When mice were infected with virulent Mycobacterium tuberculosis H37Rv by the intra-tracheal route, there was an early phase of adrenal hyperplasia, histologically resembling the adrenocorticotropic (ACTH)-driven changes seen in Cushing's disease. This was followed at 3 weeks by progressive atrophy until the weight of the adrenals was approximately 50% of that seen in control uninfected mice, in spite of the fact that the adrenals were not infected. All layers of the adrenal cortex were affected, but the medulla was normal. Electron microscope studies revealed apoptosis. The switch from adrenal hyperplasia to adrenal atrophy corresponded to onset of an IgG1 response recognising a wide range of mycobacterial components in Western blots. Delayed type hypersensitivity (DTH) responses were seen throughout, but differed in their sensitivity to TNF alpha. Thus if TNF alpha was injected at 24 h into DTH sites elicited during the phase of adrenal hyperplasia, there was no increment in swelling at 48 h. However similar injections of TNF alpha resulted in a doubling of the swelling in DTH sites elicited during the phase of adrenal atrophy. This may be relevant to the pathogenesis of cytokine-mediated tissue damage in the human disease. If 2 months before mice received the intratracheal infection, they were pre-immunised with 1 x 1097) autoclaved Mycobacterium vaccae, a stimulus previously shown to induce a Th1 pattern of response, the early increase in adrenal weight was attenuated and delayed, and the subsequent atrophy did not occur. In sharp contrast, pre-immunisation with 1 x 10(9) autoclaved M. vaccae, known to prime a mixed pattern of cytokine release (IFN gamma and IL-4), resulted in adrenal atrophy that began within 4 days of infection, and was complete by day 14. These results suggested that the pattern of cytokine release provoked by the infection, modulated the adrenal changes, perhaps in synergy with products derived from the organisms themselves. Since we have already shown that profound adrenal changes also occur in human tuberculosis, we now propose that a change somewhere in the cytokine-hypothalamo-pituitary-adrenal axis may underlie the T cell dysfunction and immunologically-mediated tissue damage in this disease.
