Kadar Moideen

Coincident diabetes mellitus modulates Th1-, Th2-, and Th17-cell responses in latent tuberculosis in an IL-10- and TGF-β-dependent manner.

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.

Impaired Cytokine but Enhanced Cytotoxic Marker Expression in Mycobacterium tuberculosis–Induced CD8+ T Cells in Individuals With Type 2 Diabetes and Latent Mycobacterium tuberculosis Infection

Type 2 diabetes mellitus (DM) is a risk factor for tuberculosis among individuals with latent Mycobacterium tuberculosis infection. To explore the influence of DM on CD8(+) T-cell responses during latent M. tuberculosis infection, we estimated the cytokine and cytotoxic marker expression pattern in individuals with latent M. tuberculosis infection with DM and those with latent M. tuberculosis infection without DM. Among individuals with latent M. tuberculosis infection, those with DM had diminished frequencies of CD8(+) T-helper type 1 (Th1), Th2, and Th17 cells following stimulation by M. tuberculosis antigen and enhanced frequencies of CD8(+) T cells expressing cytotoxic markers, compared with those without DM. Thus, our results suggest that coincident DM modulates CD8(+) T-cell function during latent M. tuberculosis infection.

Effect of standard tuberculosis treatment on naive, memory and regulatory T cell homeostasis in tuberculosis‐diabetes co‐morbidity

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.

Profiling leucocyte subsets in tuberculosis-diabetes co-morbidity.

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.

IL‐27 and TGFβ mediated expansion of Th1 and adaptive regulatory T cells expressing IL‐10 correlates with bacterial burden and disease severity in pulmonary tuberculosis

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.

Reduced systemic and mycobacterial antigen-stimulated concentrations of IL-1β and IL-18 in tuberculous lymphadenitis

Background Type 1, Type 17 and other pro‐inflammatory cytokines are known to play an important role in resistance to pulmonary tuberculosis. The role of these cytokines in tuberculous lymphadenitis (TBL) is not well characterized. Methods To estimate the systemic and mycobacterial antigen ‐ stimulated cytokine concentrations of Type 1, Type 17, other pro‐inflammatory and regulatory cytokines in TBL, we examined both the systemic and the antigen‐specific concentrations of these cytokines in TBL (n = 31) before and after chemotherapy, and compared them with those with latent tuberculosis infection (LTB, n = 31). Results We observed significantly reduced systemic concentrations of the pro‐inflammatory cytokines ‐ IL‐1&bgr; and IL‐18 but not other Type 1 or Type 17 cytokines in TBL compared to LTB. Following standard anti‐tuberculosis (TB) treatment, we observed a significant increase in the concentrations of both IL‐1&bgr; and IL‐18. In addition, we also observed significantly reduced baseline or mycobacterial ‐ antigen or mitogen stimulated concentrations of IL‐1&bgr; and IL‐18 in TBL individuals. Similar to systemic cytokine concentrations, anti‐TB treatment resulted in significantly increased concentrations of these cytokines following antigen stimulation. Conclusions TBL is therefore, characterized by reduced systemic and antigen‐specific concentrations of IL‐1&bgr; and IL‐18, which are reversible following anti‐TB treatment, indicating that these cytokines are potential correlates of protective immunity in TBL. HighlightsReduced circulating concentrations of IL‐1&bgr; and IL‐18 in tuberculous lymphadenitis.Reduced baseline and antigen‐specific concentrations of IL‐1&bgr; and IL‐18 in tuberculous lymphadenitis.This reduction is reversible upon standard anti‐tuberculous treatment of lymphadenitis individuals.

Heightened circulating levels of antimicrobial peptides in tuberculosis-Diabetes co-morbidity and reversal upon treatment.

Background The association of antimicrobial peptides (AMPs) with tuberculosis—diabetes comorbidity (PTB-DM) is not well understood. Methods To study the association of AMPs with PTB-DM, we examined the systemic levels of cathelicidin (LL37), human beta defensin– 2 (HBD2), human neutrophil peptides 1–3, (HNP1-3) and granulysin in individuals with either PTB-DM, PTB, latent TB (LTB) or no TB infection (NTB). Results Circulating levels of cathelicidin and HBD2 were significantly higher and granulysin levels were significantly lower in PTB-DM compared to PTB, LTB or NTB, while the levels of HNP1-3 were significantly higher in PTB-DM compared to LTB or NTB individuals. Moreover, the levels of cathelicidin and/or HBD2 were significantly higher in PTB-DM or PTB individuals with bilateral and cavitary disease and also exhibited a significant positive relationship with bacterial burden. Cathelidin, HBD2 and HNP1-3 levels exhibited a positive relationship with HbA1c and/or fasting blood glucose levels. Finally, anti-tuberculosis therapy resulted in significantly diminished levels of cathelicidin, HBD2, granulysin and significantly enhanced levels of HNP1-3 and granulysin in PTB-DM and/or PTB individuals. Conclusion Therefore, our data demonstrate that PTB-DM is associated with markedly enhanced levels of AMPs and diminished levels of granulysin.

