scholarly journals Multidimensional analysis of immune responses identified biomarkers of recent Mycobacterium tuberculosis infection

2021 ◽  
Vol 17 (7) ◽  
pp. e1009197
Author(s):  
Tessa Lloyd ◽  
Pia Steigler ◽  
Cheleka A. M. Mpande ◽  
Virginie Rozot ◽  
Boitumelo Mosito ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell Activation ◽  
Missing Values ◽  
Multidimensional Analysis ◽  
Receiver Operating Curve ◽  
Tuning Parameter ◽  
Ratio Test ◽  
Model Average ◽  
Remote Infection ◽  
Biomarker Analysis

The risk of tuberculosis (TB) disease is higher in individuals with recent Mycobacterium tuberculosis (M.tb) infection compared to individuals with more remote, established infection. We aimed to define blood-based biomarkers to distinguish between recent and remote infection, which would allow targeting of recently infected individuals for preventive TB treatment. We hypothesized that integration of multiple immune measurements would outperform the diagnostic performance of a single biomarker. Analysis was performed on different components of the immune system, including adaptive and innate responses to mycobacteria, measured on recently and remotely M.tb infected adolescents. The datasets were standardized using variance stabilizing scaling and missing values were imputed using a multiple factor analysis-based approach. For data integration, we compared the performance of a Multiple Tuning Parameter Elastic Net (MTP-EN) to a standard EN model, which was built to the individual adaptive and innate datasets. Biomarkers with non-zero coefficients from the optimal single data EN models were then isolated to build logistic regression models. A decision tree and random forest model were used for statistical confirmation. We found no difference in the predictive performances of the optimal MTP-EN model and the EN model [average area under the receiver operating curve (AUROC) = 0.93]. EN models built to the integrated dataset and the adaptive dataset yielded identically high AUROC values (average AUROC = 0.91), while the innate data EN model performed poorly (average AUROC = 0.62). Results also indicated that integration of adaptive and innate biomarkers did not outperform the adaptive biomarkers alone (Likelihood Ratio Test χ2 = 6.09, p = 0.808). From a total of 193 variables, the level of HLA-DR on ESAT6/CFP10-specific Th1 cytokine-expressing CD4 cells was the strongest biomarker for recent M.tb infection. The discriminatory ability of this variable was confirmed in both tree-based models. A single biomarker measuring M.tb-specific T cell activation yielded excellent diagnostic potential to distinguish between recent and remote M.tb infection.

scholarly journals Multidimensional analysis of immune response identified biomarkers of recent Mycobacterium tuberculosis infection

2021 ◽  
Author(s):  
Tessa Lloyd ◽  
Pia Steigler ◽  
Cheleka A.M. Mpande ◽  
Virginie Rozot ◽  
Boitumelo Mosito ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell Activation ◽  
Missing Values ◽  
Multidimensional Analysis ◽  
Receiver Operating Curve ◽  
Tuning Parameter ◽  
Ratio Test ◽  
Model Average ◽  
Remote Infection ◽  
Biomarker Analysis

AbstractThe risk of tuberculosis (TB) disease is higher in individuals with recent Mycobacterium tuberculosis (M.tb) infection compared to individuals with more remote, established infection. We aimed to define blood-based biomarkers to distinguish between recent and remote infection, which would allow targeting of recently infected individuals for preventive TB treatment. We hypothesized that integration of multiple immune measurements would outperform the diagnostic performance of a single biomarker. Analysis was performed on different components of the immune system, including adaptive and innate responses to my-cobacteria, measured on recently and remotely M.tb infected adolescents. The datasets were standardized using variance stabilizing (vast) scaling and missing values were imputed using a multiple factor analysis-based approach. For data integration, we compared the performance of a Multiple Tuning Parameter Elastic Net (MTP-EN) to a standard EN model, which was built to the single datasets. Biomarkers with non-zero coefficients from the optimal single data EN models were then isolated to build logistic regression models. A decision tree and random forest model were used for statistical validation. We found no difference in the predictive performances of the optimal MTP-EN model and the EN model [average area under the receiver operating curve (AUROC)=0.93]. EN models built to the integrated dataset and the adaptive dataset yielded identically high AUROC values (average AUROC=0.91), while the innate data EN model performed poorly (average AUROC=0.62). Results also indicated that integration of adaptive and innate biomarkers did not outperform the adaptive biomarkers alone (Likelihood Ratio Test χ2=6.09, p=0.808). From a total of 193 variables, the level of HLA-DR on ESAT6/CFP10-specific Th1 cytokine-expressing CD4 cells was the strongest biomarker for recent M.tb infection. The discriminatory ability of this variable was confirmed in both tree-based models.A single biomarker measuring M.tb-specific T cell activation yielded excellent diagnostic potential to distinguish between recent and remote M.tb infection.

