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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 from TB patients (n = 37) before and after treatment.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 within the groups (over time) was performed by paired t-test.
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pone-0001522-g002: Comparison of relative levels of cytokine mRNA from unstimulated leukocytes from TB patients (n = 37) before and after treatment.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 within the groups (over time) was performed by paired t-test.

Mentions: We attempted to control for some of this variability by investigating the cytokine responses in these groups 6–8 months after entry to the study, by which time a better assessment of their clinical prognosis could be made. At this stage, all the TB patients but one had completed chemotherapy and had become asymptomatic and culture negative, indicative of successful therapy. We assessed cytokine production by PCR as before and as shown in figure 2A, significant declines in mRNA for IL-4 and IL-4δ2 were seen, while IFN-γ levels were essentially unchanged. The steep decline in IL-4 mRNA contributed to a significant increase in both the IFN-γ/IL-4 and IL-4δ2/IL-4 ratios, suggestive of a move towards a more Th1-like response even though IL-4δ2 mRNA also declined somewhat (Figure 2B).


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 from TB patients (n = 37) before and after treatment.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 within the groups (over time) was performed by paired t-test.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001522-g002: Comparison of relative levels of cytokine mRNA from unstimulated leukocytes from TB patients (n = 37) before and after treatment.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 within the groups (over time) was performed by paired t-test.
Mentions: We attempted to control for some of this variability by investigating the cytokine responses in these groups 6–8 months after entry to the study, by which time a better assessment of their clinical prognosis could be made. At this stage, all the TB patients but one had completed chemotherapy and had become asymptomatic and culture negative, indicative of successful therapy. We assessed cytokine production by PCR as before and as shown in figure 2A, significant declines in mRNA for IL-4 and IL-4δ2 were seen, while IFN-γ levels were essentially unchanged. The steep decline in IL-4 mRNA contributed to a significant increase in both the IFN-γ/IL-4 and IL-4δ2/IL-4 ratios, suggestive of a move towards a more Th1-like response even though IL-4δ2 mRNA also declined somewhat (Figure 2B).

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