic prediction.Plasma cytokine concentrations in TB-IRIS and non-IRIS patients at week 0 and week 2 were measured. Results were analysed by Mann–Whitney U-test between non-IRIS and TB-IRIS at each time point. The median value of each group was shown and P-value was designated: *P≤0.05, **P≤0.01.
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f4: Cytokine production at week 2 of TB-IRIS reflects the transcriptomic prediction.Plasma cytokine concentrations in TB-IRIS and non-IRIS patients at week 0 and week 2 were measured. Results were analysed by Mann–Whitney U-test between non-IRIS and TB-IRIS at each time point. The median value of each group was shown and P-value was designated: *P≤0.05, **P≤0.01.

Mentions: As the transcriptomic signatures predicted activation of many proinflammatory cytokines (Fig. 3), we measured the concentration of these analytes in patient plasma at both week 0 and week 2, to assess whether the transcriptomic prediction was reflected in the blood protein. Congruent with the transcriptomic signature prediction of week 2, we detected significantly higher concentrations of IL-12p40, IFN-γ, TNF-α and IL-6 in TB-IRIS patients at week 2 (Fig. 4), indicating a circulating inflammatory response at the time when clinical symptoms were observed. Our data agree with those previously reported28, further indicating that TB-IRIS is strongly associated with dysregulated cytokine and chemokine production. Although IL-8 and type I IFN were also predicted to be elevated at week 2, we did not detect any differences in plasma proteins between non-IRIS and TB-IRIS patients (Fig. 4).


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)

Cytokine production at week 2 of TB-IRIS reflects the transcriptomic prediction.Plasma cytokine concentrations in TB-IRIS and non-IRIS patients at week 0 and week 2 were measured. Results were analysed by Mann–Whitney U-test between non-IRIS and TB-IRIS at each time point. The median value of each group was shown and P-value was designated: *P≤0.05, **P≤0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Cytokine production at week 2 of TB-IRIS reflects the transcriptomic prediction.Plasma cytokine concentrations in TB-IRIS and non-IRIS patients at week 0 and week 2 were measured. Results were analysed by Mann–Whitney U-test between non-IRIS and TB-IRIS at each time point. The median value of each group was shown and P-value was designated: *P≤0.05, **P≤0.01.
Mentions: As the transcriptomic signatures predicted activation of many proinflammatory cytokines (Fig. 3), we measured the concentration of these analytes in patient plasma at both week 0 and week 2, to assess whether the transcriptomic prediction was reflected in the blood protein. Congruent with the transcriptomic signature prediction of week 2, we detected significantly higher concentrations of IL-12p40, IFN-γ, TNF-α and IL-6 in TB-IRIS patients at week 2 (Fig. 4), indicating a circulating inflammatory response at the time when clinical symptoms were observed. Our data agree with those previously reported28, further indicating that TB-IRIS is strongly associated with dysregulated cytokine and chemokine production. Although IL-8 and type I IFN were also predicted to be elevated at week 2, we did not detect any differences in plasma proteins between non-IRIS and TB-IRIS patients (Fig. 4).

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