Abstract
Objectives: One third of the world population is considered latently infected with Mycobacterium tuberculosis (LTBI) and sterilizing this reservoir of bacteria that may reactivate is required for tuberculosis (TB) elimination. The group of individuals with LTBI is heterogeneous with some of them being more at risk to develop TB disease than others. Improved diagnosis of subjects with LTBI is needed, allowing to differentiate subjects with LTBI from those with active TB, and to select among LTBI subjects those who are more at risk to develop active TB. We have characterized at the cellular level both the quantitative and qualitative T cell responses to different mycobacterial antigens in selected populations of infected subjects in order to identify new biomarkers that could help to identify M. tuberculosis-infected subjects and to stratify them in risk groups for reactivation of the infection. Methods: lymphoblast frequencies and cytokine production (IFN-γ, TNF-α, IL-2) among CD4+ and CD8+ T cells were analyzed by flow cytometry after in vitro stimulation with the latency antigen heparin-binding haemagglutinin (HBHA) or early-secreted antigen Target-6 (ESAT-6) of peripheral blood mononuclear cells from clinically well characterized M. tuberculosis-infected humans (28 LTBI, 22 TB disease,12 controls). The LTBI group defined according to the Center for Disease Control guidelines was subdivided into QuantiFERON-TB Gold in-Tube (QFT) positive and negative subgroups. Results: similar to TB patients, QFT+ LTBI subjects had higher proportions of HBHA-induced TNF-αsingle+ CD4+ lymphocytes than QFT- LTBI subjects (p<0.05). Compared to LTBI subjects, TB patients had higher frequencies of ESAT-6-induced CD8+ lymphoblasts (p<0.001), higher proportions of ESAT-6-induced IFN-γ+TNF-α+ CD4+ T lymphocytes (p<0.05), and lower proportions of HBHA-induced IFN-γ+TNF-α+IL-2+ (p<0.05) CD4+ T lymphocytes. Conclusions: these data provide new biomarkers to discriminate active TB from LTBI, and more interestingly, help to identify LTBI subjects with increased likelihood to develop TB disease.
Highlights
Tuberculosis (TB) remains a major global health problem being the second leading cause of death from infection, after human immunodeficiency virus infection [1]
We extend the characterization of the immune responses of the subgroups of subjects with latently infected with Mycobacterium tuberculosis (LTBI) previously defined by combining the IFN-γ responses to heparin-binding haemagglutinin (HBHA) and to early-secreted antigen Target-6 (ESAT-6), to a more profound quantitative and qualitative analysis at the cellular level of the T cell responses
The frequency of HBHA-induced lymphoblasts among CD4+ T cells was significantly higher for LTBI subjects and TB patients than for non-infected controls (p ≤ 0.01), but no significant differences were noted between LTBI subjects and TB patients (Figure 1A)
Summary
Tuberculosis (TB) remains a major global health problem being the second leading cause of death from infection, after human immunodeficiency virus infection [1]. Most latently TB infected (LTBI) subjects control the infection thanks to appropriate immune responses, and they do not develop any sign of disease These LTBI subjects have a lifetime risk of about 10% to reactivate their infection, leading to progression to TB disease, this risk being higher in different clinical conditions associated with immune deficiency [2,3]. Despite being asymptomatic, these subjects constitute an enormous reservoir of M. tuberculosis and TB elimination requires focus on sterilizing the pool of LTBI individuals [4,5]. The WHO recommends systematic screening of contacts of TB patients and high-risk groups in
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