In this study, we explored the local cytokine/chemokine profiles in patients with active pulmonary or pleural tuberculosis (TB) using multiplex protein analysis of bronchoalveolar lavage and pleural fluid samples. Despite increased pro-inflammation compared to the uninfected controls; there was no up-regulation of IFN-γ or the T cell chemoattractant CCL5 in the lung of patients with pulmonary TB. Instead, elevated levels of IL-4 and CCL4 were associated with high mycobacteria-specific IgG titres as well as SOCS3 (suppressors of cytokine signaling) mRNA and progression of moderate-to-severe disease. Contrary, IL-4, CCL4 and SOCS3 remained low in patients with extrapulmonary pleural TB, while IFN-γ, CCL5 and SOCS1 were up-regulated. Both SOCS molecules were induced in human macrophages infected with Mycobacterium tuberculosis in vitro. The Th2 immune response signature found in patients with progressive pulmonary TB could result from inappropriate cytokine/chemokine responses and excessive SOCS3 expression that may represent potential targets for clinical TB management.

Objective. Immunotherapy using vitamin D (vitD 3 ) and phenylbutyrate (PBA) may support standard drug regimens used to treat infectious diseases. We investigated if vitD 3 + PBA enhanced clinical recovery from pulmonary tuberculosis (TB).Methods. A randomized controlled trial was conducted in Addis Ababa, Ethiopia. Patients with smear-positive or smear-negative TB received daily oral supplementation with 5000 IU vitD 3 and 2 9 500 mg PBA or placebo for 16 weeks, together with 6-month chemotherapy. Primary end-point: reduction of a clinical composite TB score at week 8 compared with baseline using modified intentionto-treat (mITT, n = 348) and per-protocol (n = 296) analyses. Secondary end-points: primary and modified TB scores (week 0, 4, 8, 16, 24), sputum conversion, radiological findings and plasma 25 (OH)D 3 concentrations.Results. Most subjects had low baseline plasma 25 (OH)D 3 levels that increased gradually in the vitD 3 + PBA group compared with placebo (P < 0.0001) from week 0 to 16 (mean 34.7 vs. nmol L À1). In the adjusted mITT analysis, the primary TB score was significantly reduced in the intervention group at week 8 (À0.52, 95% CI À0.93, À0.10; P = 0.015) while the modified TB score was reduced at week 8 (À0.58, 95% CI À1.02, À0.14; P = 0.01) and 16 (À0.34, 95% CI À0.64, À0.03; P = 0.03). VitD 3 + PBA had no effect on longitudinal sputum-smear conversion (P = 0.98). Clinical adverse events were more common in the placebo group (24.3%) compared with the vitD 3 + PBA group (12.6%).Conclusion. Daily supplementation with vitD 3 + PBA may ameliorate clinical TB symptoms and diseasespecific complications, while the intervention had no effect on bacterial clearance in sputum.

BackgroundDiagnosis of active tuberculosis (TB) among sputum-negative cases, patients with HIV infection and extra-pulmonary TB is difficult. In this study, assessment of BCG-specific IgG-secreting peripheral plasmablasts, was used to identify active TB in these high-risk groups.MethodsPeripheral blood mononuclear cells were isolated from patients with TB and controls and cultured in vitro using an assay called Antibodies in Lymphocyte Supernatant, which measures spontaneous IgG antibody release from migratory plasmablasts. A BCG-specific ELISA and flow cytometry were used to quantify in vivo activated plasmablasts in blood samples from Ethiopian subjects who were HIV negative or HIV positive. Patients diagnosed with different clinical forms of sputum-negative active TB or other diseases (n=96) were compared with asymptomatic individuals including latent TB and non-TB controls (n=85). Immunodiagnosis of TB also included the tuberculin skin test and the interferon (IFN)-γ release assay, QuantiFERON.ResultsThis study demonstrated that circulating IgG+ plasmablasts and spontaneous secretion of BCG-specific IgG antibodies were significantly higher in patients with active TB compared with latent TB cases and non-TB controls. BCG-specific IgG titres were particularly high among patients coinfected with TB and HIV with CD4 T-cell counts <200 cells/ml who produced low levels of Mycobacterium tuberculosis-specific IFNγ in vitro.ConclusionsThese results suggest that BCG-specific IgG-secreting peripheral plasmablasts could be successfully used as a host-specific biomarker to improve diagnosis of active TB, particularly in people who are HIV positive, and facilitate administration of effective treatment to patients. Elevated IgG responses were associated with impaired peripheral T-cell responses, including reduced T-cell numbers and low M tuberculosis-specific IFNγ production.