The clinical recovery of tuberculosis patients undergoing specific treatment is associated with changes in the immune and neuroendocrine responses

Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a health problem worldwide. Patients with pulmonary TB show a neuro-immune-endocrine imbalance characterized by an impaired cellular immunity together with increased plasma levels of cortisol, pro- and anti-inflammatory cytokines and markedly decreased dehydroepiandrosterone (DHEA) levels. Extending these findings, we now investigated the immune-endocrine profile of TB patients undergoing specific treatment. Patients (n = 24) were bled at diagnosis (T0), 2, 4, 6 months after treatment initiation and 3 months following its completion. At T0, TB patients showed increased plasma levels of interleukin-6 (IL-6), C reactive protein, interferon-gamma (IFN-γ) and transforming growth factor beta (TGF-β). These mediators decreased during treatment, reaching levels similar to those from healthy controls (n = 26). Specific treatment led to an increased lymphoproliferative response along with clinical improvement. Newly diagnosed patients had low levels of DHEA, with increased cortisol amounts and cortisol/DHEA ratio, which normalized upon specific treatment. As regards glucocorticoid receptors (GR), TB patients at diagnosis presented a reduced mRNA GRα/GRβ ratio in their peripheral blood mononuclear cells. Furthermore, multivariate analysis showed that cortisol/DHEA ratio was positively associated with inflammatory mediators for which this ratio may constitute a disease biomarker. Anti-mycobacterial treatment results in a better immune-endocrine scenario for the control of physiopathological processes accompanying disease development and hence implied in clinical recovery.

Evidence for a More Disrupted Immune-Endocrine Relation and Cortisol Immunologic Influences in the Context of Tuberculosis and Type 2 Diabetes Comorbidity

“…As in previous studies (32)(33)(34), patients with only TB showed decreased blastogenesis, which in turn correlated negatively with IL-10 levels, a cytokine of recognized inhibitory effect on lymphoproliferation (35). Such decreased specific proliferation may be partly attributed to a recruitment of cells committed toward the site of the lesion (19).…”

“…As seen in former studies (33,34,47,48), the unbalanced relationship between steroid hormones recorded in TB patients, increased and decreased levels of cortisol and DHEA-DHEA-S, respectively, was also found in TB+DM patients. This may be explained by assuming that the adrenal gland is trying to preserve cortisol production at the expense of DHEA synthesis, to counteract the inflammatory response accompanying active disease.…”

Can we predict tuberculosis cure? What tools are available?

“…Although promising, further research is needed to establish the efficacy of this new assay as marker for treatment monitoring and/or outcome. 166,195,196] [158] [172,173,197] [ 162,175] Markers of lung tissue repair (platelet activity VEGF, TGF-β, MMPs) [195,196] [135].…”

“…Additional candidates are the evaluation of the proportions of M. tuberculosis-specific CD27low CD4 + T-cells, which decline in parallel to the reduction of lung tissue damage [65]. Other potential serum markers are vascular endothelial growth factor, matrix metalloproteinase-9, transforming growth factor (TGF)-β1 and aminoterminal propeptide of type III procollagen (PIIINP) [172][173][174][175][176]. [177][178][179][180][181], but also in cohorts containing both HIV-co-infected and HIV-uninfected individuals [182].…”

Tuberculosis, the Disrupted Immune-Endocrine Response and the Potential Thymic Repercussion As a Contributing Factor to Disease Physiopathology

“…Although at the experimental level low GCs concentrations may rescue thymocytes from the TCR-mediated apoptosis ( 81 , 82 ), the scenario in TB patients is characterized by a chronic elevation of cortisol that while being of moderate intensity remained so even after several months of treatment initiation ( 83 ). Furthermore, TB patients also present quite reduced amounts of circulating leptin levels ( 45 ).…”