scholarly journals Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection

2020 ◽  
Author(s):  
Cheleka A.M. Mpande ◽  
Virginie Rozot ◽  
Boitumelo Mosito ◽  
Munyaradzi Musvosvi ◽  
One B Dintwe ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Differentially Expressed ◽  
Cd4 T Cell ◽  
Remote Infection ◽  
Ifn Γ

AbstractBackgroundRecent Mycobacterium tuberculosis (M.tb) infection is associated with a higher risk of progression to tuberculosis disease, compared to persistent infection after remote exposure. However, current immunodiagnostic tools fail to distinguish between recent and remote infection. We aimed to characterise the immunobiology associated with acquisition of M.tb infection and identify a biomarker that can distinguish recent from remote infection.MethodsHealthy South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 months) and persistent (QuantiFERON-TB+ for >1.5 year) infection. We characterized M.tb-specific CD4 T cell functional (IFN-γ, TNF, IL-2, CD107, CD154), memory (CD45RA, CCR7, CD27, KLRG-1) and activation (HLA-DR) profiles by flow cytometry after CFP-10/ESAT-6 peptide pool or M.tb lysate stimulation. We then assessed the diagnostic performance of immune profiles that were differentially expressed between individuals with recent or persistent QuantiFERON-TB+.FindingsCFP-10/ESAT-6-specific CD4 T cell activation but not functional or memory phenotypes distinguished between individuals with recent and persistent QuantiFERON-TB+. In response to M.tb lysate, recent QuantiFERON-TB+ individuals had lower proportions of highly differentiated IFN-γ+TNF+ CD4 T cells expressing a KLRG-1+ effector phenotype and higher proportions of early differentiated IFN-γ-TNF+IL-2+ and activated CD4 T cells compared to persistent QuantiFERON-TB+ individuals. Among all differentially expressed T cell features CFP-10/ESAT-6-specific CD4 T cell activation was the best performing diagnostic biomarker of recent infection.InterpretationRecent M.tb infection is associated with highly activated and moderately differentiated functional M.tb-specific T cell subsets, that can be used as biomarkers to distinguish between recent and remote infection.

scholarly journals A POWERFUL TEST OF THE AUTOREGRESSIVE UNIT ROOT HYPOTHESIS BASED ON A TUNING PARAMETER FREE STATISTIC

2009 ◽  
Vol 25 (6) ◽  
pp. 1515-1544 ◽  
Author(s):  
Morten Ørregaard Nielsen
Keyword(s):  
Asymptotic Distribution ◽  
Unit Root ◽  
Linear Time ◽  
Nonparametric Test ◽  
Tuning Parameter ◽  
Ratio Test ◽  
Local Power ◽  
Finite Sample ◽  
Power Of The Test ◽  
The Family

