Limits...
Monocyte unresponsiveness and impaired IL1β, TNFα and IL7 production are associated with a poor outcome in Malawian adults with pulmonary tuberculosis.

Waitt CJ, Banda P, Glennie S, Kampmann B, Squire SB, Pirmohamed M, Heyderman RS - BMC Infect. Dis. (2015)

Bottom Line: Lower TB antigen-induced IL1β (p = 0.006), TNFα (p = 0.02) and IL7 (p = 0.009) were produced in the poor outcome group.Lower TNFα responses to H37Rv paralleled lower responses to a panel of TLR ligands, suggesting an underlying perturbation in common TLR signalling pathways.Future work should explore the role of TLR polymorphisms in immune response and clinical outcome in TB patients.

View Article: PubMed Central - PubMed

Affiliation: Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, PO Box 30096, Chichiri, Blantyre, Malawi. cwaitt@liv.ac.uk.

ABSTRACT

Background: Early death during TB treatment is associated with depressed TNFα response to antigenic stimulation and propensity to superadded bacterial infection. Hypothesising the role of monocyte unresponsiveness, we further compared the immunological profile between patients who died or suffered a life-threatening deterioration ('poor outcome') during the intensive phase of TB treatment with patients who had an uneventful clinical course ('good outcome') who had been recruited as part of a larger prospective cohort study of Malawian TB patients.

Methods: Using Luminex, IL1β, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12, IL13, IL17, GCSF, GMCSF, MCP1, MIP1b, IFNγ and TNFα were measured in whole blood assay supernatants (stimulated with Mycobacterium tuberculosis H37Rv and LPS) and serum from 44 Malawian adult TB patients (22 of each outcome) immediately prior to commencing treatment, after 7 days and on day 56 of TB treatment. Monocyte surface expression of CD14, CD16, TLR2, TLR4, CD86 and HLADR, and intracellular TNFα were measured by flow cytometry as was intracellular TNFα response to purified TLR ligands.

Results: Lower TB antigen-induced IL1β (p = 0.006), TNFα (p = 0.02) and IL7 (p = 0.009) were produced in the poor outcome group. TNFα was produced by 'classical' CD14(hi)CD16(lo) monocytes, with no correlation between this response and expression of monocyte surface markers. Response to TB antigens correlated with responses to the purified TLR 2, 3 and 4 ligands.

Conclusions: Dysregulated monocyte cytokine production was identified in TB patients with poor outcome. Lower TNFα responses to H37Rv paralleled lower responses to a panel of TLR ligands, suggesting an underlying perturbation in common TLR signalling pathways. Future work should explore the role of TLR polymorphisms in immune response and clinical outcome in TB patients.

No MeSH data available.


Related in: MedlinePlus

Cytokine responses to stimulation with H37Rv and LPS, expressed as the area under the concentration time curve (AUC) between Day 0 (immediately prior to commencing treatment) and Day 7 of TB treatment. Patients who had a poor outcome had lower production of TNFα, IL1β and IL7 compared to matched control patients who had an uneventful clinical course. No significant differences were identified between patient groups in the other cytokines and chemokines analysed
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4643523&req=5

Fig2: Cytokine responses to stimulation with H37Rv and LPS, expressed as the area under the concentration time curve (AUC) between Day 0 (immediately prior to commencing treatment) and Day 7 of TB treatment. Patients who had a poor outcome had lower production of TNFα, IL1β and IL7 compared to matched control patients who had an uneventful clinical course. No significant differences were identified between patient groups in the other cytokines and chemokines analysed

Mentions: Patients with poor clinical outcome had trends towards lower whole blood IL1β (median 196 [IQR 133–308] vs 894 [IQR 498–1368] p = 0.006 for H37Rv; median 630 [IQR 144–1447] vs 1661 [IQR 548–2134] p = 0.05 for LPS), TNFα (median 4355 [IQR 981–8598] vs 11977 [IQR 6221–22285] p = 0.02 for H37Rv; median 3512 [IQR 809–4927] vs 8623 [IQR 3309–19846] p = 0.01 for LPS) and IL7 (median 3.75 [IQR 0–57] vs 105 [IQR 37 – 479] p = 0.009 for H37Rv; median 4.64 [IQR 0–61] vs 131 [IQR 18.7 – 349] p = 0.01 for LPS) production in response to both H37Rv and LPS (Fig. 2) in comparison with patients who had an uneventful clinical course. No significant differences were identified in the levels of the other analytes (IL2, IL4, IL10, IL12, IL13, IL17, GCSF and IFNγ) measured in response to these agonists (see Additional file 1: Table S1 for a complete list of analyses performed), or in any of the panel measured in serum at the same time points. No statistically significant differences in cytokine profile were identified between the groups of patients when assessing the values at commencement of TB treatment alone. Follow-up of patients who survived a life-threatening deterioration until the end of the 56 day intensive phase of TB treatment revealed a trend towards restoration of the initially depressed IL1β (p = 0.04) and TNFα responses (p = 0.18) when compared with controls (Fig. 3).Fig. 2


Monocyte unresponsiveness and impaired IL1β, TNFα and IL7 production are associated with a poor outcome in Malawian adults with pulmonary tuberculosis.

