IL-18/IL-37/IP-10 signalling complex as a potential biomarker for discriminating active and latent TB.
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ABSTRACT:
SUBMITTER: Wawrocki S
PROVIDER: S-EPMC6903724 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
IL-18/IL-37/IP-10 signalling complex as a potential biomarker for discriminating active and latent TB.
Wawrocki Sebastian S Seweryn Michal M Kielnierowski Grzegorz G Rudnicka Wieslawa W Wlodarczyk Marcin M Druszczynska Magdalena M
PloS one 20191210 12
<h4>Background</h4>Currently, there are serious limitations in the direct diagnosis of active tuberculosis (ATB). We evaluated the levels of the IL-18/IL-37/IP-10 signalling complex proteins in Mycobacterium tuberculosis (M.tb)-specific antigen-stimulated QuantiFERON® Gold In-Tube (QFT) cultures and in serum samples from ATB patients, healthy individuals with latent M.tb infection (LTBI) and healthy controls (HC) to examine whether combined analyses of these proteins were useful in the different ...[more]
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Project description:BACKGROUND: There is a need for simple tools such as the M.tuberculosis specific IFN-gamma release assays (IGRA) to improve diagnosis of M.tuberculosis-infection in children. The aim of the study was to evaluate the performance of an IP-10 and IL-2 based tests for the diagnosis of M.tuberculosis-infection in recently exposed children from Nigeria. METHODOLOGY AND PRINCIPAL FINDINGS: Samples were obtained from 59 children at high risk of infection with M.tuberculosis (contacts of adults with smear and culture-positive tuberculosis) and 61 at low risk (contacts of smear-negative/culture-positive tuberculosis or community controls). IP-10 and IL-2 was measured in plasma after stimulation of whole-blood with M.tuberculosis specific antigens and mitogen. Previously developed criteria for positive IP-10 and IL-2 tests were used and the diagnostic performances of the IP-10 and IL-2 tests were compared with the Quantiferon In-Tube (QFT-IT) and the Tuberculin Skin Tests (TST). In response to M.tuberculosis specific antigens, the high-risk children expressed significantly higher levels of IP-10 (1358 pg/ml[IQR 278-2535 pg/ml]) and IL-2 (164 pg/ml[11-590 pg/ml]) than low risk groups 149 pg/ml(25-497 pg/ml), and 0 pg/ml(0-3 pg/ml), respectively. There was excellent agreement (>89%,k>0.80) between IP-10, IL-2 tests and QFT-IT, better than with TST (>74%,k>0.49). The IP-10 and IL-2 responses were strongly associated with M.tuberculosis exposure and with grade of infectiousness of the index cases (p<0.0001). IP-10, IL-2, and TST but not QFT-IT was associated with age of the child in the low risk groups (p<0.02). CONCLUSIONS/SIGNIFICANCE: IP-10 is expressed in high levels and results of the IP-10 test were comparable to the QFT-IT. IL-2 was released in low amounts in response to the antigens and not in response to the mitogen therefore IL-2 seems a less useful marker. We have demonstrated that IP-10 and possibly IL-2 could be alternative or adjunct markers to IFN-gamma in the diagnosis infection with M.tuberculosis.
| S-EPMC2483344 | biostudies-literature
Project description:In recent years, pediatric research on tuberculosis (TB) has focused on addressing new biomarkers with the potential to be used as immunological non-sputum-based methods for the diagnosis of TB in children. The aim of this study was to characterize a set of cytokines and a series of individual factors (ferritin, 25-hydroxyvitamin D [25(OH)D], parasite infections, and nutritional status) to assess different patterns for discriminating between active TB and latent TB infection (LTBI) in children. The levels of 13 cytokines in QuantiFERON-TB Gold In-Tube (QFT-GIT) supernatants were analyzed in 166 children: 74 with active TB, 37 with LTBI, and 55 uninfected controls. All cytokines were quantified using Luminex or ELISA. Ferritin and 25(OH)D were also evaluated using CLIA, and Toxocara canis Ig-G antibodies were detected with a commercial ELISA kit. The combination of IP-10, IFN-?, ferritin, and 25(OH)D achieved the best diagnostic performance to discriminate between active TB and LTBI cases in children in relation to the area under receiver operating characteristic (ROC) curve 0.955 (confidence interval 95%: 0.91-1.00), achieving optimal sensitivity and specificity for the development of a new test (93.2 and 90.0%, respectively). Children with TB showed higher ferritin levels and an inverse correlation between 25(OH)D and IFN-? levels. The model proposed includes a combination of biomarkers for discriminating between active TB and LTBI in children to improve the accuracy of TB diagnosis in children. This combination of biomarkers might have potential for identifying the onset of primary TB in children.
