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Epithelioid Cells and Phagocytosing Macrophages in Experimental Mycobacterial Granulomas J.L

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Epithelioid Cells and Phagocytosing Macrophages in Experimental Mycobacterial Granulomas J.L Br. 1. Exp. Path. (I989) 70, 589-596 Current Status Review: A comparison of secretory epithelioid cells and phagocytosing macrophages in experimental mycobacterial granulomas J.L. Turk Department ofPathology, Royal College ofSurgeons ofEngland, Lincoln's Inn Fields, London WC2A 3PN, UK The different histological appearance of gra- The production of epithelioid cell and non- nulomas induced by the same micro-orga- epithelioid cell granulomas nism dependent on the immunological status ofthe host is no better shown than in leprosy. The intradermal injection of BCG vaccine or In tuberculoid leprosy, where there is a high cobalt-irradiated Mycobacterium leprae into resistance to proliferation of the organism the dorsum of the ear of the guinea-pig and the development of T-lymphocyte- induced the development of granulomas in mediated allergic reactions, granulomas are the post-auricular lymph node immediately typically of the epithelioid cell type. In draining the site ofinjection. A direct paralle- lepromatous leprosy, where there is a failure lism was observed between the area of of T-cell-mediated immune reactions and granulomatous infiltration and the increase widespread proliferation of the infective in weight of the lymph node followed over a organism, the granulomas consist of macro- I 2-week period after intradermal injection of phages containing large numbers of the mycobacteria. Animals injected with BCG mycobacteria. In tuberculosis, epithelioid showed peak granuloma development 2 cell granulomas are classically associated weeks after injection, whereas those injected with fibroblast proliferation and increased with M. leprae developed maximum granulo- local collagen synthesis. This is also a strong mas at 5 weeks (Narayanan et al. I982). The feature of epithelioid cell granulomas histological appearance ofthe lesion induced induced by other agents, such as beryllium, by BCG was that of a typical epithelioid cell and in sarcoidosis. The demonstration of granuloma containing giant cells. As the rough endoplasmic reticulum in epithelioid lesions resolved there was an increase in the cells in granulomas in man (Ridley et al. amount of collagen as shown by conventio- I980) suggested a secretory function for nal stains and ultrastructurally (Fig. 3). these cells and indicated a need for the These granulomatous areas were heavily development ofsuitable experimental models infiltrated with cells of the mononuclear of these granulomas, particularly to study phagocyte series (MPS) showing no evidence the possible connection between this func- of phagocytosis but containing extensive tion and fibroblast activation. One possible areas of rough endoplasmic reticulum model ofsecretory epithelioid cells associated suggestive ofa secretory function (Figs i and with increased fibroblast activation is the 4). By contrast, nodes from guinea-pigs zirconium granuloma in the guinea-pig injected with M. leprae showed a more mixed (Turk et al. 1978). However, these granulo- macrophage infiltration and under electron mas occur irregularly and being in the skin microscopy were found to have phagocy- are difficult to dissect out and study with any tosed organisms as well as a large amount of quantitative detail. degraded material (Figs 2 and 4) (Narayanan 589 J.L. Turk Fig. i. Secretory epithelioid cell BCG granuloma 2 weeks. x 88oo. et al. i98 ia). Fibroblasts were not a striking mon to other cells of the MPS. Moreover, by feature ofthese granulomas. In both types of the use of a monoclonal antibody directed granulomas the cells of the MPS were ester- against guinea-pig MHC Class II antigen, it ase positive and showed the presence of was found that although this antigen was fibronectin. However, the majority did not well expressed on the phagocytosing macro- carry receptors for the Fc component of IgG phages of the M. leprae granulomas, it was or the C3 component ofcomplement, nor did poorly expressed on the secretory epithelioid they exhibit peroxidase activity. The macro- cells of the BCG granulomas (Mathew et al. phages from the M. Ieprae granulomas were I983). highly glass adherent, whereas 80% of the Although in human leprosy the two types cells ofthe MPS in the BCG granulomas were of granuloma develop as a result of differ- non-glass adherent (Narayanan et al. I982). ences in the host's T-cell immune response, By the use of a monoclonal antibody that so far, these granulomas could be reproduced reacted specifically with activated macro- only by using the two different forms of phages, it was possible to demonstrate that mycobacteria. To bring the models into line the secretory epithelioid cells in the BCG with the human