Waitt CJ, Banda P, Glennie S, Kampmann B, Squire SB, Pirmohamed M, Heyderman RS - BMC Infect. Dis. (2015)

Cytokine responses to stimulation with H37Rv and LPS, expressed as the area under the concentration time curve (AUC) between Day 0 (immediately prior to commencing treatment) and Day 7 of TB treatment. Patients who had a poor outcome had lower production of TNFα, IL1β and IL7 compared to matched control patients who had an uneventful clinical course. No significant differences were identified between patient groups in the other cytokines and chemokines analysed
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4643523&req=5

Fig2: Cytokine responses to stimulation with H37Rv and LPS, expressed as the area under the concentration time curve (AUC) between Day 0 (immediately prior to commencing treatment) and Day 7 of TB treatment. Patients who had a poor outcome had lower production of TNFα, IL1β and IL7 compared to matched control patients who had an uneventful clinical course. No significant differences were identified between patient groups in the other cytokines and chemokines analysed
Mentions: Patients with poor clinical outcome had trends towards lower whole blood IL1β (median 196 [IQR 133–308] vs 894 [IQR 498–1368] p = 0.006 for H37Rv; median 630 [IQR 144–1447] vs 1661 [IQR 548–2134] p = 0.05 for LPS), TNFα (median 4355 [IQR 981–8598] vs 11977 [IQR 6221–22285] p = 0.02 for H37Rv; median 3512 [IQR 809–4927] vs 8623 [IQR 3309–19846] p = 0.01 for LPS) and IL7 (median 3.75 [IQR 0–57] vs 105 [IQR 37 – 479] p = 0.009 for H37Rv; median 4.64 [IQR 0–61] vs 131 [IQR 18.7 – 349] p = 0.01 for LPS) production in response to both H37Rv and LPS (Fig. 2) in comparison with patients who had an uneventful clinical course. No significant differences were identified in the levels of the other analytes (IL2, IL4, IL10, IL12, IL13, IL17, GCSF and IFNγ) measured in response to these agonists (see Additional file 1: Table S1 for a complete list of analyses performed), or in any of the panel measured in serum at the same time points. No statistically significant differences in cytokine profile were identified between the groups of patients when assessing the values at commencement of TB treatment alone. Follow-up of patients who survived a life-threatening deterioration until the end of the 56 day intensive phase of TB treatment revealed a trend towards restoration of the initially depressed IL1β (p = 0.04) and TNFα responses (p = 0.18) when compared with controls (Fig. 3).Fig. 2

Bottom Line: Lower TB antigen-induced IL1β (p = 0.006), TNFα (p = 0.02) and IL7 (p = 0.009) were produced in the poor outcome group.Lower TNFα responses to H37Rv paralleled lower responses to a panel of TLR ligands, suggesting an underlying perturbation in common TLR signalling pathways.Future work should explore the role of TLR polymorphisms in immune response and clinical outcome in TB patients.

View Article: PubMed Central - PubMed

Affiliation: Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, PO Box 30096, Chichiri, Blantyre, Malawi. cwaitt@liv.ac.uk.

ABSTRACT

Background: Early death during TB treatment is associated with depressed TNFα response to antigenic stimulation and propensity to superadded bacterial infection. Hypothesising the role of monocyte unresponsiveness, we further compared the immunological profile between patients who died or suffered a life-threatening deterioration ('poor outcome') during the intensive phase of TB treatment with patients who had an uneventful clinical course ('good outcome') who had been recruited as part of a larger prospective cohort study of Malawian TB patients.

Methods: Using Luminex, IL1β, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12, IL13, IL17, GCSF, GMCSF, MCP1, MIP1b, IFNγ and TNFα were measured in whole blood assay supernatants (stimulated with Mycobacterium tuberculosis H37Rv and LPS) and serum from 44 Malawian adult TB patients (22 of each outcome) immediately prior to commencing treatment, after 7 days and on day 56 of TB treatment. Monocyte surface expression of CD14, CD16, TLR2, TLR4, CD86 and HLADR, and intracellular TNFα were measured by flow cytometry as was intracellular TNFα response to purified TLR ligands.

Results: Lower TB antigen-induced IL1β (p = 0.006), TNFα (p = 0.02) and IL7 (p = 0.009) were produced in the poor outcome group. TNFα was produced by 'classical' CD14(hi)CD16(lo) monocytes, with no correlation between this response and expression of monocyte surface markers. Response to TB antigens correlated with responses to the purified TLR 2, 3 and 4 ligands.

Conclusions: Dysregulated monocyte cytokine production was identified in TB patients with poor outcome. Lower TNFα responses to H37Rv paralleled lower responses to a panel of TLR ligands, suggesting an underlying perturbation in common TLR signalling pathways. Future work should explore the role of TLR polymorphisms in immune response and clinical outcome in TB patients.

No MeSH data available.


Related in: MedlinePlus