| S-EPMC6702835 | biostudies-literature
Project description:BackgroundThe early and accurate diagnosis of tuberculosis (TB) is critical for controlling the global TB epidemic. Although early studies have supported the potential role of cytokine biomarkers in blood for the diagnosis of TB, this method requires further investigation and validation in different populations. A set of biomarkers that can discriminate between active TB (ATB) and latent TB infection (LTBI) remains elusive.MethodsIn the current study, we organized two retrospective cohorts and one prospective cohort to investigate the immune responses at different clinical stages of TB infection, as determined by candidate cytokine biomarkers detected with a multiplex cytokine platform. Using a pre-established diagnostic algorithm, participants were classified as ATB, LTBI, and TB uninfected controls (CON). Based on our multiplex cytokine assay, a multi-cytokine biosignature was modelled for the optimal recognition of the different TB infection status.ResultsOur analysis identified a six-cytokine biosignature of TB-antigen stimulated IFN-γ, IP-10, and IL-1Ra, and unstimulated IP-10, VEGF, and IL-12 (p70) for a biomarker screening group (n = 88). The diagnostic performance of the biosignature was then validated using a biomarker validation cohort (n = 216) and resulted in a sensitivity of 88.2% and a specificity of 92.1%. In a prospectively recruited clinical validation cohort (n = 194), the six-cytokine biosignature was further evaluated, and displayed a sensitivity of 85.7%, a specificity of 91.3% and an overall accuracy of 88.7%.ConclusionsWe have identified a six-cytokine biosignature for accurately differentiating ATB patients from subjects with LTBI and CON. This approach holds promise as an early and rapid diagnostic test for ATB.
| S-EPMC6054748 | biostudies-literature
Project description:We sought to identify biomarker responses to tuberculosis specific antigens which could 1) improve the diagnosis of tuberculosis infection and 2) allow the differentiation of active and latent infections. Seventy subjects with active tuberculosis (N = 12), latent tuberculosis (N = 32), or no evidence of tuberculosis infection (N = 26) were evaluated. We used the Luminex Multiplexed Bead Array platform to simultaneously evaluate 25 biomarkers in the supernatant of whole blood samples following overnight stimulation using the Quantiferon(®) Gold In-Tube kit. We defined the response to stimulation as the difference (within an individual patient) between the response to the pooled tuberculosis antigens and the negative control. IP-10 response was significantly higher in tuberculosis-infected (active or latent) subjects compared to the uninfected group (p < 0.0001). Among the 25 parameters, expression levels of IL-15 and MCP-1 were found to be significantly higher in the active tuberculosis group compared to the latent tuberculosis group (p = 0.0006 and 0.0030, respectively). When combined, IL-15 and MCP-1 accurately identified 83% of active and 88% of latent infections. The combination of IL-15 and MCP-1 responses was accurate in distinguishing persons with active tuberculosis from persons with latent tuberculosis in this study.
| S-EPMC3090479 | biostudies-literature
Project description:There is an urgent need for accurate and sensitive diagnostic tools that can overcome the current challenge to distinguish individuals with latent tuberculosis infection (LTBI) from individuals with active tuberculosis (TB). Recent literature has suggested that a group of cytokines may serve as biomarkers of TB disease progression. Using a multiplex ELISA, we quantified 27 circulatory markers present within the unstimulated plasma of individuals in Durban, South Africa who were healthy (n=20), LTBI (n=13), or had active TB (n=30). RT-qPCR was performed to measure gene expression of the cytokines of interest, using RNA isolated from healthy (n=20), LTBI (n=20), or active TB (n=30). We found that at the protein level, IL-1RA, IL-6, and IP-10 were significantly more abundant in participants with active TB (p< 0.05) compared to those with LTBI individuals. IP-10 also showed the strongest association with active TB compared to healthy and LTBI at mRNA level. Our data shows that these proteins may serve as biomarkers of TB at both the protein and gene level.
