Immunological AspectsAn adverse immune-endocrine profile in patients with tuberculosis and type 2 diabetes
Introduction
Pulmonary tuberculosis (TB) is a major cause of mortality around the world. In 2014, 1.5 million people died of TB (0.4 million HIV-positive) and 9.6 million people worldwide are estimated to have contracted the disease during this period [1]. The clinical manifestations are greatly influenced by the immune response to Mycobacterium tuberculosis, its etiologic agent, but the mechanisms underlying the outcome of the disease are not fully understood [2]. Endocrine responses during chronic infections such as lung tuberculosis are worth studying since some of the cytokines produced during this disease are likely to affect endocrine mechanisms that, in turn, influence the course of the infectious process [3], [4]. In fact, proinflammatory cytokines released from affected tissues that reach the central nervous system are known to influence the secretory activity of the hypothalamic–pituitary–adrenal (HPA) axis. The adrenal gland is responsible for the release of glucocorticoids (GCs), which generally inhibit or modulate inflammation, as well as dehydroepiandrosterone (DHEA), a steroid that counteracts GCs effects on cytokine production, but also exerts itself potent anti-inflammatory effects [3], [5]. Interactions between the endocrine and the immune system also involve the hypothalamic–pituitary–gonadal (HPG) axis, since macrophages and lymphocytes have receptors for gonadal steroids and these hormones can affect macrophage and lymphocyte development and function [6], [7].
By evaluating hormonal and cytokine levels in patients with TB, we have previously shown imbalanced immune-endocrine responses in which levels of pro-inflammatory cytokines, cortisol and estradiol concentrations were increased whereas testosterone and DHEA amounts were diminished in patients, together with an increased Cort/DHEA ratio even more pronounced in those with a severe disease [8].
Endocrine disturbances can also contribute to the pathology of patients with TB, as illustrated by the detrimental influence of type 2 diabetes mellitus (T2DM) on TB development. Several studies have shown that T2DM may be associated with an increased risk of developing active TB, whereas TB patients with concomitant diabetes are at higher rates of treatment failure and death [9], [10], [11].
Type 2 DM is characterized by the failure of beta cells to compensate for insulin resistance, with inflammatory or immunological factors being implied in such alterations [12]. Thus, the simultaneous occurrence of both diseases may impose a particular set of alterations in immune and endocrine parameters that is worth exploring.
On these bases, we analyzed the blood levels of several cytokines, hormones and the specific immune response to mycobacteria in the context of the TB and diabetes association. Studies included the assessment of the plasma levels of IL-6, IFN-γ and IL-10, adrenal (cortisol, DHEA) and gonadal (estradiol, testosterone) steroids, hormones involved in immune-metabolic effects like growth hormone (GH), prolactin and insulin-like growth factor-1 (IGF-1), in parallel to the specific lymphoproliferative capacity of peripheral blood mononuclear cells.
Section snippets
Sample population
Patients (6 females and 29 males) with no HIV co-infection and newly diagnosed pulmonary TB of moderate to severe degree were included. Pulmonary TB diagnosis was based on positive clinical symptoms and radiological chest results as well as sputum smear positivity for acid fast bacillus (AFB) by Ziehl Neelsen staining and a confirmatory positive culture for Mtb on Lowenstein–Jensen medium. Fourteen of these patients were diagnosed as also having T2DM (TB + T2DM). Criteria for diabetes diagnosis
Results
The subject profile is shown in Table 1. There were no between-group differences in age and sex distribution, while the presence of the BCG scar was less prevalent among TB patients. Both groups of TB patients (with or without T2DM) had a BMI lower than HCo (p < 0.001, Table 1). Data from in vitro proliferation of PBMC from patients and HCo are also presented in Table 1. PBMC from HCo had higher median proliferative responses to Mtb than both groups of TB patients (p < 0.02), which was more
Discussion
The endocrine and immune systems interact in a bidirectional way. Hormones can affect immune functions, and in turn the immune response influences neuroendocrine functions [3], [5]. The HPA axis is a key element in the communication between the endocrine and immune systems, for which it has to be finely tuned. Chronic activation of the HPA axis can affect the susceptibility or severity of infectious diseases, mainly through immunosuppressive effects of glucocorticoids. In general terms,
Acknowledgments
This work was supported by grants from FONCYT (PICT 2012-1523), the Secretariat for Science and Technology of Santa Fe Province, Argentina, and Research Group in-house funds from the Inst. of Physiology and Pathophysiology, Marburg.
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These authors made equal contributions to the present study.