Apoptosis of macrophages and T cells in tuberculosis associated caseous necrosis

Abstract

Immunity against mycobacteria is almost exclusively confined to epithelioid cell granulomas, where a long-lasting but labile balance exists between host and bacilli. The relationship between immunity and mycobacteria results in regression, growth, or caseation of granulomas. To prove whether caseation is associated with apoptosis, biopsy specimens of patients with tuberculosis were analysed by electron microscopy and by in situ end-labelling combined with immunofluorescence. Apoptotic cells were not detected in regressive granulomas. Whereas productive granulomas without histologically recognizable caseous necrosis revealed only single apoptotic cells, large numbers of apoptotic CD68+ macrophages and apoptotic CD3+, CD45RO+ T cells were observed within caseous foci. As prime candidates undergoing and/or eliciting apoptosis, vital cells surrounding caseous foci were characterized. Immunohistochemistry showed that the majority of vital CD68+ macrophages surrounding caseous foci are negative for the anti-apoptotic protein bcl2, but positive for the pro-apoptotic protein bax. In situ hybridization combined with immunofluorescence demonstrated that the majority of the adjacent lymphocytes are activated CD3+, CD45RO+ cells expressing the pro-inflammatory cytokine interferon gamma (IFN gamma) and the death ligand FasL. These results suggest that caseation is strongly associated with apoptosis of macrophages and T lymphocytes; that the onset of apoptosis in macrophages may be promoted 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.

Expression of apoptosis‐related genes in an Ethiopian cohort study correlates with tuberculosis clinical status

“…This hypothesis is compatible with the in vitro data already published showing inhibition of apoptosis in infected macrophages by virulent M. tuberculosis (but not avirulent mycobacteria) [27,28,55,[59][60][61][62][63]. It is also consistent with multiple reports suggesting that upregulation of Fas/FasL in vivo is specifically associated with T-cell death in TB [38,[64][65][66][67]. A bias in cell death towards activated T cells in TB patients might explain the anergy seen in advanced TB patients, which appears to be TNF-a related [68,69].…”

Foamy Macrophages within Lung Granulomas of Mice Infected withMycobacterium tuberculosisExpress Molecules Characteristic of Dendritic Cells and Antiapoptotic Markers of the TNF Receptor-Associated Factor Family

“…All these events are required for effective elimination of bacteria and resolution of a granulomatous/inflammatory response during an infection. However, although apoptosis has been observed in mononuclear phagocytic cells after M. tuberculosis infection (27-31, 61, 62) and in macrophages and T cells from tuberculous lesions (63), our study demonstrated that apoptosis was present primarily in cells exterior to the granuloma. Therefore, we argue against the idea that apoptosis is an effective mechanism within the granuloma environment.…”

Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: their relationship to mycobacterial virulence

“…Th1 lymphocytes appear to be more susceptible than Th0 or Th2 cells to Fas-mediated apoptosis [11]. In mycobacterial infection, caseous necrosis in human tuberculous granulomas showed a large number of apoptotic T cells [26]. Similarly, the production of IFN-c and IL-2, but not of IL-4, is significantly reduced due to T cell apoptosis in mice infected with mycobacteria [11].…”