Abstract
New biomarkers are needed for discriminating active tuberculosis (TB) from latent TB infection (LTBI), especially in vulnerable groups representing the major diagnostic challenge. This pilot study was carried out to explore the diagnostic potential of selected genes, IFN-γ, IL-17, IL-4, and FoxP3, associated with TB immunity and immunopathology. IFN-γ, IL-17, IL-4, and FoxP3 mRNA expression levels were measured by quantitative reverse transcription PCR (RT-qPCR) from antigen-stimulated peripheral blood mononuclear cells of patients with active TB (n = 25); patients with miscellaneous inflammatory disorders and concomitant LTBI (n = 20), rheumatoid arthritis (RA) being the most predominant in the group (n = 11); and in healthy Bacillus Calmette–Guérin (BCG) vaccinees (n = 8). While the levels of FoxP3 mRNA did not differ between the tested groups, the cumulative expression levels of purified protein derivative-stimulated IFN-γ, IL-17, and IL-4 mRNAs were found to distinguish active TB from the whole group of LTBI with 48% sensitivity and 85% specificity. When restricting the LTBI group to RA cases only, the sensitivity was 56% and specificity 100%. When interpreting the result as positive in at least one of the mRNAs IFN-γ, IL-17, or IL-4, sensitivity of 64% and specificities of 75% (heterogeneous group of LTBI) or 100% (LTBI with RA) were achieved. Moderate discrimination of active TB from LTBI with miscellaneous inflammatory underlying conditions by using combined quantitative expression of IFN-γ, IL-17, and IL-4 mRNA seems not to be of high diagnostic potential.
Highlights
T cell-mediated immunity through the Th1-arm of the immunologic system serves an important function in controlling tuberculosis (TB)
culture filtrate protein 10 (CFP-10) and ESAT-6 Peptide Pools As Gene Expression Stimulators mRNA expression levels of IFN-γ, IL-17, IL-4, and forkhead box P3 (FoxP3) were analyzed after stimulation with a pool of peptides derived from CFP-10 and ESAT-6
Peptides stimulated IFN-γ and IL-4 mRNA expression, but difference was not observed between the medians of the IFN-γ expression in the TB and the latent TB infection (LTBI) groups (Figure 1)
Summary
T cell-mediated immunity through the Th1-arm of the immunologic system serves an important function in controlling tuberculosis (TB). Almost everyone infected with Mycobacterium tuberculosis (Mtb) produces IFN-γ and TNF-α, yet these cytokines cannot confer protection against clinical disease [1]. T cell-based IFN-γ release assays (IGRAs) developed a decade ago are the first diagnostic tests conceived after the century-old tuberculin skin test for identification of contact with Mtb [2]. [3] From the diagnostic point of view, patients with miscellaneous inflammatory musculoskeletal disorders responding poorly to conventional therapy present a great diagnostic challenge. In these patients, LTBI should be excluded before the commencement of the so-called biological therapy with, e.g., TNF-α blockers, due to the risk of TB reactivation [4]
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