| S-EPMC9184682 | biostudies-literature
Project description:Background:Sickle cell anemia (SCA) is associated with a chronic proinflammatory state characterized by elevated leukocyte count, mortality from severe recurrent infections, and subsequent vasoocclusive complications with leukocyte adhesion to the endothelium and increased plasma levels of inflammatory cytokines. The immune system has a close connection with morbidity in SCA, but further studies are needed to uncover the involvement of innate and adaptive immunities in modulating the SCA physiopathology. We performed measurements of the frequency of innate and adaptive immunity cells, cytokines, chemokines, and growth factors and immunophenotyping of Toll-like receptor and adhesion molecule expression in the blood of SCA patients and healthy donors to evaluate the different profiles of these biomarkers, the relationship among them, and their correlation to laboratory records and death risk. Material and Methods. Immunophenotyping of cells, Toll-like receptors, and adhesion molecules were performed from peripheral blood samples of SCA patients and healthy donors by flow cytometry and cytokine/chemokine/growth factor measurement by the Luminex technique performed from the serum of the same subjects. Results:Cells of adaptive immunity such as IL-12, IL-17, and IL-10 cytokines; IL-8, IP-10, MIP-1?, MIP-1?, and RANTES chemokines; and VEGF, FGF-basic, and GM-CSF growth factors were higher in SCA patients than healthy donors regardless of any laboratorial and clinical condition. However, high death risk appears to have relevant biomarkers. Conclusion:In the SCA pathophysiology at steady state, there is a broad immunological biomarker crosstalk highlighted by TCD4+CD69+ lymphocytes, IL-12 and IL-17 inflammatory and IL-10 regulatory cytokines, MIP-1?, MIP-1?, and IP-10 chemokines, and VEGF growth factor. High expression of TLR2 in monocytes and VLA-4 in TCD8+ lymphocytes and high levels of MIP-1? and RANTES appear to be relevant in high death risk conditions. The high reticulocytosis and high death risk conditions present common correlations, and there seems to be a balance by the Th2 profile.
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Project description:While blood transcriptional profiling has improved diagnosis and understanding of disease pathogenesis of adult tuberculosis (TB), no studies applying gene expression profiling of children with TB have been described so far. In this study, we have compared whole blood gene expression in childhood TB patients, as well as in healthy latently infected (LTBI) and uninfected (HC) children in a cohort of Warao Amerindians in the Delta Amacuro in Venezuela. We identified a 116-gene signature set by means of random forest analysis that showed an average prediction error of 11% for TB vs. LTBI and for TB vs. LTBI vs. HC in our dataset. Furthermore, a minimal set of only 9 genes showed a significant predictive value for all previously published adult studies using whole blood gene expression, with average prediction errors between 17% and 23%. Additionally, a minimal gene set of 42 genes with a comparable predictive value to the 116-gene set in both our dataset and the previously published literature cohorts for the comparsion of TB vs. LTBI vs. HC was identified. In order to identify a robust representative gene set that would hold stand among different ethnic populations, we selected ten genes that were highly discriminative between TB, LTBI and HC in all literature datasets as well as in our dataset. Functional annotation of these ten genes highlights a possible role for genes involved in calcium signaling and calcium metabolism as biomarkers for active TB. These ten genes were validated by quantitative real-time polymerase chain reaction in an additional cohort of 54 Warao Amerindian children with LTBI, HC and non-TB pneumonia. Decision tree analysis indicated that five of the ten genes were sufficient to diagnose 78% of the TB cases correctly with 100% specificity. We conclude that our data justify the further exploration of our signature set as biomarkers to diagnose childhood TB. Furthermore, as the identification of different biomarkers in ethnically distinct cohorts is apparent, it is important to cross-validate newly identified markers in all available cohorts. In this study, 27 children 1 to 15 years of age with TB (n=9), LTBI (n=9) and HC (n=9) were recruited between May 2010 and December 2010. Tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assay (QFT-GIT) were performed on all children. A sputum sample was collected from all children with expectoration and a gastric aspirate was taken from all children under 6 years of age. Children with active TB were diagnosed based on culture of M. tuberculosis (n=2) or on the basis of clinical, epidemiological and radiological features (n=7). The latter group were children with a TST = 10 mm or a positive QFT-GIT result who presented all of: persistent fever >38°C objectively recorded daily for at least two weeks, persistent cough for more than three weeks, weight loss (>5% reduction in weight compared with the highest weight recorded in last three months) or failure to thrive (documented crossing of percentile lines in the preceding three months), persistent lethargy or decrease in playfulness/activity reported by the parent and absence of clinical response on broad-spectrum antibiotics. Standard antero-posterior and lateral chest radiographs (CXRs) were taken from all children. Two independent experts, blinded to all clinical information, evaluated the CXRs and documented their findings on a standard report form. Where the two objective experts disagreed, a third expert was consulted and final consensus was achieved. A diagnosis of TB was only made when the CXR was consistent with TB9 and the child showed a positive clinical response to anti-TB treatment. Children were followed up clinically, radiologically and, in case of a negative TST at inclusion, by means of TST at six and 12 months after inclusion. LTBI was defined as a TST = 10mm and a positive QFT-GIT with a negative culture result on inclusion in the absence of radiological and clinical evidence of TB disease on inclusion as well as on t=6 and t=12 months. HC were children with a TST = 0 mm at inclusion and at t=6 and t=12 months. The HC had a negative QFT-GIT and a negative culture result at inclusion without radiological or clinical evidence of TB disease on inclusion nor on t=6 and t=12 months. TB patients were sampled before initiation of anti-TB treatment. Of three of the nine TB patients, a follow-up sample was taken when the patient was in anti-TB treatment for five months. All children were HIV-negative.
2013-02-05 | GSE41055 | GEO
Project description:Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the development of autoantibodies to nuclear antigens and inflammatory responses mediated by multiple cytokines. Although previous studies have determined clinical associations between SLE and the anti-inflammatory cytokines IL-10 and IL-37, their role in the disease, or their potential as biomarkers, remains unclear. We examined serum levels of IL-10 and IL-37 in a large cohort of SLE patients, with detailed longitudinal clinical data. We demonstrate a statistically significant association of serum IL-10 with disease activity, with higher levels in active compared to inactive disease. High first visit IL-10 was predictive of high subsequent disease activity; patients with IL-10 in highest quartile at first visit were 3.6 times more likely to have active disease in subsequent visits. Serum IL-37 was also higher in SLE patients compared to control, and was strongly associated with Asian ethnicity. However, IL-37 was not statistically significantly associated with disease activity. IL-37 was significantly reduced in patients with organ damage but this association was attenuated in multivariable analysis. The data suggest that IL-10, but not IL-37, may have potential as a biomarker predictive for disease activity in SLE.
| S-EPMC5052569 | biostudies-literature
Project description:While blood transcriptional profiling has improved diagnosis and understanding of disease pathogenesis of adult tuberculosis (TB), no studies applying gene expression profiling of children with TB have been described so far. In this study, we have compared whole blood gene expression in childhood TB patients, as well as in healthy latently infected (LTBI) and uninfected (HC) children in a cohort of Warao Amerindians in the Delta Amacuro in Venezuela. We identified a 116-gene signature set by means of random forest analysis that showed an average prediction error of 11% for TB vs. LTBI and for TB vs. LTBI vs. HC in our dataset. Furthermore, a minimal set of only 9 genes showed a significant predictive value for all previously published adult studies using whole blood gene expression, with average prediction errors between 17% and 23%. Additionally, a minimal gene set of 42 genes with a comparable predictive value to the 116-gene set in both our dataset and the previously published literature cohorts for the comparsion of TB vs. LTBI vs. HC was identified. In order to identify a robust representative gene set that would hold stand among different ethnic populations, we selected ten genes that were highly discriminative between TB, LTBI and HC in all literature datasets as well as in our dataset. Functional annotation of these ten genes highlights a possible role for genes involved in calcium signaling and calcium metabolism as biomarkers for active TB. These ten genes were validated by quantitative real-time polymerase chain reaction in an additional cohort of 54 Warao Amerindian children with LTBI, HC and non-TB pneumonia. Decision tree analysis indicated that five of the ten genes were sufficient to diagnose 78% of the TB cases correctly with 100% specificity. We conclude that our data justify the further exploration of our signature