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IL10 haplotype associated with tuberculin skin test response but not with pulmonary TB.

ABSTRACT: Evidence from genetic association and twin studies indicates that susceptibility to tuberculosis (TB) is under genetic control. One gene implicated in susceptibility to TB is that encoding interleukin-10 (IL10). In a group of 2010 Ghanaian patients with pulmonary TB and 2346 healthy controls exposed to Mycobacterium tuberculosis, among them 129 individuals lacking a tuberculin skin test (PPD) response, we genotyped four IL10 promoter variants at positions -2849 , -1082 , -819 , and -592 and reconstructed the haplotypes. The IL10 low-producer haplotype -2849A/-1082A/-819C/-592C, compared to the high-producer haplotype -2849G/-1082G/-819C/-592C, occurred less frequent among PPD-negative controls than among cases (OR 2.15, CI 1.3-3.6) and PPD-positive controls (OR 2.09, CI 1.2-3.5). Lower IL-10 plasma levels in homozygous -2849A/-1082A/-819C/-592C carriers, compared to homozygous -2849G/-1082G/-819C/-592C carriers, were confirmed by a IL-10 ELISA (p = 0.016). Although we did not observe differences between the TB patients and all controls, our results provide evidence that a group of individuals exposed to M. tuberculosis transmission is genetically distinct from healthy PPD positives and TB cases. In these PPD-negative individuals, higher IL-10 production appears to reflect IL-10-dependent suppression of adaptive immune responses and sustained long-term specific anergy.

SUBMITTER: Thye T

PROVIDER: S-EPMC2671601 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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IL10 haplotype associated with tuberculin skin test response but not with pulmonary TB.

Thye Thorsten T Browne Edmund N EN Chinbuah Margaret A MA Gyapong John J Osei Ivy I Owusu-Dabo Ellis E Brattig Norbert W NW Niemann Stefan S Rüsch-Gerdes Sabine S Horstmann Rolf D RD Meyer Christian G CG

PloS one 20090501 5

Evidence from genetic association and twin studies indicates that susceptibility to tuberculosis (TB) is under genetic control. One gene implicated in susceptibility to TB is that encoding interleukin-10 (IL10). In a group of 2010 Ghanaian patients with pulmonary TB and 2346 healthy controls exposed to Mycobacterium tuberculosis, among them 129 individuals lacking a tuberculin skin test (PPD) response, we genotyped four IL10 promoter variants at positions -2849 , -1082 , -819 , and -592 and reco ...[more]

PMID: 19412539

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Project description:BackgroundWorld Health Organization (WHO) recommends systematic screening of high-risk populations, including household contacts (HHCs) of adult pulmonary tuberculosis (TB) patients, as a key strategy for elimination of TB. QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and tuberculin skin test (TST) are two commonly used tools for the detection of latent tuberculosis infection (LTBI) but may yield differential results, affecting eligibility for TB preventive therapy.Materials and methodsA prospective cohort study of adult pulmonary TB patients and their HHCs were recruited in 2 cities of India, Pune and Chennai. HHCs underwent QFT-GIT (QIAGEN) and TST (PPD SPAN 2TU/5TU). A positive QFT-GIT was defined as value ?0.35 IU/ml and a positive TST as an induration of ?5 mm. A secondary outcome of TST induration ?10mm was explored. Proportion positive by either or both assays, discordant positives and negatives were calculated; test concordance was assessed using percentage agreement and kappa statistics; and risk factors for concordance and discordance including age categories were assessed using logistic regression. Sensitivity and specificity was estimated by latent class model.ResultsOf 1048 HHCs enrolled, 869 [median (IQR) age: 27 years (15-40)] had both TST and QFT-GIT results available and prevalence of LTBI by QFT-GIT was 54% [95% CI (51, 57)], by TST was 55% [95% CI (52, 58)], by either test was 74% [95% CI (71, 77) and by both tests was 35% [95% CI (31, 38)]. Discordance of TST+/QFT-GIT- was 21% while TST-/QFT-GIT+ was 26%. Poor to fair agreement occurred with TST 5mm or 10mm cutoff (60 and 61% agreement with kappa value of 0.20 and 0.25 respectively). Test agreement varied by age, TST strength and induration cut-off. In multivariate analysis, span PPD was a risk factor for QFT-GIT+ and TST- while absence of BCG scar was for TST+ and QFT-GIT-. Being employed and exposure to TB case outside the household case were associated with positivity by both the tests. Sensitivity of TST and QFT-GIT to diagnose LTBI was 77% and 69%. Probability of having LTBI was >90% when both tests were positive irrespective of exposure gradient.ConclusionPrevalence of LTBI among HHCs of adult pulmonary TB patients in India is very high and varies by test type, age, and exposure gradient. In our high TB burden setting, a strategy to treat all HHCs or a targeted strategy whereby an exposure index is used should be assessed in future preventive therapy and vaccine studies as HHCs have several factors that place them at high risk for progression to TB disease.