This paper presents a family of simple nonparametric unit root tests indexed by one parameter,d, and containing the Breitung (2002,Journal of Econometrics108, 342–363) test as the special cased= 1. It is shown that (a) each member of the family withd> 0 is consistent, (b) the asymptotic distribution depends ondand thus reflects the parameter chosen to implement the test, and (c) because the asymptotic distribution depends ondand the test remains consistent for alld> 0, it is possible to analyze the power of the test for different values ofd. The usual Phillips–Perron and Dickey–Fuller type tests are indexed by bandwidth, lag length, etc., but have none of these three properties.It is shown that members of the family withd< 1 have higher asymptotic local power than the Breitung (2002) test, and whendis small the asymptotic local power of the proposed nonparametric test is relatively close to the parametric power envelope, particularly in the case with a linear time trend. Furthermore, generalized least squares (GLS) detrending is shown to improve power whendis small, which is not the case for the Breitung (2002) test. Simulations demonstrate that when applying a sieve bootstrap procedure, the proposed variance ratio test has very good size properties, with finite-sample power that is higher than that of the Breitung (2002) test and even rivals the (nearly) optimal parametric GLS detrended augmented Dickey–Fuller test with lag length chosen by an information criterion.

scholarly journals Interleukin 12 (IL-12) Is Crucial to the Development of Protective Immunity in Mice Intravenously Infected with Mycobacterium tuberculosis

1997 ◽  
Vol 186 (1) ◽  
pp. 39-45 ◽  
Author(s):  
Andrea M. Cooper ◽  
Jeanne Magram ◽  
Jessica Ferrante ◽  
Ian M. Orme
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
T Cell Activation ◽  
Bacterial Growth ◽  
Cell Activation ◽  
Interferon Γ ◽  
Delayed Type Hypersensitivity ◽  
Interleukin 12 ◽  
Mycobacterium Tuberculosis Infection ◽  
Ifn Γ

Immunity to Mycobacterium tuberculosis infection is associated with the emergence of protective CD4 T cells that secrete cytokines, resulting in activation of macrophages and the recruitment of monocytes to initiate granuloma formation. The cytokine-mediating macrophage activation is interferon-γ (IFN-γ), which is largely dependent on interleukin-12 (IL-12) for its induction. To address the role of IL-12 in immunity to tuberculosis, IL-12 p40−/− mice were infected with M. tuberculosis and their capacity to control bacterial growth and other characteristics of their immune response were determined. The IL-12 p40−/− mice were unable to control bacterial growth and this appeared to be linked to the absence of both innate and acquired sources of IFN-γ. T cell activation as measured by delayed type hypersensitivity and lymphocyte accumulation at the site of infection were both markedly reduced in the IL-12 p40−/− mice. Therefore, IL-12 is essential to the generation of a protective immune response to M. tuberculosis, with its main functions being the induction of the expression of IFN-γ and the activation of antigen-specific lymphocytes capable of creating a protective granuloma.

scholarly journals Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs

2007 ◽  
Vol 205 (1) ◽  
pp. 105-115 ◽  
Author(s):  
Andrea J. Wolf ◽  
Ludovic Desvignes ◽  
Beth Linas ◽  
Niaz Banaiee ◽  
Toshiki Tamura ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Lymph Node ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Adaptive Immune Response ◽  
Adaptive Immune ◽  
Initial Activation ◽  
Local Lymph Node

The onset of the adaptive immune response to Mycobacterium tuberculosis is delayed compared with that of other infections or immunization, and allows the bacterial population in the lungs to expand markedly during the preimmune phase of infection. We used adoptive transfer of M. tuberculosis Ag85B-specific CD4+ T cells to determine that the delayed adaptive response is caused by a delay in initial activation of CD4+ T cells, which occurs earliest in the local lung-draining mediastinal lymph node. We also found that initial activation of Ag85B-specific T cells depends on production of antigen by bacteria in the lymph node, despite the presence of 100-fold more bacteria in the lungs. Although dendritic cells have been found to transport M. tuberculosis from the lungs to the local lymph node, airway administration of LPS did not accelerate transport of bacteria to the lymph node and did not accelerate activation of Ag85B-specific T cells. These results indicate that delayed initial activation of CD4+ T cells in tuberculosis is caused by the presence of the bacteria in a compartment that cannot be mobilized from the lungs to the lymph node, where initial T cell activation occurs.

