The granulomatous inflammatory response

The granulomatous response can be defined as a specialized immunological reaction characterized by a localized collection of epithelioid cells, macrophages and lymphocytes. It is phylogenetically a primitive response, seen as a method of ingestion and removal of pathogens and persistant irritants. I t is a manifestation of many infective. allergic, autoimmune, and neoplastic disorders, including tuberculosis, leprosy, schistosomiasis, berylliosis, and many fungal infections. Multisystem granulomatous inflammation is also pathognomic of sarcoidosis. a disease of unknown aetiology. The evolution of the granuloma depends on the nature of the irritant, its degradability and its ability to induce an immunological response. Epithelioid cell granulomas are characterized by a cohesive collection of cells of the mononuclearphagocyte system of various types. The cells range from phagocytic and activated macrophages to epithelioid cells. All originate from circulating monocytes recruited into the site of inflammation. The origin of epithelioid cells from macrophage precursors is supported by the observation that monocytes in culture are capable of differentiating into epithelioid cells. ' Plasma cells and fibroblasts may surround the lesions. In contrast to macrophages, epithelioid cells show a well developed secretory apparatus with little in the way of phagocytic activity. On electron microscopy, epithelioid cells are closely apposed and interdigitate; the cytoplasm contains large numbers of pale-staining secretory vacuoles and shows morphological features of pronounced secretory activity, including prominent rough endoplasmic reticulum, Golgi apparatus and numerous cytoplasmic bristle coated vesicles. The nature of the contents of these secretory vacuoles is unknown; they do not contain acid phosphatase, suggesting that they are not of lysosomal origin. The vacuoles contain mucopolysaccharides, and angiotensin converting enzyme has been localized within them. ' Epithelioid cell granulomas are differentiated from foreign body granulomas at light microscopy by the presence of lymphocytes which show close interactions with the epithelioid cells; in practice this is the most specific feature of epithelioid cell granulomas. In such granulomas, the lymphocytes are characteristically scattered between the epithelioid cells but they may also encircle the granulomas. forming a peripheral 'mantle'. In mature granulomas, these two populations of lymphocytes differ in phenotype. Lymphocytes at the centre of the granulomas are mainly of CD4 helperiinducer type and many appear activated, whereas the lymphocytes at the periphery are mainly CD8 suppressor/cytotoxic lymphocytes and they frequently form a ring around the granulomas. ' This supports the concept that granulomas form isolated microenvironments. Paradoxically, some CD4 helper-inducer lymphocytes can show suppressor functional activity. In sarcoidosis, there is evidence that these CD4 lymphocytes and peripheral CD8 lymphocytes may mediate the spontaneous regression of sarcoido~is. ~ Ifso, the presence or absence of these cells may have prognostic importance. Multinucleated giant cells are frequently seen in the centre of granulomas; these are the result of fusion of mononuclear cells rather than nuclear division. In foreign body granulomas the nuclei are randomly distributed within the cell. By definition, Langhans giant cells, however, show nuclei distributed around the periphery of the cell in an organized fashion. All the centrioles are found in one area of the cell, cytofilaments radiating away towards their respective nuclei. These collections of filaments may occasionally be accentuated and become visible at light microscopy as so-called cytoplasmic asteroid bodies. Schaumann bodies are different in that they represent residual sequestered lysosomal debris5 Although the epithelioid cells within the central and peripheral areas of granulomas are indistinguishable on routine sections, monoclonal antibody studies reveal differences.6 Delayed type hypersensitivity has been implicated in granulomatous diseases in man, such as specific sensitivity to beryllium and zirconium, and