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Summary: Alteration in the frequency of monocyte subsets is a hallmark of tuberculosis–diabetes co‐morbidity (TB‐DM). To study this association, we examined the plasma levels of sCD14, sCD163, C‐reactive protein (CRP) and soluble tissue factor (sTF) in individuals with TB‐DM, TB or diabetes mellitus (DM), and in healthy controls (HC). Circulating levels of sCD14, sCD163 and sTF were significantly increased in TB‐DM and DM compared with TB and HC; however, CRP was significantly increased in TB‐DM and TB compared with DM and HC. During longitudinal follow up, sCD14, CRP and sTF levels remained significantly increased in TB‐DM compared with TB from baseline (pre‐treatment), during treatment (2nd month) and at the completion (6th month) of anti‐TB treatment (ATT), whereas sCD163 was significantly higher in TB‐DM compared with TB only at baseline. Moreover, the levels of sCD14 and sCD163 were significantly higher in TB‐DM individuals with bilateral and cavitary disease and exhibited a significant positive relationship with bacterial burden. Levels of sCD14, sCD163 and CRP exhibited a positive relationship with HbA1c levels. Within the TB‐DM group, those with known diabetes before incident TB (KDM) exhibited significantly higher levels of sCD14 and sCD163 compared with individuals with newly diagnosed DM with TB (NDM). Finally, KDM individuals on metformin treatment exhibited significantly lower levels of sCD14, sCD163 and CRP compared with those on non‐metformin‐containing regimens. Our data demonstrate that systemic monocyte activation marker levels reflect baseline disease severity and extent in TB‐DM, differentiate KDM from NDM and are modulated by ATT and metformin therapy. Our data demonstrate that systemic monocyte activation marker levels reflect baseline disease severity and extent in TB with diabetes, differentiate known DM from new DM and are modulated by anti‐TB treatment and metformin therapy. [ABSTRACT FROM AUTHOR]

Perturbations in CD4+ and CD8+ T-cell phenotype and function are hallmarks of tuberculosis-diabetes co-morbidity. However, their contribution to the pathogenesis of this co-morbidity and the effect of anti-tuberculosis treatment on the phenotype of the T-cell subsets is poorly understood. In this study, we examined the frequency of different T-cell subsets in individuals with pulmonary tuberculosis (PTB) with diabetes mellitus (DM) or without coincident diabetes mellitus (NDM) before, during and after completion of anti-tuberculosis chemotherapy. PTB-DM is characterized by heightened frequencies of central memory CD4+ and CD8+ T cells and diminished frequencies of naive, effector memory and/or effector CD4+ and CD8+ T cells at baseline and after 2 months of treatment but not following treatment completion in comparison with PTB-NDM. Central memory CD4+ and CD8+ T-cell frequencies exhibited a positive correlation with fasting blood glucose and glycated haemoglobin A1c levels, whereas the frequencies of naive and effector memory or effector CD4+ and CD8+ T cells exhibited a negative correlation. However, the frequencies of CD4+ and CD8+ T-cell subsets in individuals with PTB exhibited no significant relationship with bacterial burdens. Finally, although minor alterations in the T-cell subset compartment were observed at 2 months of treatment, significantly decreased frequencies of central memory and significantly enhanced frequencies of naive CD4+ and CD8+ T cells were observed at the completion of treatment. Our data reveal a profound effect of coexistent diabetes on the altered frequencies of central memory, effector memory and naive T cells and its normalization following therapy. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (DM) is a risk factor for the development of active tuberculosis (TB), although its role in the TB-induced responses in latent TB (LTB) is not well understood. Since Th1, Th2, and Th17 responses are important in immunity to LTB, we postulated that coincident DM could alter the function of these CD4+ T-cell subsets. To this end, we examined mycobacteria-induced immune responses in the whole blood of individuals with LTB-DM and compared them with responses of individuals without DM (LTB-NDM). T-cell responses from LTB-DM are characterized by diminished frequencies of mono- and dual-functional CD4+ Th1, Th2, and Th17 cells at baseline and following stimulation with mycobacterial antigens-purified protein derivative, early secreted antigen-6, and culture filtrate protein-10. This modulation was at least partially dependent on IL-10 and TGF-β, since neutralization of either cytokine resulted in significantly increased frequencies of Th1 and Th2 cells but not Th17 cells in LTB-DM but not LTB individuals. LTB-DM is therefore characterized by diminished frequencies of Th1, Th2, and Th17 cells, indicating that DM alters the immune response in latent TB leading to a suboptimal induction of protective CD4+ T-cell responses, thereby providing a potential mechanism for increased susceptibility to active disease. [ABSTRACT FROM AUTHOR]

The immune system plays an important role in the pathogenesis of pulmonary tuberculosis-type 2 diabetes mellitus ( PTB- DM) co-morbidity. However, the phenotypic profile of leucocyte subsets at homeostasis in individuals with active or latent tuberculosis ( LTB) with coincident diabetes is not known. To characterize the influence of diabetes on leucocyte phenotypes in PTB or LTB, we examined the frequency ( Fo) of leucocyte subsets in individuals with TB with ( PTB- DM) or without ( PTB) diabetes; individuals with latent TB with ( LTB- DM) or without ( LTB) diabetes and non- TB-infected individuals with ( NTB- DM) or without ( NTB) diabetes. Coincident DM is characterized by significantly lower Fo of effector memory CD4+ T cells in LTB individuals. In contrast, DM is characterized by significantly lower Fo of effector memory CD8+ T cells and significantly higher Fo of central memory CD8+ T cells in PTB individuals. Coincident DM resulted in significantly higher Fo of classical memory B cells in PTB and significantly higher Fo of activated memory and atypical B cells in LTB individuals. Coincident DM resulted in significantly lower Fo of classical and intermediate monocytes in PTB, LTB and NTB individuals. Finally, DM resulted in significantly lower Fo of myeloid and plasmacytoid dendritic cells in PTB, LTB and NTB individuals. Our data reveal that coincident diabetes alters the cellular subset distribution of T cells, B cells, dendritic cells and monocytes in both individuals with active TB and those with latent TB, thus potentially impacting the pathogenesis of this co-morbid condition. [ABSTRACT FROM AUTHOR]

CD4+ T cell expression of IL-10 is an important mechanism controlling immunity to tuberculosis (TB). To identify the CD4+ T cell subsets producing IL-10 in human TB, we enumerated the frequencies of IL-10 expressing CD4+ T cell subsets following TB-antigen stimulation of cells from individuals with pulmonary (PTB) and latent TB (LTB). We first demonstrate that TB antigens induce an expansion of IL-10 expressing Th1 (IL-10+, IFNγ+, T-bet+), Th2 (IL-10+, IL-4+, GATA-3+), Th9 (IL-10+, IL-9+, IL-4−), Th17 (IL-10+, IL-17+, IFNγ−), and natural and adaptive regulatory T cells [nTregs; IL-10+, CD4+, CD25+, Foxp3+ and aTregs; IL-10 single+, CD4+, CD25−, Foxp3−] in PTB and LTB individuals, with frequencies being significantly higher in the former. However, only Th1 cells and adaptive Tregs expressing IL-10 exhibit a positive relationship with bacterial burdens and extent of disease in PTB. Finally, we show that IL-27 and TGFβ play an important role in the regulation of IL-10+ Th cell subsets. Thus, active PTB is characterized by an IL-27 and TGFβ mediated expansion of IL-10 expressing CD4+ T cell subsets, with IL-10+ Th1 and IL-10+ aTreg cells playing a potentially pivotal role in the pathogenesis of active disease. [ABSTRACT FROM AUTHOR]