Baker, Robert William; (2001) Investigation of glucocorticoid and local immunological function in tuberculosis and inflammation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Tuberculosis is a unique disease in having been declared a global emergency by the World Health Organisation. Three million people are believed to die from infection with the bacillus each year. Understanding the pathogenesis of the disease is therefore a vital step towards developing new therapies and vaccines. In this study the metabolism of certain crucial glucocorticoids - in particular cortisol and cortisone (corticosterone and dehydrocorticosterone in rodents) - has been analysed in the context of tuberculosis in humans and comparable inflammatory models in mice. Cortisol is an immunologically active glucocorticoid, where cortisone is its inactive form. Glucocorticoids, in their active form, influence the effectiveness of cell mediated immunity to disease. Conversely, products of cell-mediated immunity, particularly cytokines, influence the peripheral metabolism of cortisol. Cortisol metabolism has been addressed in health and disease, in humans and laboratory animals. The principal pathological state which has been investigated is tuberculosis. In the first part of the study, the central regulation of cortisol secretion via the hypothalamo- pituitary-adrenal axis was addressed in human tuberculosis, cured human tuberculosis and healthy humans. The HPAA was found to be intact in patients with pulmonary TB. Evidence of abnormal peripheral cortisol handling in acute human pulmonary TB was demonstrated, in that the conversion of inactive cortisone to its active and immunoregulatory metabolite cortisol is enhanced in patients with pulmonary TB. The enzymes responsible for this interconversion are the 11 beta-hydroxysteroid dehydrogenases. In the second part of the study, the site of abnormal peripheral cortisol metabolism in humans with acute pulmonary TB was demonstrated to be within the lung. Based on the premise that the abnormality was likely to arise at the site of disease, and the observation that the enzyme 11-[beta] HSD type 1 and 11-[beta] HSD type 2 are present in lung, the interconversion of cortisol and cortisone at this site was analysed, and the ratio of cortisol to cortisone was found to be higher in the broncho-alveolar lavage of patients with TB than healthy volunteers or patients cured of TB. Analysis of cytokine production by lymphocytes in the lungs and peripheral blood was also performed, and although there was a trend for more CD4 and CD8 T-cells to produce Th2 cytokines, this was not found to be significant. The study has taken the investigation of the hypothalamo-pituitary-adrenal axis further by assessing 24-hour urinary production of IL-6, an inflammatory cytokine involved with immunity to TB that is capable of stimulating the hypothalamo-pituitary-adrenal axis, and its soluble receptor S-IL-6R. No difference was found between IL-6 and S-IL-6R output in patients with TB, pneumonia or patients cured of TB when compared with healthy controls, an interesting observation given that overall cortisol output was not elevated. In the third part of the study, activity of the enzyme 11-[beta] HSD 1 in several different murine tissues was investigated in certain inflammatory models relevant to human disease. The findings confirmed that shifts in the equilibrium point of the cortisol-cortisone shuttle occur in sites of inflammation.

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