The Structure of Mononuclear Phagocytes Differentiating in Vivo. I. Sequential Fine and Histologic Studies of the Effect of Bacillus Calmette-Guerin (BCG)

Although the differentiation of mononuclear phagocytes is fundamental to their multifarious activities, their differentiation is incompletely understood-particularly in vivo. The development of an epithelioid granuloma may be hypothesized to represent such differentiation in vivo. To test this, the sequential ultrastructure of developing epithelioid granulomas was examined. Viable bacilli Calmette-Guerin (BCG) injected into the subcutaneum of guinea pigs produced epithelioid granulomatous inflammation, which was sampled for light and electron microscopy on alternate days until the 33rd day after injection. Initially, monocytes invaded the tissues and then coalesced, enlarged and formed small granulomas which ultimately evolved into epithelioid granulomas. The monocytes, ultrastructurally very simple cells, developed increased nuclear euchromatin, prominent nucleoli, extensive cytoplasm, free ribosomes, abundant Golgi profiles, many mitochondria and numerous large lysosomes and became macrophages. The macrophages in turn underwent further enlargement and became closely intertwined with one another to form epithelioid cells-large polygonal macrophages, containing euchromatic nuclei, numerous lysosomes, plentiful mitochondria and prominent synthetic apparatus. These changes undergone by monocytes during their development into epithelioid cells, which may be divided into five stages, are interpreted as differentiation in vivo of the mononuclear phagocytes. The observations demonstrate directly the differentiation of these cells in vivo and suggest some, if not all, characteristic features of granulomatous inflammation result from such differentiation.