set as biomarkers to diagnose childhood TB. Furthermore, as the identification of different biomarkers in ethnically distinct cohorts is apparent, it is important to cross-validate newly identified markers in all available cohorts. In this study, 27 children 1 to 15 years of age with TB (n=9), LTBI (n=9) and HC (n=9) were recruited between May 2010 and December 2010. Tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube assay (QFT-GIT) were performed on all children. A sputum sample was collected from all children with expectoration and a gastric aspirate was taken from all children under 6 years of age. Children with active TB were diagnosed based on culture of M. tuberculosis (n=2) or on the basis of clinical, epidemiological and radiological features (n=7). The latter group were children with a TST = 10 mm or a positive QFT-GIT result who presented all of: persistent fever >38M-BM-0C objectively recorded daily for at least two weeks, persistent cough for more than three weeks, weight loss (>5% reduction in weight compared with the highest weight recorded in last three months) or failure to thrive (documented crossing of percentile lines in the preceding three months), persistent lethargy or decrease in playfulness/activity reported by the parent and absence of clinical response on broad-spectrum antibiotics. Standard antero-posterior and lateral chest radiographs (CXRs) were taken from all children. Two independent experts, blinded to all clinical information, evaluated the CXRs and documented their findings on a standard report form. Where the two objective experts disagreed, a third expert was consulted and final consensus was achieved. A diagnosis of TB was only made when the CXR was consistent with TB9 and the child showed a positive clinical response to anti-TB treatment. Children were followed up clinically, radiologically and, in case of a negative TST at inclusion, by means of TST at six and 12 months after inclusion. LTBI was defined as a TST = 10mm and a positive QFT-GIT with a negative culture result on inclusion in the absence of radiological and clinical evidence of TB disease on inclusion as well as on t=6 and t=12 months. HC were children with a TST = 0 mm at inclusion and at t=6 and t=12 months. The HC had a negative QFT-GIT and a negative culture result at inclusion without radiological or clinical evidence of TB disease on inclusion nor on t=6 and t=12 months. TB patients were sampled before initiation of anti-TB treatment. Of three of the nine TB patients, a follow-up sample was taken when the patient was in anti-TB treatment for five months. All children were HIV-negative. 27 samples in total where analyzed, active TB infection (TB, n=9), Latent TB infection (LTBI, n=9) and healthy controls (HC, n=9) . Gene expression values were log2-transformed and differentially expressed genes were identified based on log2 fold changes (M-values). P values were calculated with a Bayes-regularized one-way ANOVA. Random Forest recursive feature elimination was used to find a signature geneset capable of discrimination active TB from latent TB and from non-infected individuals.
2013-02-05 | E-GEOD-41055 | biostudies-arrayexpress
Project description:Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines and was initially described as an IFN-?-inducing factor derived from anti-CD3-stimulated T-helper (Th)1 cells. IL-18 plays a significant role in the activation of hematopoietic cell types mediating both Th1 and Th2 responses and is the primary inducer of interferon-? in these cells. The biological activity of IL-18 is mediated through its binding to the IL-18 receptor complex and activation of nuclear factor-?B (NF-?B), culminating in the production and release of several cytokines, chemokines, and cellular adhesion molecules. In certain cell types, IL-18 also activates mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase/ AKT serine/threonine kinase (PI3K/AKT) signaling modules leading to the production and release of proinflammatory cytokines. IL-18-mediated signaling acts as one of the vital components of the immunomodulatory cytokine networks involved in host defense, inflammation, and tissue regeneration. Albeit its biomedical importance, a comprehensive resource of IL-18 mediated signaling pathway is currently lacking. In this study, we report on the development of an integrated pathway map of IL-18/IL-18R signaling. The pathway map was developed through literature mining from published literature based on manual curation guidelines adapted from NetPath and includes information on 16 protein-protein interaction events, 38 enzyme-catalysis events, 12 protein translocation events, 26 activations/inhibition events, transcriptional regulators, 230 gene regulation events and 84 induced protein expression events. The IL-18 signaling pathway can be freely accessed through the WikiPathways database (https://www.wikipathways.org/index.php/Pathway:WP4754).
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