PATHOGENETIC ROLE, IN HUMAN AND MURINE TUBERCULOSIS, OF CHANGES IN THE PERIPHERAL METABOLISM OF GLUCOCORTICOIDS AND ANTIGLUCOCORTICOIDS

Immunity to tuberculosis (TB) requires a Th1 pattern of cytokine relea se, dominated by interleukin-2 (IL-2) and interferon gamma (IFN gamma) . In experimental models even a minor Th2 component (characterized by production of IL-4) abrogates immunity, and leads to an immunopatholog y that mimics the human disease. Increased exposure of T cells to gluc ocorticoids drives them towards a Th2 cytokine profile and could there fore help to explain the presence of an inappropriate Th2 component in TB. Analysis of adrenal steroid metabolites in 24-h urine collections revealed a striking increase in metabolites of active cortisol relati ve to metabolites of inactive cortisone. This indicates a change in th e balance of 11 beta-hydroxysteroid dehydrogenase to 11 beta-ketostero id reductase. The site of this disease-associated alteration in reduct ase/dehydrogenase balance may be the lung. The lung contains 11 beta H SD-1, (a reversible oxido-reductase) which in the liver works as a red uctase. In the normal lung it functions paradoxically as a reductase, but it can alter its function in the presence of cytokines. TB patient s (like other ill individuals) also show reduced 24-h urinary secretio n of dehydroepiandrosterone (DHEA) derivatives. Since these have antig lucocorticoid functions in vivo, this fall may exacerbate the effects of the reduced inactivation of cortisol and loss of diurnal rhythm, an d contribute to immunological dysfunction. Recent studies of TB in mic e, and in children during infancy, adrenarche and puberty, suggest tha t the ratio of cortisol to DHEA may be crucial both to susceptibility and to the pathology of the disease that develops. (C) 1997 Elsevier S cience Ltd.