The endocrine component

There is a further physiological correlate of the events seen in Figs 1—3. During the phase of Th1 dominance, the adrenals increase in weight, presumably because of activation of the hypothalamopituitary-adrenal axis by cytokines (see Fig. 5). However, when the response switches to Th2 the adrenals start to atrophy (Rook & Hernandez-Pando 1996). This is not an acute renal cortical necrosis but rather progressive atrophy with apoptosis. These observations have led to detailed studies of endocrine function in human tuberculosis. The subject is complex, and Fig. 4 shows some of the pathways that control glucocorticoid function in the tissues. The regulatory pathways shown are rich in genetic polymorphisms, and could be a source of new genetic insights into individual susceptibility to tuberculosis.

The cortisonej Cortisol shuttle

Local control of glucocorticoid activity is important because T cells that mature in the presence of raised glucocorticoid levels tend to mature into Th2 cells (Ramirez et al 1996). Moreover, simultaneous exposure of T cells to IL-2 and IL-4, as will occur in mixed Th1 + Th2 inflammation, causes reduced affinity of glucocorticoid receptors, and therefore glucocorticoid resistance (Kam et al 1993).

A study of the steroid metabolites in 24 h urine samples from tuberculosis patients has shown that paradoxically the total 24 h output of glucocorticoids is often not raised, and can be low (Rook et al 1996). However, cortisol levels are maintained because there is a striking switch in the balance of metabolites of cortisol and cortisone in favour of cortisol, the active compound. This implies a

FIG. 5. Factors that determine the effective Cortisol function in lymphoid tissue and lesions. Cytokines from the immune response (bottom right) contribute additional drive to the hypothalamopituitary-adrenal (HPA) axis. The eventual output of the adrenal (left) can vary in diurnal rhythm and in cortisol/sulfated dehydroepiandrosterone (DHEAS) ratio. The circulating cortisol level can then be modulated by changes in the cortisol/cortisone ratio, due to the 'cortisol/cortisone shuttle' enzymes in the kidney, liver, lung and other tissues. Within lesions and lymphoid tissues (box on right), both DHEAS and cortisol are subject to regulated local metabolism. Tumour necrosis factor a and interleukin-1 [ upregulate the reductase activity of 11-[-hydroxy steroid dehydrogenase type 1 (11[-OH SD) activity and so locally increase the proportion of active cortisol (surrounded by heavy rectangle). The pathway of conversion of DHEA to the putative active antiglucocorticoid, indicated as (-), is unknown, because we do not know which are the active metabolites. ACTH, adrenocorticotrophic hormone; CRH, corticotrophin-releasing hormone. Th, T helper.

FIG. 5. Factors that determine the effective Cortisol function in lymphoid tissue and lesions. Cytokines from the immune response (bottom right) contribute additional drive to the hypothalamopituitary-adrenal (HPA) axis. The eventual output of the adrenal (left) can vary in diurnal rhythm and in cortisol/sulfated dehydroepiandrosterone (DHEAS) ratio. The circulating cortisol level can then be modulated by changes in the cortisol/cortisone ratio, due to the 'cortisol/cortisone shuttle' enzymes in the kidney, liver, lung and other tissues. Within lesions and lymphoid tissues (box on right), both DHEAS and cortisol are subject to regulated local metabolism. Tumour necrosis factor a and interleukin-1 [ upregulate the reductase activity of 11-[-hydroxy steroid dehydrogenase type 1 (11[-OH SD) activity and so locally increase the proportion of active cortisol (surrounded by heavy rectangle). The pathway of conversion of DHEA to the putative active antiglucocorticoid, indicated as (-), is unknown, because we do not know which are the active metabolites. ACTH, adrenocorticotrophic hormone; CRH, corticotrophin-releasing hormone. Th, T helper.

change in the activity of the enzymes of the cortisol/cortisone shuttle (Fig. 5), which we have confirmed by showing accelerated conversion of an oral cortisone load to active cortisol (B. Baker, B. R. Walker, R. J. Shaw, A. Zumla, J. W. Honour, S. L. Lightman & G. A. W. Rook, unpublished work 1997). This is of particular interest because the appropriate change in the function of 11[-hydroxysteroid dehydrogenase type 1 (11[HSD1) has been shown to be induced by TNF-a and IL-1[ (Escher et al 1997). We do not yet know where this is happening, but the tuberculous lung seems a likely site, since it is where cytokine concentrations will be highest. In the normal lung there is also evidence for inactivation of cortisol to cortisone (Escher et al 1994, Hubbard et al 1994).

The antiglucocorticoidrole of dehydroepiandrosterone

A second set of the pathways shown in Fig. 5 is also important in tuberculosis. Many of the effects of Cortisol on the immune system are opposed by dehydroepiandrosterone (DHEA). In humans, levels of the sulfated form of this hormone (DHEAS) are low up to adrenarche (about five years), intermediate between five and 10 years, and at adult levels by puberty. Levels decline again later in life. These age-related changes correlate with changes in susceptibility to tuberculosis, and changes in the type of disease that results (Table 1; Donald et al 1996). Could these correlations be biologically meaningful? In recent experiments we have manipulated the ratio ofglucocorticoid to DHEA (or appropriate DHEA metabolites) in a murine model of pulmonary tuberculosis, and found that too much DHEA relative to glucocorticoid, or too little, both exacerbate disease, but they cause differing pathological changes that are reminiscent of the pathology of tuberculous babies and adults, respectively (Table 1).

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