Project description:Understanding mechanisms of resistance to M. tuberculosis (M.tb) infection in humans could identify novel therapeutic strategies as it has for other infectious diseases. We hypothesized that monocytes from household contacts of pulmonary tuberculosis patients that failed to convert their tuberculin skin tests (TSTNEG) would respond differently to M.tb infection when compared to matched tuberculin skin test positive controls (TSTPOS). We obtained genome-wide transcriptional profiles of M.tb-infected peripheral blood monocytes from 10 TSTNEG and 18 TSTPOS Ugandans. We used Gene Set Enrichment Analysis and interaction networks to identify cellular processes associated with TST status. We discovered gene sets associated with histone deacetylases that were differentially expressed when comparing TSTPOS and TSTNEG subjects. We used small molecule inhibitors to demonstrate that histone deacetylase function is important for the pro-inflammatory response to M.tb infection in monocytes. Monocytes from individuals who appear to resist M.tb infection differentially activate pathways controlled by histone deacetylase in response to M.tb infection when compared to those who are susceptible to infection. These data identify a potential cellular mechanism underlying the clinical phenomenon of persistently negative tuberculin skin tests despite known exposure to an infectious contact. CD14+ monocytes from 18 TSTPOS and 10 TSTNEG subjects were isolated by positive selection. Depending on the yield, between 5E5 and 1E6 monocytes were plated in duplicate in a 24-well tissue culture plate and rested overnight at 37oC, 5% CO2. The next day, cells were mock-infected or infected with virulent M. tuberculosis strain H37Rv at a multiplicity of infection (MOI) 10:1. After a six hour incubation at 37C, 5% CO2, the mycobacteria were killed and total RNA harvested using TRIzol-LS (Invitrogen). TRIzol samples were stored at -80oC until all infections were completed. To minimize batch effects, equal numbers of TSTPOS and TSTNEG subjects were processed on each of six days and frozen aliquots of M.tb were used for infections. RNA was extracted using the RNeasy Mini Kit with on-column DNAse digestion. RNA was transcribed into complementary DNA, labeled, and hybridized onto Illumina HT-12 microarrays according to the manufacturerâs instructions. Probe intensities were quantified using Illumina iScan platform and processed using BeadArray without performing normalization or background correction.

Project description:BACKGROUND: Interferon-gamma release assays have emerged as a more specific alternative to the tuberculin skin test (TST) for detection of tuberculosis (TB) infection, especially in Bacille Calmette-Guérin (BCG) vaccinated people. We determined the prevalence of Mycobacterium tuberculosis infection by TST and QuantiFERON®-TB Gold In-Tube (QFT-GIT) and assessed agreement between the two test methods and factors associated with positivity in either test in Warao Amerindian children in Venezuela. Furthermore, progression to active TB disease was evaluated for up to 12 months. METHODS: 163 HIV-negative childhood household contacts under 16 years of age were enrolled for TST, QFT-GIT and chest X-ray (CXR). Follow-up was performed at six and 12 months. Factors associated with TST and QFT-GIT positivity were studied using generalized estimation equations logistic regression models. RESULTS: At baseline, the proportion of TST positive children was similar to the proportion of children with a positive QFT-GIT (47% vs. 42%, p = 0.12). Overall concordance between QFT-GIT and TST was substantial (kappa 0.76, 95% CI 0.46-1.06). Previous BCG vaccination was not associated with significantly increased positivity in either test (OR 0.68, 95% CI 0.32-1.5 for TST and OR 0.51, 95% CI 0.14-1.9 for QFT-GIT). Eleven children were diagnosed with active TB at baseline. QFT-GIT had a higher sensitivity for active TB (88%, 95% CI 47-98%) than TST (55%, 95% CI 24-83%) while specificities were similar (respectively 58% and 55%). Five initially asymptomatic childhood contacts progressed to active TB disease during follow-up. CONCLUSION: Replacement of TST by the QFT-GIT for detection of M. tuberculosis infection is not recommended in this resource-constrained setting as test results showed substantial concordance and TST positivity was not affected by previous BCG vaccination. The QFT-GIT had a higher sensitivity than the TST for the detection of TB disease. However, the value of the QFT-GIT as an adjunct in diagnosing TB disease is limited by a high variability in QFT-GIT results over time.

Dataset Information

IL10 haplotype associated with tuberculin skin test response but not with pulmonary TB.

Publications

IL10 haplotype associated with tuberculin skin test response but not with pulmonary TB.

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