Interactions between the im mune system and endocrine system

There is much evidence to show that the cytokines can act on the endocrine system. For instance, IFNy acts on neural and endocrine cells causing steroidogenesis, melanogensis and iodine uptake. Another example is that IL-1 and IL-6 cause a release of adrenal corticotrophic hormone (ACTH) and endorphin from a cultured

IL-6 may work as hypothalamic-releasing factors. The

responsiveness of hypothalamic neurones and pituitary cells to IL-1 suggests that neuroendocrine cells may express IL-1 receptors.

Neuroendocrine cells express type I and type II receptors (IL-IR, IL- IIR). In the pituitary gland, Savino and Dardenne (1995)

demonstrated that IL-2 and IL-6 alter the proliferation pattern of anterior pituitary cells in vitro as well as the secretion of growth hormone (GH) and adrenocorticotrophic hormones. IL-2 stimulates secretion of corticotrophin-releasing factor (CRH) from

hypothalamic neurones by increasing NO (Savino & Dardenne 1995). Distinct cytokines including IL-5, IL-7, IL-9 and TGF-p are

involved in the regulation of neuronal differentiation (Blalock 1994). The cells of the immune system in both primary and secondary

lymphoid organs are able to produce hormones and neuropeptides, whereas classical endocrine glands, neurones and glial cells can produce a variety of cytokines. Moreover, receptors for all of these types of molecules are expressed in the cells of both the immune and neuroendocrine systems (Besedovsky & Rey 1996; Savino &

Dardenne 1995). However, it is not clear how IL-1, IL-6 and IFNy generated by infection and immune responses can signal to the hypothalamus, because very little can cross the blood-brain barrier. At least some signalling is via the vagus nerve. An immune stimulus in the periphery causes a signal via the vagus to the hypothalamus, when IL-1 is released locally (Bluthe et al. 1996).

1.4.1 The link between adrenal and pituitary gland

There is a link between the adrenal gland and the pituitary gland via (ACTH). The hypothalamic-pituitary-adrenal (HPA) axis is the main key in stress responses. During psychological stress, the higher centres of the central nervous system cause the release of corticotrophin-releasing hormone (CRH) from the hypothalamus into the portal circulation between the hypothalamus and the pituitary gland. CRH acts on pituitary corticotrophs to elicit ACTH synthesis and its release into the circulation. ACTH acts on the adrenal gland and causes the production of glucocorticoid hormones. These data have drawn attention to the relationship between the immune and endocrine systems in the case of infectious diseases.

1.4.2 Changes in the adrenal gland and consequences for the immune system

In human immune deficiency virus (HIV) patients, the ratio of cortisol / dehydroepiandrosterone (DHEA) increases at the same time as the decline in CD4 count. Also, these changes correlate with the appearance of HIV symptoms in patients (Laudat et al. 1995). A similar finding has been observed in TB (Rook et al. 1996). It has long been suspected that there is impaired adrenal function in tuberculosis, mainly because of the occurrence of sudden death during treatment resembling acute adrenal insufficiency. It has been found that there are subtle changes in adrenal function in human tuberculosis. Output of both glucocorticoid and androgen (DHEA) derivatives is reduced by approximately 50% in some patients though

maintained, with greatly reduced conversion to inactive cortisone, whilst dehydroepiandrosterone sulphate (DHEA-S) levels are not. Some patients have low levels of DHEA-S. In normal humans of either sex, DHEA-S is the major product of the adrenal cortex. Lack of the steroid may have serious consequences because both DHEA and DHEA-S are anti-glucocorticoid. DHEA enhances T H l activity and inhibits the effects of glucocorticoids, including their tendency to suppress T H l lymphocytes and enhance TH2. For instance, a single dose of DHEA given before dexamethasone, (the corticosteroid analogue (DEX), which has a longer 1/2 life, and fails to bind to minerolocorticoid receptors), can block the ability of the DEX to cause depletion of thymocytes and temporary unresponsiveness of peripheral T cells to mitogens (Blauer et a l 1991). Furthermore, DHEA itself might be not the most active form of the anti­

glucocorticoid hormones. For example, DHEA can be converted to 5- androstene-17|3-diol (AED) and 5-androstene-3 p-713- 17|3-triol

(AET) which are claimed by one group to play an important role in up-regulation of the immune system (Loria & Padgett 1992).

A second change in tuberculosis patients, is the abnormal balance of cortisol to cortisone. In normal individuals cortisol is converted to inactive cortisone in the kidney by the enzyme l l p - hydroxy steroid dehydrogenase 2, (llp-H S D -2). This cortisone is rapidly converted back to active cortisol in the liver by llp -H S D -1 , acting as a reductase. Most tissues contains enzymes of this type, three or four different ones are now known.

In 24 hr urine samples from tuberculosis patients, levels of cortisone metabolites are very low and an oral cortisone load is very

communication). Therefore, there is either abnormally low

dehydrogenase activity, or exaggerated reductase activity. The site of the abnormality is unknown, but it may be the lung, the site of the tuberculosis infection. Therefore, T cells of tuberculosis patients may be chronically exposed to glucocorticoid effects, unopposed by the anti-glucocorticoid influence of DHEA or of its derivatives. This may not only encourage a T H l to TH2 switch, but even contribute to the fall in CD4 T cell count and in the CD4/CD8 ratio (Rook &

Hemandez-Pando 1994; Rook et a l 1994; Rook et a l 1993). The findings in humans are reinforced by the observation that when mice are infected with tuberculosis by the intra-tracheal route, the adrenals increase in size for two weeks and then decrease to 50% of their normal weight. This is an early stage of the lung infection, and the adrenals themselves are not directly infected. The mechanism leading to the atrophy is uncertain, but it has been found that the changes in cytokines may lead to adrenal abnormality. These changes may be attributable to TN Fa.

1.4.3 Factors which may cause adrenal atrophy

T N Fa, IL-1 and IL-6, acting via the hypothalamus and pituitary gland to release ACTH, may drive the enlargement of the adrenal in the first three weeks after infection with M. tuberculosis (Stankovic et al. 1994). In addition, T N F a alone has a direct toxic effect on the adrenal gland even in the absence of infection. In vitro T N F a acts directly on adrenal cells to reduce steroid output (Jaattela et a l 1991). Death of tubercle bacilli leads to the release of some of their components such as lipoarabinomannan (LAM) which may have

a role in enhancing the production of T N Fa (Moreno et al. 1989). A further explanation for the atrophy of the adrenal gland is the

presence of TGFp Stankovic et a l (1994) showed that TGFP has a direct effect on adrenal cells in vitro. Like TN Fa, TGFp inhibits DHEA-S more than cortisol. This may be important because TGFp is also abundant in tuberculosis lesions and has been implicated in the suppressive effects of patients' monocytes in vitro (Maeda et a l 1993).