Neoadjuvant ipilimumab in locally/regionally advanced melanoma: Clinical outcome and biomarker analysis.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 76-76 ◽  
Author(s):  
Ahmad A. Tarhini ◽  
Howard Edington ◽  
Lisa H. Butterfield ◽  
Yongli Shuai ◽  
Yan Lin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Clinical Outcome ◽  
T Cell Activation ◽  
Stage Iiib ◽  
Clinical Activity ◽  
Baseline Serum ◽  
Cell Immunity ◽  
Biomarker Analysis ◽  
Grade 3

76 Background: Neoadjuvant ipilimumab (Ipi) for stage IIIB-C melanoma may improve the clinical outcome and provide access to pre/post Ipi blood. Methods: Pts were treated with Ipi (10mg/kg IV q3wks x 2 doses) bracketing definitive surgery. Tissue samples were obtained at baseline and at surgery (wk ≥ 6) and serum/PBMC collected at baseline, 6 wks, 3, 6, 9, 12 mos and/or progression. Flow cytometry was used to monitor the host immune response in blood and evaluable tumor. IHC for select markers was also performed. Baseline and wk-6 serum cytokines were tested by xMAP multiplex technology (Luminex Corp). Results: 31 pts were enrolled, 6 had stage IIIB (N2b, N2c), and 25 IIIC (N3) melanoma. Worst toxicities (N=31 pts) included grade 3 diarrhea/colitis (5 pts; 16%), hepatitis (2; 6%), rash (1; 3%), lipase (2; 6%), all manageable. Median f/u was 19 mos: among 29 evaluable pts, median PFS was 12.9 mos, 95% CI = (7.4,-). Only 2 pts died. Peripherally, a significant increase in circulating T-regs (CD4+CD25hi+ Foxp3+; p=0.02 CD4+CD25hi+CD39+; p=0.001) from baseline to 6 wks was observed. Significant decreases in circulating MDSCs, were observed in monocytic HLA-DR+/low/CD14+ MDSC (p<0.0001). Greater increases in T-regs were associated with improved PFS (p=0.034; HR=0.57). Spontaneous in vivo cross-presentation was observed resulting in Th1CD4+ and CD8+ antigen specific T-cell immunity (gp-100, MART-1, NY-ESO-1 peptides). Significant fold increase (3-10-fold) in CD3+/CD4+/INF-γ+ antigen specific T cells was seen only in pts who were progression free at 6 mos. Baseline serum IL-17 correlates with grade 3 diarrhea (p=0.02). In tumor, Tregs appeared higher at wk 6 in PD group while the opposite in clinical benefit group (p=0.09). In tumor, Ipi induced TIL T-cell activation as evidenced by CD69 in the absence of other in vitro stimulation and induced T cell memory (CD45RO+) and not naïve (CD45RO-). By IHC, there was significant increase in CD8+ TIL after ipilimumab (p=0.02). Conclusions: Neoadjuvant ipi exhibited promising clinical activity and significantly modulated the host effector and suppressor immune response. Functional studies and prediction modeling analyses of biomarker findings are ongoing.

scholarly journals Binary Logistic Model to Identify the Factors Associated with Households with Bank Accounts in Nepal

2020 ◽  
Vol 2 (2) ◽  
pp. 323-336
Author(s):  
Santosh Kumar Shah
Keyword(s):  
Logistic Regression ◽  
Financial Institutions ◽  
Goodness Of Fit ◽  
Receiver Operating Curve ◽  
P Value ◽  
Ratio Test ◽  
Multiple Logistic Regression ◽  
Goodness Of Fit Test ◽  
Factors Associated ◽  
Bank Accounts