Tuberculous Lymphadenitis Is Associated with Enhanced Baseline and Antigen-Specific Induction of Type 1 and Type 17 Cytokines and Reduced Interleukin-1β (IL-1β) and IL-18 at the Site of Infection

ABSTRACT Tuberculous lymphadenitis (TBL) is characterized by an expansion of Th1 and Th17 cells with altered serum levels of proinflammatory cytokines. However, the cytokine profile at the site of infection, i.e., the affected lymph nodes, has not been examined in detail. To estimate the baseline and mycobacterial antigen-stimulated concentrations of type 1, type 17, and other proinflammatory cytokines in patients with TBL (n = 14), we examined both the baseline and the antigen-specific concentrations of these cytokines before and after chemotherapy and compared them with those in individuals with pulmonary tuberculosis (PTB) (n = 14). In addition, we also compared the cytokine responses in whole blood and those in the lymph nodes of TBL individuals. We observed significantly enhanced baseline and antigen-specific levels of type 1 cytokines (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]) and a type 17 cytokine (interleukin-17 [IL-17]) and significantly diminished baseline and antigen-specific levels of proinflammatory cytokines (IL-1β and IL-18) in the whole blood of TBL individuals compared to those in the whole blood of PTB individuals. Moreover, we also observed a pattern of baseline and antigen-specific cytokine production at the site of infection (lymph node) similar to that in the whole blood of TBL individuals. Following standard antituberculosis (anti-TB) treatment, we observed alterations in the baseline and/or antigen-specific levels of IFN-γ, TNF-α, IL-1β, and IL-18. TBL is therefore characterized by enhanced baseline and antigen-specific production of type 1 and type 17 cytokines and reduced baseline and antigen-specific production of IL-1β and IL-18 at the site of infection.

Modulation of dendritic cell and monocyte subsets in tuberculosis-diabetes co-morbidity upon standard tuberculosis treatment

Type 2 diabetes mellitus (DM) is a major risk factor for the development of active pulmonary tuberculosis (PTB), with development of DM pandemic in countries where tuberculosis (TB) is also endemic. However, the effect of anti-TB treatment on the changes in dentritic cell (DC) and monocyte subset phenotype in TB-DM co-morbidity is not well understood. In this study, we characterized the frequency of DC and monocyte subsets in individuals with PTB with (PTB-DM) or without coincident diabetes mellitus (PTB-NDM) before, during and after completion of anti-TB treatment. PTB-DM is characterized by diminished frequencies of plasmacytoid and myeloid DCs and classical and intermediate monocytes at baseline and 2 months of anti-TB treatment but not following 6 months of treatment completion in comparison to PTB-NDM. DC and monocyte subsets exhibit significant but borderline correlation with fasting blood glucose and glycated hemoglobin levels. Finally, while minor changes in the DC and monocyte compartment were observed at 2 months of treatment, significantly increased frequencies of plasmacytoid and myeloid DCs and classical and intermediate monocytes were observed at the successful completion of anti-TB treatment. Our data show that coincident diabetes alters the frequencies of innate subset distribution of DC and monocytes in TB-DM co-morbidity and suggests that most of these changes are reversible following anti-TB therapy.

Prediabetes is associated with the modulation of antigen-specific Th1/Tc1 and Th17/Tc17 responses in latent Mycobacterium tuberculosis infection

Type 2 diabetes mellitus (DM) is associated with the down modulation of Th1, Th2 and Th17 responses in latent Mycobacterium tuberculosis infection but the role of prediabetes (PDM) in this setting is not well understood. To examine the role of CD4+ and CD8+ T cell cytokines in latent tuberculosis (LTB) with coincident PDM, we studied the baseline, mycobacterial, control antigen and mitogen–stimulated T cell cytokine responses in LTB individuals with (LTB-PDM; n = 20) or without (LTB-NDM; n = 20) concomitant prediabetes. LTB-PDM is characterized by diminished frequencies of mono–and dual–functional CD4+ Th1 and Th17 cells and mono-functional Th2 cells at baseline and/or following mycobacterial—antigen stimulation in comparison to LTB-NDM. LTB-PDM is also characterized by diminished frequencies of mono–functional CD8+ Tc1, Tc2 and Tc17 cells at baseline and/or following mycobacterial–antigen stimulation in comparison to LTB-NDM. LTB-PDM is therefore characterized by diminished frequencies of antigen–specific Th1/Tc1 and Th17/Tc17 cells, indicating that PDM is associated with alterations of the immune response in latent TB associated with compromised CD4+ and CD8+ T cell function.