Event Abstract

An analysis of the immune-endocrine changes occurring in tuberculosis patients from the time of disease diagnosis to treatment completion and clinical recovery

  • 1 Instituto de Inmunología Clínica y Experimental de Rosario, IDICER-CONICET, Argentina
  • 2 Laboratorio Central, Hospital Provincial del Centenario, Argentina
  • 3 Servicio de Neumonología, Hospital Provincial del Centenario, Argentina
  • 4 Servicio de Neumonología, Hospital Escuela Eva Perón, Argentina
  • 5 Servicio de Neumonología, Hospital Intendente Carrasco, Argentina

Tuberculosis (TB) mainly caused by Mycobacterium tuberculosis (Mtb) is a major health problem not only for its worldwide distribution but also for its morbidity and at times fatal course. While the cellular immune response (IR) is critical for containment and resolution of this infectious process, immune-mediated reactions can also lead to tissue pathology. We have earlier demonstrated that patients with pulmonary TB, at the time of diagnosis, showed a significant neuro-immune-endocrine imbalance. Briefly, patients had increased plasma levels of cortisol, pro- and anti-inflammatory cytokines together with impaired cellular IR and markedly decreased dehydroepiandrosterone (DHEA) amounts, resulting in an unbalanced cortisol/DHEA ratio. In terms of immune influences, cortisol inhibits the production of pro-inflammatory cytokines and the development of the cellular IR, whereas DHEA displays anti-inflammatory effects and promotes Th1 response. Extending these observations and given the relevance of the broad defensive response in infectious pathology we now investigated the immune-endocrine profile of TB patients from the time of disease diagnosis to treatment completion and clinical recovery. We sought to find out whether any of the immune-endocrine parameters under analysis (hormones, cytokines, acute phase proteins, lymphocyte populations -regulatory T cells-) could emerge as a biomarker of the disease course. Blood samples from 26 healthy controls (HCo) and 24 TB patients, HIV negative showing no sex or age differences were studied. Patients were bled at the time of diagnosis (T0) and 2 (T2), 4 (T4) and 6 months (T6) after the initiation of specific treatment, as well as 3 months following its completion (T9). At T0 patients showed increased plasma levels of interleukin 6 (IL-6, vs. HCo p<0.01), C reactive protein (CRP, vs. HCo p<0.01), interferon gamma (IFN-γ) and transforming growth factor beta (TGF-β, vs. HCo p<0.05). These compounds decreased during treatment, reaching levels similar to those seen in HCo. Anti-mycobacterial treatment was accompanied by an increased lymphoproliferative response (T0 vs. T2, T4 and T6 p<0.05) along with a significant clinical improvement (recovered body mass index). Regulatory T cells were found augmented at T0 (vs. HCo p<0.05) even further at T2 and T4 (vs. T0 p<0.05 and p<0.01 respectively), being negatively correlated with INF-γ plasma levels at T4 (r=-0,79; p<0,02; n=16); to reach normal values by T6. As seen previously, newly diagnosed patients had low levels of DHEA and DHEA-S (vs. HCo p<0.001 and p<0.01 respectively) along with increased cortisol levels (vs. HCo p<0.05) and Cortisol/DHEA ratio (vs. HCo p<0.01), the latter one associated with disease severity (r=0,65; p<0,02; n=24). Most of the anti-inflammatory and immunological effects of cortisol are exerted through the interaction with glucocorticoid receptors (GR), which possesses two main isoforms, GRα and GRβ, the former being biologically active with GRβ lacking the ability to bind cortisol. At diagnosis, TB patients presented a reduced mRNA GRα/GRβ ratio in their peripheral blood mononuclear cells respect to HCo (p<0.05), resembling some degree of cortisol resistance. Patients also had an increased expression of the 11β-hydroxysteroid dehydrogenase type 1 transcript (11βHSD1, p<0.05 vs. HCo), an enzyme controlling the intracellular bioavailability of cortisol at tissue levels likely as an attempt to increase the intracellular cortisol availability. Treatment initiation led to a normalization of transcript expression. This was not the case for cortisol levels, which remained moderately increased throughout treatment, whereas DHEA levels reached the values seen in HCo, resulting in a restored Cortisol/DHEA ratio, compatible with an adrenal improvement. Unlike at the time of diagnosis, the GRα/GRβ ratio was increased at T2 (vs. T0 p<0.05), because of a marked decrease of GRβ, that may favor the anti-inflammatory response of cortisol. An statistical approach by means of the Main Component Analysis showed that the T0 Cortisol/DHEA ratio was positively associated with inflammatory mediators such as IL-6, IFN-γ and CRP as well as the erythrosedimentation rate –ESR (e.g. vs. IL-6: r=0.87, p<0.01; vs. IFN-γ: r=0.59, p<0.05). Further analysis at T2 confirmed the clinical improvement and decrease of inflammatory mediators, although Cortisol/DHEA ratio continued to be correlated with CRP and ESR (r=0.89, p<0.01; r=0.82, p<0.01, respectively), suggesting that Cortisol/DHEA ratio may be an inflammation biomarker. In essence, anti-mycobacterial treatment results in a better immunoregulatory scenario suitable for a more adequate control of the physiopathological processes accompanying disease development and hence favoring clinical recovery.

Keywords: pulmonary tuberculosis, Cellular Immune Response, cortisol, DHEA, Pro-inflammatory cytokines, regulatory T cells, glucocorticoid receptors

Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015.

Presentation Type: Oral Presentation

Topic: Infectious and parasitic diseases

Citation: Diaz A, D’Attilio L, Bongiovanni B, Santucci N, Dídoli G, Lioi S, Massoni C, Danielle S, Radcliffe S, Gardeñez W, Brandan N, Nannini L, Bogue C, Marchesini M, Bottasso O and Bay ML (2015). An analysis of the immune-endocrine changes occurring in tuberculosis patients from the time of disease diagnosis to treatment completion and clinical recovery. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00297

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Received: 27 May 2015; Published Online: 15 Sep 2015.

* Correspondence: Dr. Ariana Diaz, Instituto de Inmunología Clínica y Experimental de Rosario, IDICER-CONICET, Rosario, Santa Fe, 2000, Argentina, ariana_d@hotmail.com.ar