Th1 CD41 T cells and their derived cytokines are crucial for protection against Mycobacterium tuberculosis. Using multiparametric flow cytometry, we have evaluated the distribution of seven distinct functional states (IFN-c/IL-2/TNF-a triple expressors, IFN-c/IL-2, IFN-c/TNF-a or TNF-a/IL-2 double expressors or IFN-c, IL-2 or TNF-a single expressors) of CD4 1 T cells in individuals with latent M. tuberculosis infection (LTBI) and active tuberculosis (TB). We found that triple expressors, while detectable in 85-90%TB patients, were only present in 10-15% of LTBI subjects. On the contrary, LTBI subjects had significantly higher (12-to 15-fold) proportions of IL-2/IFN-c double and IFN-c single expressors as compared with the other CD4 1 T-cell subsets. Proportions of the other double or single CD4 1 T-cell expressors did not differ between TB and LTBI subjects. These distinct IFN-c, IL-2 and TNF-a profiles of M. tuberculosis-specific CD4 1 T cells seem to be associated with live bacterial loads, as indicated by the decrease in frequency of multifunctional T cells in TB-infected patients after completion of anti-mycobacterial therapy. Our results suggest that phenotypic and functional signatures of CD4 1 T cells may serve as immunological correlates of protection and curative host responses, and be a useful tool to monitor the efficacy of anti-mycobacterial therapy. IntroductionInfections with Mycobacterium tuberculosis (M. tuberculosis) cause a global epidemic with almost 9 million new cases and over 1.6 million deaths per year [1,2]. Outcome of M. tuberculosis infection depends on early identification and proper treatment of individuals with active tuberculosis (TB), but the lack of accurate diagnostic techniques has contributed to the re-emergence of TB as a global health threat. More than 2 billion individuals are estimated to be latently infected with M. tuberculosis (LTBI). To date, however, Ã These authors have contributed equally to this work. There were a number of differences between TB patients and subjects with LTBI following stimulation with ESAT-6, Ag85B and the 16-kDa antigen (Fig. 2). Most notably, and in contrast with the previously reported results in chronic viral infections, we found a significantly higher proportion of 31 CD4 1 T cells simultaneously secreting IFN-g, IL-2 and TNF-a in patients with TB, as compared with LTBI subjects, upon stimulation with any of the three tested M. tuberculosis antigens (Fig. 2). Using a threshold of 0.01% to avoid systematic biases incurred by zeroing negative values (frequency values o0.01% were set to zero), we found that 31 CD4 1 T cells were detectable in very few LTBI subjects (3/18, 3/18 and 2/18 in response to Ag85B, ESAT-6 and 16 kDa, respectively), but were frequently detected in most TB patients (17/20, 18/20 and 17/20, in Eur. J. Immunol. 2010. 40: 2211-2220 Nadia Caccamo et al. 2212& 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu response to Ag85B, ESAT-6 and 16 kDa, respectively; see also Table 1 for comparison).In contrast, ...

Blood test results were associated with exposure, whereas the TST was not. A possible lack of sensitivity of IFN-gamma assays in detecting individuals with TST of 15 mm or greater, despite negative bacillus Calmette-Guérin vaccination status, warrants further investigation into alternative cutoff values.

The authors determined the positive predictive value (PPV) for progression to tuberculosis (TB) of two interferon-c release assays (IGRAs), QuantiFERON-TB1 Gold In-tube (QFT-GIT) and T-SPOT.TB1, and the tuberculin skin test (TST) in immigrants contacts.Immigrant close contacts of sputum smear-positive TB patients were included when aged o16 yrs and their TST result was o5 mm 0 or 3 months after diagnosis of the index patient.Contacts were followed for the next 2 yrs for development of TB disease.Of 339 immigrant contacts with TST o5 mm, 324 and 299 had valid results of QFT-GIT and T-SPOT.TB1, respectively. Nine contacts developed active TB. One patient had not been tested with TST, while another patient had not been tested with QFT-GIT and T-SPOT.TB1. The PPV for progression to TB during this period was 9/28853.1% (95% CI 1.3-5.0%) for TST o10 mm, 7/ 18453.8% (95% CI 1.7-5.9%) for TST o15 mm, 5/17852.8% (95% CI 1.0-4.6%) for QFT-GIT and 6/ 18153.3% (95% CI 1.3-5.3%) for T-SPOT.TB1. Sensitivity was 100%, 88%, 63% and 75%, respectively.The predictive values of QFT-GIT, T-SPOT.TB1 and TST for progression to TB disease among immigrant close contacts were comparable.

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In 2005, a 24-year-old man with Crohn disease who had been treated with infliximab for several months was exposed to an individual with smear-positive tuberculosis. Soon after exposure, he complained of malaise, dry cough, and weight loss. Despite normal chest radiograph findings and negative tuberculin skin test results, tuberculosis was considered to be the most likely diagnosis. The results of a whole-blood assay for detection of interferon- gamma production in response to Mycobacterium tuberculosis-specific antigen were positive. Acid-fast staining and polymerase chain reaction of bronchoalveolar lavage fluid samples had negative results, but M. tuberculosis was cultured. After the initiation of 4 antitubercular drugs and the discontinuation of infliximab therapy, the patient developed an immune reconstitution syndrome accompanied by enlarged mediastinal lymph nodes and multiple intrapulmonary miliary lesions. This case of de novo tuberculosis during anti-tumor necrosis factor alpha treatment illustrates the uncharacteristic presentation of the disease and the elusiveness of the diagnosis, as well as the fact that discontinuation of anti-tumor necrosis factor alpha treatment can be accompanied by an immune reconstitution syndrome similar to that observed in human immunodeficiency virus-infected individuals with tuberculosis.