Apoptosis of macrophages and T cells in tuberculosis associated caseous necrosis

Immunity against mycobacteria is almost exclusively confined to epithelioid cell granulomas, where a long-lasting but labile balance exists between ho st and bacilli. The relationship between immunity and mycobacteria results in regression, growth, or caseation of granulomas. To prove whether caseati on is associated with apoptosis, biopsy specimens of patients with tubercul osis were analysed by electron microscopy and by in situ end-labelling comb ined with immunofluorescence. Apoptotic cells were not detected in regressi ve granulomas. Whereas productive granulomas without histologically recogni zable caseous necrosis revealed only single apoptotic cells, large numbers of apoptotic CD68+ macrophages and apoptotic CD3+, CD45RO+ T cells were obs erved within caseous foci. As prime candidates undergoing and/or eliciting apoptosis, vital cells surrounding caseous foci were characterized. Immunoh istochemistry showed that the majority of vital CD68+ macrophages surroundi ng caseous foci are negative for the anti-apoptotic protein bcl2, but posit ive for the pro-apoptotic protein bax. In situ hybridization combined with immunofluorescence demonstrated that the majority of the adjacent lymphocyt es are activated CD3+, CD45RO+ cells expressing the pro-inflammatory cytoki ne interferon gamma (IFN gamma) and the death ligand FasL. These results su ggest that caseation is strongly associated with apoptosis of macrophages a nd T lymphocytes; that the onset of apoptosis in macrophages may be promote d by the lack of bcl2 and the abundance of bax; and that activation-induced cell death (AICD) may be responsible for the apoptosis of T cells. Copyrig ht (C) 2000 John Wiley & Sons, Ltd.