condition it was important granulomas, as well as the phagocytosing to see if changes in granuloma could be macrophages in the M. leprae granuloma, induced by changing the host's immune showed surface membrane antigenicity com- reaction to the organism. It was found that if Epitihelial cells and macrophages in granulomas 59I i i t ' f , ,t. a i F~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.p Fig. 2. Phagocytic macrophage M. leprae granuloma 5 weeks. x i8 000. the immune response was reduced by treat- on M. leprae. It was decided to add an extra ment with hydrocortisone or cyclosporine, strong antigenic determinant to M. leprae by the granulomas that developed in response the addition of the hapten fluorescein, by to BCG did not contain secretory epithelioid treating the organism with fluorescein isoth- cells. The cells of the MPS did not contain iocyanate. Such treatment caused the M. rough endoplasmic reticulum in their cyto- Ieprae to induce a secretory epithelioid cell plasm. In the case of cyclosporine-treated granuloma in which the cells of the MPS animals the cells contained phagocytosed were non-phagocytosing and contain rough material similar to that found in the M. leprae endoplasmic reticulum. At the same time granulomas (Gupta et al. I985b). Thus, the there was a marked increase in cell-mediated presence of secretory epithelioid cells in BCG immunity (Verghese et al. I987). Thus, there granuloma appeared to depend upon the appears to be a strong association between presence of a strong cell-mediated immune epithelioid cell formation and T-cell- response. mediated immunity in this model. The next question to be asked was, whether a secretory epithelioid cell granu- The association between epithelioid loma could be induced by M. leprae if the formation and increased collagen synthesis antigenicity of this organism was enhanced. It has been suggested that BCG contained a One of the ways to assay collagen synthesis number of antigens that were either not in tissues is that described by Peterkofsky and present or not as strongly expressed as those Diegelmann (I97I). In this, the tissue is 592 J.L. Turk Fig. 3. Fibroblasts embedded in collagen BCG granuloma i week. X 1200. incubated with '4C-proline for 24 h. After genase used in these experiments contained homogenization the tissue is divided into two less than i% non-specific protease activity equal aliquots. One is then hydrolysed with when tested on '4C-tryptophan-labelled pro- the enzyme collagenase. The radioactivity in tein prepared from guinea-pig skin fibro- this fraction (H) is then subtracted from the blasts cultured in vitro. The specificity of the radioactivity in the unhydrolysed fraction collagenase was further assessed by its effect (T). The difference T-H then gives the '4C- on '4C-glycine labelled collagen prepared proline incorporated into collagen. The colla- from guinea-pig skin. There was a release of Epithelial cells and macrophages in granulomas 593 Antigen Lymphokine T-Lymphocyte Activated macrophage Monocyte Epithelioid cell Fig. 4. Maturation of cells of the mononuclear phagocyte system. 90% of counts from the labelled collagen. It association between epithelioid cell forma- was clear that the nodes from BCG injected tion and increased fibroblast activity. As the animals synthesized high levels of collagen epithelioid cells were particularly character- when compared with nodes draining the site ized by the presence of a rough endoplasmic of application with the chemical sensitizer reticulum, it seemed reasonable to look for 2,4-dinitrofluorobenzene (DNFB) to the skin. the production of soluble mediators pro- Only nine out of 82 lymph nodes from duced by those cells that might affect fibro- animals injected with M. leprae showed blast function (Narayanan et al. i98ib). positive incorporation of '4C into collagen, Supernatants from the culture of lymph whereas 23 out of 84 nodes from the animals nodes containing BCG and M. leprae granulo- injected with the same dose of BCG showed mas were studied for their effect on protein positive incorporation (Narayanan et al. and DNA synthesis in homologous fibroblast 1982). Maximum collagen synthesis in BCG cultures. Supernatants from both types of nodes was between the fourth and fifteenth granulomas stimulated amino acid incorpor- weeks after injection. A similar increased ation and depressed DNA synthesis. A simi- incorporation of '4C-proline into collagen lar activity was released from lymph nodes has been described in the livers of mice containing lymphocytes activated by DNFB. infected with Schistosoma mansoni (Dunn et This suggested that the activity was derived al. I977). The finding of a significant in- from activated T-lymphocytes rather than crease in collagen synthesis by lymph nodes from cells of the MPS. However, dissociation containing epithelioid cell granulomas over from migration inhibitory factor
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