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Ex vivo cytokine mRNA levels correlate with changing clinical status of ethiopian TB patients and their contacts over time.

Wassie L, Demissie A, Aseffa A, Abebe M, Yamuah L, Tilahun H, Petros B, Rook G, Zumla A, Andersen P, Doherty TM, VACSEL Study Gro - PLoS ONE (2008)

Bottom Line: This correlated with a decrease in the relative amount of IL-4 expressed.IL-4 expression was disproportionately increased in this group.However, the data also suggest that there are no clear-cut differences between groups: the immune response over time appears to include changes in the expression of IFN-gamma, IL-4 and IL-4delta2, and it is the relative, not absolute levels of cytokine expression that are characteristic of clinical status.

View Article: PubMed Central - PubMed

Affiliation: Armauer Hansen Research Institute, Addis Ababa, Ethiopia.

ABSTRACT
There is an increasing body of evidence which suggests that IL-4 plays a role in the pathogenesis of TB, but a general consensus on its role remains elusive. We have previously published data from a cohort of Ethiopian TB patients, their contacts, and community controls suggesting that enhanced IL-4 production is associated with infection with M. tuberculosis, rather than overt disease and that long-term protection in infected community controls is associated with co-production of the IL-4 antagonist IL-4d2, alongside elevated IL-4. Here, for the first time, we compare data on expression of IFN-gamma, IL-4 and IL-4delta2 over time in TB patients and their household contacts. During the follow-up period, the TB patients completed therapy and ceased to display TB-like symptoms. This correlated with a decrease in the relative amount of IL-4 expressed. Over the same period, the clinical status of some of their contacts also changed, with a number developing TB-like symptoms or clinically apparent TB. IL-4 expression was disproportionately increased in this group. The findings support the hypothesis that elevated IL-4 production is generally associated with infection, but that TB disease is associated with a relatively increased expression of IL-4 compared to IFN-gamma and IL-4delta2. However, the data also suggest that there are no clear-cut differences between groups: the immune response over time appears to include changes in the expression of IFN-gamma, IL-4 and IL-4delta2, and it is the relative, not absolute levels of cytokine expression that are characteristic of clinical status.

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Comparison of relative levels of IL-4, IL-4δ2 and IFN-γ mRNA from unstimulated leukocytes of household contacts who remained symptom-free during the study period (n = 35).Results are presented as medians and ranges of either (A) cytokine message, assessed by RT-PCR, and normalized against β-actin as a housekeeping gene or (B) the ratio of the normalized values of IL-4δ2 and IFN-γ divided by the normalized IL-4 value, as a proxy for the Th1/Th2 balance. Levels of gene expression which were significantly different between groups are indicated, as are the associated p values. Analysis of differences between the groups was performed by Kruskal-Wallis, analysis of differences within the groups was performed by paired t-test.
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pone-0001522-g003: Comparison of relative levels of IL-4, IL-4δ2 and IFN-γ mRNA from unstimulated leukocytes of household contacts who remained symptom-free during the study period (n = 35).Results are presented as medians and ranges of either (A) cytokine message, assessed by RT-PCR, and normalized against β-actin as a housekeeping gene or (B) the ratio of the normalized values of IL-4δ2 and IFN-γ divided by the normalized IL-4 value, as a proxy for the Th1/Th2 balance. Levels of gene expression which were significantly different between groups are indicated, as are the associated p values. Analysis of differences between the groups was performed by Kruskal-Wallis, analysis of differences within the groups was performed by paired t-test.

Mentions: We performed a similar analysis of cytokine expression in the household contact cohorts, but here the heterogeneous nature of these groups became apparent. Where the inclusion criteria initially designated contacts enrolled as Healthy (HHC–meaning no symptoms or signs of TB) by 6–8 months after entry, some of the contacts had begun to show TB-like symptoms (though they were almost all sputum negative and only a few received a clinical diagnosis of TB (one case of pulmonary TB, 2 cases of extrapulmonary TB). As shown in Figure 3, when we compared immune responses in the contacts who had remained asymptomatic throughout the observation period, there was very little variation in cytokine mRNA expression whether compared singly or as ratios.


