Human tuberculosis: a clear case of disturbed neuroimmunoregulation

Abstract

Listen

Translate article

The hypothalamic-pituitary-adrenal (HPA) axis and the immune system have evolved in simultaneous and communicate each other, by a series common mediators, hormones and cytokines. As endogenous peptides primarily released from immune cells cytokines coordinate the immune response and also lead to the HPA activation, particularly those with inflammatory effects. A major effector mechanism of the HPA axis deals with the production of adrenal steroids, glucocorticoids (GCs) and dehydroepiandrosterone (DHEA). GCs and DHEA influence innate and adaptive mechanisms of the immune response downregulating inflammatory responses, but displaying differenzial effects on the development of Th2 and Th1 responses, respectively. Tuberculosis (TB) is a disease in which tissue pathology has an immune-mediated component encompassing an excessive and/or protracted cytokine production liable to affect the immunoendocrine communication. We have shown that TB patients present increased IFN-γ, IL-10, and IL-6 plasma levels, in presence of modest increases in cortisol, prolactin, and thyroid hormones and highly augmented concentrations of growth hormone. In contrast, testosterone, leptin and DHEA levels were markedly decreased. In vitro studies demonstrate that culture supernatants from M. tuberculosis-stimulated PBMC of TB patients inhibited DHEA secretion by a human adrenal cell line. Treatment of peripheral blood mononuclear cells (PBMC) from TB patients with physiological concentrations of cortisol inhibits mycobacterial antigen-driven lymphoproliferation and IFN-γ production, whereas DHEA suppresses TGF-β production by PBMC from patients with progressive disease. Supporting the role of immune and endocrine mediators in energy expenditure and metabolism, results also show that the consumption state of TB patients is linked to the immuno-endocrine disturbances. It was found that the body mass index of active TB patients is negatively associated with circulating IL-6 levels, which in turn correlate positively with cortisol concentrations Most immunomodulating effects of GCs are achieved through the interaction with GC receptors (GR), in particular the GR-α isoform since the GR-β lacks the ability to bind GC and seems to function as an inhibitor of GR-α-mediated transcriptional activation. Current studies reveal a reduced mRNA GRα/β ratio in PBMC of severe TB patients with hormone and cytokine environment influencing the expression of GR isoforms. Taken together, its is clear that the bidirectional communication between the neuroendocrine and immune systems in TB, results in an abnormal immuno-endocrine relation taking part in the consumption state, disturbed anti-infective immune response and pathological hormonal profile.