Cell death in granulomata: the role of apoptosis.

Abstract

SUMMARY Unequivocal apoptoses were seen by light microscopy in examples of leprosy, sarcoidosis, tuberculosis, Crohn's disease and foreign body granulomata. A limited electron microscopic investigation showed typical apoptotic bodies in both sarcoid and leprosy granulomata. The number of apoptoses and mitoses in granulomata were counted and their densities calculated. The wide variation in the results between individual lesions may reflect differences in disease activity.Current understanding of cell turnover in granulomata is based largely on studies of experimentally induced granulomata in animals by Dannenberg, Spector, and others.' These experiments established that mononuclear phagocytes in granulomata have a finite life span and that this varies with the eliciting agent. The eventual fate of mononuclear cells in granulomata is not clear, although evidence from some studies suggests that cell death has a major role.2 Cell necrosis is not readily apparent in noncaseating granulomata, however, and hence regression of differentiated mononuclear phagocytes to less mature forms with subsequent emigration from the lesion has been proposed as an alternative explanation.3Another possible mechanism for the loss of mononuclear phagocytes from granulomata is apoptosis, a morphologically distinctive form of cell death which affects isolated cells in living tissue.4 Apoptosis occurs in a wide range of physiological and pathological circumstances, including involution of the adrenal cortex,5 secretory endometrium,6 tadpole tails,7 and basal cell carcinoma.8 Cells undergoing apoptosis show condensation and fragmentation into a number of membrane bound eosinophilic fragments which are then endocytosed by surrounding cells, even if these are not normally phagocytic.9 In contrast with true necrosis, cells undergoing apoptosis do not provoke an inflammatory response. As the process lasts a matter of hours, detection of even small numbers of apoptotic bodies within tissues indicates appreciable cell loss.During a recent study of the histology of leprosy lesions, we observed apoptoses within both tuberculoid and lepromatous lesions.10 We now have ex-

Patterns of cell death: the significance of apoptosis for dermatology

“…(3. 6, 7) and the granulotnata of both sarcoidosis and leprosy (51). Apoptosis is found under irradiation and cytostatic therapy as well as during tumor regression (4,6,7,9).…”

Lethal Granuloma Disintegration in Mycobacteria-Infected TNFRp55−/− Mice Is Dependent on T Cells and IL-12

“…The integrity of granulomas is a critical determinant of the outcome of mycobacterial diseases, and apoptosis and necrosis are common events in granulomas associated with human tuberculosis (2,3,24,42,43). The mycobacteria-infected TNFRp55 Ϫ/Ϫ mouse may prove useful in defining suitable molecular targets for therapeutic interventions aimed at reducing tissue-destroying and lifethreatening immunopathology caused by an excess of T cells.…”

The role of macrophage cell death in tuberculosis

“…An early light microscopic survey of tuberculous granulomas reported the infrequent occurrence of cells with morphologic changes consistent with apoptosis. 45 Using the more sensitive in situ TUNEL method, Keane et al 22 examined lung sections from clinical cases of tuberculosis and estimated that 450% of cells in the periphery of granulomas were positive. Furthermore, Mancino et al (unpublished observations) found that in similar sections, typical tuberculous granulomata characterized by a core of caseous necrosis containing dying cells were surrounded by a cuff of apoptotic MF.…”