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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 cytokine mRNA from unstimulated leukocytes of initially healthy household contacts who developed TB-like symptoms during the study period (n = 10).Results are presented as (A) medians and ranges of 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-g004: Comparison of relative levels of cytokine mRNA from unstimulated leukocytes of initially healthy household contacts who developed TB-like symptoms during the study period (n = 10).Results are presented as (A) medians and ranges of 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: However, when, we analyzed the data in the cohort who were initially without symptoms but later developed TB-like symptoms (n = 10) a different pattern emerges, as shown in Figure 4. Although the median expression of IFN-γ and IL-4δ2, increased over time, these changes were not significant. This appears to be due to the very variable response, particularly for IL-4δ2: while some showed increased expression of IL-4δ2, nearly half showed the opposite trend. In contrast, all members of this cohort showed an increase in IL-4 mRNA expression leading to a falling ratio of IFN-γ and IL-4δ2 to IL-4 (Figures 4A and 4B).


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 cytokine mRNA from unstimulated leukocytes of initially healthy household contacts who developed TB-like symptoms during the study period (n = 10).Results are presented as (A) medians and ranges of 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-g004: Comparison of relative levels of cytokine mRNA from unstimulated leukocytes of initially healthy household contacts who developed TB-like symptoms during the study period (n = 10).Results are presented as (A) medians and ranges of 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: However, when, we analyzed the data in the cohort who were initially without symptoms but later developed TB-like symptoms (n = 10) a different pattern emerges, as shown in Figure 4. Although the median expression of IFN-γ and IL-4δ2, increased over time, these changes were not significant. This appears to be due to the very variable response, particularly for IL-4δ2: while some showed increased expression of IL-4δ2, nearly half showed the opposite trend. In contrast, all members of this cohort showed an increase in IL-4 mRNA expression leading to a falling ratio of IFN-γ and IL-4δ2 to IL-4 (Figures 4A and 4B).

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