Ex vivo cytokine mRNA levels correlate with changing clinical status of ethiopian TB patients and their contacts over time.

Wassie L, Demissie A, Aseffa A, Abebe M, Yamuah L, Tilahun H, Petros B, Rook G, Zumla A, Andersen P, Doherty TM, VACSEL Study Gro - PLoS ONE (2008)

Comparison of relative levels of IL-4, IL-4δ2 and IFN-γ mRNA from unstimulated leukocytes of household contacts who remained symptom-free during the study period (n = 35).Results are presented as medians and ranges of either (A) cytokine message, assessed by RT-PCR, and normalized against β-actin as a housekeeping gene or (B) the ratio of the normalized values of IL-4δ2 and IFN-γ divided by the normalized IL-4 value, as a proxy for the Th1/Th2 balance. Levels of gene expression which were significantly different between groups are indicated, as are the associated p values. Analysis of differences between the groups was performed by Kruskal-Wallis, analysis of differences within the groups was performed by paired t-test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211401&req=5

pone-0001522-g003: Comparison of relative levels of IL-4, IL-4δ2 and IFN-γ mRNA from unstimulated leukocytes of household contacts who remained symptom-free during the study period (n = 35).Results are presented as medians and ranges of either (A) cytokine message, assessed by RT-PCR, and normalized against β-actin as a housekeeping gene or (B) the ratio of the normalized values of IL-4δ2 and IFN-γ divided by the normalized IL-4 value, as a proxy for the Th1/Th2 balance. Levels of gene expression which were significantly different between groups are indicated, as are the associated p values. Analysis of differences between the groups was performed by Kruskal-Wallis, analysis of differences within the groups was performed by paired t-test.
Mentions: We performed a similar analysis of cytokine expression in the household contact cohorts, but here the heterogeneous nature of these groups became apparent. Where the inclusion criteria initially designated contacts enrolled as Healthy (HHC–meaning no symptoms or signs of TB) by 6–8 months after entry, some of the contacts had begun to show TB-like symptoms (though they were almost all sputum negative and only a few received a clinical diagnosis of TB (one case of pulmonary TB, 2 cases of extrapulmonary TB). As shown in Figure 3, when we compared immune responses in the contacts who had remained asymptomatic throughout the observation period, there was very little variation in cytokine mRNA expression whether compared singly or as ratios.

Bottom Line: This correlated with a decrease in the relative amount of IL-4 expressed.IL-4 expression was disproportionately increased in this group.However, the data also suggest that there are no clear-cut differences between groups: the immune response over time appears to include changes in the expression of IFN-gamma, IL-4 and IL-4delta2, and it is the relative, not absolute levels of cytokine expression that are characteristic of clinical status.

View Article: PubMed Central - PubMed

Affiliation: Armauer Hansen Research Institute, Addis Ababa, Ethiopia.

ABSTRACT
There is an increasing body of evidence which suggests that IL-4 plays a role in the pathogenesis of TB, but a general consensus on its role remains elusive. We have previously published data from a cohort of Ethiopian TB patients, their contacts, and community controls suggesting that enhanced IL-4 production is associated with infection with M. tuberculosis, rather than overt disease and that long-term protection in infected community controls is associated with co-production of the IL-4 antagonist IL-4d2, alongside elevated IL-4. Here, for the first time, we compare data on expression of IFN-gamma, IL-4 and IL-4delta2 over time in TB patients and their household contacts. During the follow-up period, the TB patients completed therapy and ceased to display TB-like symptoms. This correlated with a decrease in the relative amount of IL-4 expressed. Over the same period, the clinical status of some of their contacts also changed, with a number developing TB-like symptoms or clinically apparent TB. IL-4 expression was disproportionately increased in this group. The findings support the hypothesis that elevated IL-4 production is generally associated with infection, but that TB disease is associated with a relatively increased expression of IL-4 compared to IFN-gamma and IL-4delta2. However, the data also suggest that there are no clear-cut differences between groups: the immune response over time appears to include changes in the expression of IFN-gamma, IL-4 and IL-4delta2, and it is the relative, not absolute levels of cytokine expression that are characteristic of clinical status.

Show MeSH
Related in: MedlinePlus