The Immuno‐endocrine Component in the Pathogenesis of Tuberculosis

Abstract

Tuberculosis (TB) may be regarded as a disease in which the immune response to Mycobacterium tuberculosis, its etiologic agent, is engaged both in protection and pathology. Different T‐lymphocyte subsets are involved in the immune response against M. tuberculosis, but production of interferon‐gamma (IFN‐γ) by T cells seems to be fundamental for disease control. Th1‐type cytokine responses predominate in patients with mild or moderate forms of pulmonary TB, whereas the production of Th2‐type cytokines prevails in the severe disease. Since the immune response fails to definitely eradicate the pathogen, a chronic infection is established, and it is likely that a broad range of regulatory mechanisms operate in this situation. Cytokines released during the course of an immune response activate the hypothalamus‐pituitary‐adrenal axis leading to the production of glucocorticoids and dehydroepiandrosterone (DHEA), with known immunomodulatory effects. TB patients exhibit increased concentrations of interleukin‐6 and cortisol in plasma, reduced DHEA and testosterone levels, together with remarkably increased growth hormone concentrations that were not accompanied by an expected raise in insulin‐like growth factor‐1. Significant increases in estradiol, prolactin, and thyroid hormone concentrations were also detected in patients. Cortisol inhibits the mycobacterial antigen‐driven proliferation and IFN‐γ production, whereas DHEA suppresses transforming growth factor beta production by lymphoid cells from TB patients with advanced disease. Furthermore, supernatants from cultures of M. tuberculosis‐stimulated mononuclear cells of TB patients inhibit DHEA secretion by a human adrenal cell line. This type of immuno‐endocrine interactions may affect the control of tissue damage and the development of protective immune responses, partly accounting for disease aggravation.

Immunoendocrine Alterations during Human Tuberculosis as an Integrated View of Disease Pathology

“…The series was composed of newly diagnosed, HIV-negative, male patients, presenting mild, moderate, or advanced pulmonary TB. In agreement with the reports from other laboratories [50,80] , IFN-␥ , IL-10, and IL-6 levels were increased in TB patients, as compared to healthy controls, indicating that Th1 cytokine production is not dominant during this disease. Growth hormone (GH) levels were markedly elevated in patients, in parallel with modest increases in the concentrations of cortisol, estradiol, prolactin (PRL), and thyroid hormones (T 3 and T 4 ).…”

“…IL-10 production was found increased in anergic TB patients, suggesting that M.-tuberculosis -induced IL-10 production suppresses an effective immune response [46] . Also, IL-10 downregulates the Th1-induced response to M. tuberculosis and inhibits major histocompatibility complex-restricted cytotoxicity against infected macrophages (reviewed in Bottasso et al [50] ). In line with this, our studies show that IL-10 levels increase with the progression of the disease [23,24] .…”

HIV–TB coinfection impairs CD8+ T‐cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses

“…As the amount of DHEA in plasma and the intensity of the immune response to Mtb are determined by several factors (i.e. activation of hypothalamus-pituitary axis [14], TB burden [38], or HIV disease progression [25], among others), the association between DHEA plasma levels and Mtb-specific CD8 + T cells proportions in our cohort could be masked by these other factors.Contrary to our expectations, we detected a positive correlation between cortisol plasma levels and CD107a/b + CD8 + T cells in HIV-TB individuals (Fig. 4B).…”

“…Among hormonal effects on the immune response, glucocorticoids can promote a Th2 cytokine acquisition profile [14], facilitating Th2 activities, whereas its natural antagonist dehydroepiandrosterone (DHEA) is able to favor Th1 cytokine production and interfere with Th2 cytokine synthesis [15]. In fact, the synthetic DHEA derivative, 16 α-bromoepiandrosterone, exerts beneficial effects in clinical and experimental TB and in HIV patients [16][17][18].…”

Impaired Immune Responses in Tuberculosis Patients Are Related to Weight Loss That Coexists with an Immunoendocrine Imbalance

“…A pivotal cytokine in the immune response to this pathogen is interferon-␥ (IFN-␥ ), which is responsible for macrophage activation in TB and further killing of intracellular mycobacteria [2][3][4] .…”