Introduction: Banks play an important role in ensuringthe economicand social stability, and the sustainablegrowth of the economy. The savings and other accounts in financial institutions, including banks, finances, microfinances and cooperatives, enable people to execute important financial functions. Thus, households that have accounts in any of financial institutions can have access to various banking services. Objective: The objective of the study is to identify the factors associated with households having bank accounts in Nepal. Methods: The analysis is based on household data extracted from the dataset of Nepal Demographic and Health Survey, 2016. The dependent variable is dichotomous, as the households with bank accounts and without bank accounts in any formal financial channels. In order to identify the factors associated with households receiving financial services in Nepal, multiple logistic regression models were developed by examining the model adequacy test. Results: The study finds that a total of 66.9% of the households had bank accounts. Several variables were found to be 1% of significance level. The predictive power of the model is found to be 31.2% and multicollinearity among the independent variables was absent. The Hosmer-Lemoshow goodness of fit test revealed that the data were poorly (p-value=0.056) fitted by the model. However, Osius-Rojek goodness of fit test (z=0.11; p-value=0.911), Stukel test (Z=0.683, p-value=0.494), likelihood ratio test (χ2=2770; p-value<0.0001) and area under receiver operating curve (79.8%) revealed that fitted model was good. Conclusion: Multiple logistic regression model revealed that in mountainous and hilly regions, women-headed households have less chances of not having bank accounts compared to the Terai region and men-headed households. The chances of having a bank account in province-2 is even worse than in Karnali and other provinces. The odds of not having bank accounts gradually decreased with the increase in size of agricultural land, wealth index, increase in family size and the number of family members who have completed secondary education.

Immunogenic membrane-associated proteins of Mycobacterium tuberculosis revealed by proteomics

Microbiology ◽  
2005 ◽  
Vol 151 (7) ◽  
pp. 2411-2419 ◽  
Author(s):  
Sudhir Sinha ◽  
K. Kosalai ◽  
Shalini Arora ◽  
Abdelkader Namane ◽  
Pawan Sharma ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
T Cell Activation ◽  
Gel Electrophoresis ◽  
Ribosomal Proteins ◽  
Cell Activation ◽  
Flight Mass Spectrometry ◽  
Peptide Mass ◽  
Mass Fractions ◽  
Associated Proteins

Membrane-associated proteins of Mycobacterium tuberculosis offer a challenge, as well as an opportunity, in the quest for better therapeutic and prophylactic interventions against tuberculosis. The authors have previously reported that extraction with the detergent Triton X-114 (TX-114) is a useful step in proteomic analysis of mycobacterial cell membranes, and detergent-soluble membrane proteins of mycobacteria are potent stimulators of human T cells. In this study 1-D and 2-D gel electrophoresis-based protocols were used for the analysis of proteins in the TX-114 extract of M. tuberculosis membranes. Peptide mass mapping (using MALDI-TOF-MS, matrix assisted laser desorption/ionization time of flight mass spectrometry) of 116 samples led to the identification of 105 proteins, 9 of which were new to the M. tuberculosis proteome. Functional orthologues of 73 of these proteins were also present in Mycobacterium leprae, suggesting their relative importance. Bioinformatics predicted that as many as 73 % of the proteins had a hydrophobic disposition. 1-D gel electrophoresis revealed more hydrophobic/transmembrane and basic proteins than 2-D gel electrophoresis. Identified proteins fell into the following major categories: protein synthesis, cell wall biogenesis/architecture and conserved hypotheticals/unknowns. To identify immunodominant proteins of the detergent phase (DP), 14 low-molecular-mass fractions prepared by continuous-elution gel electrophoresis were subjected to T cell activation assays using blood samples from BCG-vaccinated healthy donors from a tuberculosis endemic area. Analysis of the responses (cell proliferation and IFN-γ production) showed that the immunodominance of certain DP fractions was most probably due to ribosomal proteins, which is consistent with both their specificity for mycobacteria and their abundance. Other membrane-associated proteins, including transmembrane proteins/lipoproteins and ESAT-6, did not appear to contribute significantly to the observed T cell responses.

Sign in / Sign up

Export Citation Format

Share Document