ADRENAL CHANGES IN MURINE PULMONARY TUBERCULOSIS - A CLUE TO PATHOGENESIS

When mice were infected with virulent Mycobacterium tuberculosis H37Rv by the intra-tracheal route, there was an early phase of adrenal hype rplasia, histologically resembling the adrenocorticotropic (ACTH)-driv en changes seen in Gushing's disease. This was followed at 3 weeks by progressive atrophy until the weight of the adrenals was similar to 50 % of that seen in control uninfected mice, in spite of the fact that t he adrenals were not infected. All layers of the adrenal;cortex were a ffected, but the medulla was normal. Electron microscope studies revea led 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 hypersensitivi ty (DTH) responses were seen throughout, but differed in their sensiti vity to TNF alpha. Thus if TNF alpha was injected at 24 h into DTH sit es elicited during the phase of adrenal hyperplasia, there was no incr ement in swelling at 48 h. However similar injections of TNF alpha res ulted in a doubling of the swelling in DTH sites elicited during the p hase of adrenal atrophy. This may be relevant to the pathogenesis of c ytokine-mediated tissue damage in the human disease. If 2 months befor e mice received the intratracheal infection, they were pre-immunised w ith 1 X 10(7) autoclaved Mycobacterium vaccae, a stimulus previously s hown to induce a Th1 pattern of response, the early increase in adrena l weight was attenuated and delayed, and the subsequent atrophy did no t occur. In sharp contrast, pre-immunisation with 1 x 10(9) autoclaved M. vaccae, known to prime a mixed pattern of cytokine release (IFN ga mma and IL-4), resulted in adrenal atrophy that began within 4 days of infection, and was complete by day 14. These results suggested that t he pattern of cytokine release provoked by the infection, modulated th e adrenal changes, perhaps in synergy with products derived from the o rganisms themselves. Since we have already shown that profound adrenal changes also occur in human tuberculosis, we now propose that a chang e somewhere in the cytokine-hypothalamo-pituitary-adrenal axis may und erlie the T cell dysfunction and immunologically-mediated tissue damag e in this disease.