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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.

The development and resolution of granulomas induced by Mycobacterium tuberculosis were sequentially traced by correlated light and electron microscopy. The scattered, immature monocytes initially composing the lesions evolved by orderly steps into coalescent, well developed macrophages and ultimately into swirling nests of highly complex epithelioid cells. These ultrastructural changes represent differentiation in vivo of the mononuclear phagocytes. The number of mycobacteria present than waned markedly, and the epithelioid granulomas developed into foreign body granulomas and finally into simple chronic inflammation. Concmonitantly, the epithelioid cells evolved into macrophages and ultimately into immature, monocyte-like forms. These observations suggest that the development of a granuloma represents differntiation in vivo of the constituent mononuclear phagocytes in response to an evoking stimulus. From comparisons with previous studies, mononuclear differentiation in vivo appears to have a fixed pattern and a markedly alterable pace. The observations also suggest a previously undescribed fate for mononuclear phagocytes in developing granulomas. As the granuloma-evoking agent is destroyed, the highly differentiated mononuclear phagocytes change into less mature forms.

The effect of low levels of coherent radiation on the eye is not fully established, but is generally presumed to be noninjurious. Irradiation of the retina with a Q-switched ruby laser emitting low amounts of energy (0.1 percent probability of creating damage) consistently produces ultrastructural alterations in rods and cones. Outer segments of these cells are broken and disorganized and their lamellae are in disarray 1 day after such irradiation.